Evaluating Palin Stammering Therapy for School Children (Palin STSC 8-14): protocol for a feasibility randomised controlled trial comparing Palin STSC(8-14) with usual treatment.

BACKGROUND: Having a stammer can have a significant effect on a child's social, emotional and educational development. With approximately 66,000 children in the UK having a stammer, there is a need to establish an adequate evidence base to inform clinical practice. We describe a feasibility trial to explore the effectiveness of a new therapy programme for children aged 8-14: Palin Stammering Therapy for School Children (Palin STSC(8-14)). Preliminary data from the Michael Palin Centre, where the programme was developed, indicate that Palin STSC(8-14) is effective in reducing stammering frequency and impact for children, with beneficial effects for parents too. We will investigate the feasibility of the methods required for a definitive randomised controlled trial to investigate the application of this therapy by NHS speech and language therapists (SLTs), compared with 'treatment as usual' (TAU), beyond the specialist context in which it was developed. METHODS: This is a two-arm feasibility cluster-randomised controlled trial of Palin STSC(8-14) with TAU control arm, and randomisation at the level of the SLT. Quantitative and qualitative data will be collected to examine the following: the recruitment and retention of therapists and families, the acceptability of the research processes and the therapeutic intervention and the appropriateness of the therapy outcome measures. Assessments will be completed by children and parents at baseline and 6 months later, including measures of stammering severity; the impact of child's stammering on both children and parents; child temperament, behaviour and peer relations, anxiety; quality of life; and economic outcomes. There will also be a qualitative process evaluation, including interviews with parents, children, SLTs and SLT managers to explore the acceptability of both the research and therapy methods. Treatment fidelity will be examined through analysis of therapy session records and recordings. DISCUSSION: The findings of this feasibility trial will inform the decision as to whether to progress to a full-scale randomised controlled trial to explore the effectiveness of Palin STSC(8-14) when compared to Treatment as Usual in NHS SLT services. There is a strong need for an evidence-based intervention for school age children who stammer. TRIAL REGISTRATION: ISRCTN. ISRCTN17058884 . Registered on 18 December 2019.

A randomised controlled trial of energetic activity for depression in young people (READY): a multi-site feasibility trial protocol.

BACKGROUND: Prevalence of depression is increasing in young people, and there is a need to develop and evaluate behavioural interventions which may provide benefits equal to or greater than talking therapies or pharmacological alternatives. Exercise could be beneficial for young people living with depression, but robust, large-scale trials of effectiveness and the impact of exercise intensity are lacking. This study aims to test whether a randomised controlled trial (RCT) of an intervention targeting young people living with depression is feasible by determining whether it is possible to recruit and retain young people, develop and deliver the intervention as planned, and evaluate training and delivery. METHODS: The design is a three-arm cluster randomised controlled feasibility trial with embedded process evaluation. Participants will be help-seeking young people, aged 13-17 years experiencing mild to moderate low mood or depression, referred from three counties in England. The intervention will be delivered by registered exercise professionals, supported by mental health support workers, twice a week for 12 weeks. The three arms will be high-intensity exercise, low-intensity exercise, and a social activity control. All arms will receive a 'healthy living' behaviour change session prior to each exercise session and the two exercise groups are energy matched. The outcomes are referral, recruitment, and retention rates; attendance at exercise sessions; adherence to and ability to reach intensity during exercise sessions; proportions of missing data; adverse events, all measured at baseline, 3, and 6 months; resource use; and reach and representativeness. DISCUSSION: UK National Health Service (NHS) policy is to provide young people with advice about using exercise to help depression but there is no evidence-based exercise intervention to either complement or as an alternative to medication or talking therapies. UK National Institute for Health and Care Excellence (NICE) guidelines suggest that exercise can be an effective treatment, but the evidence base is relatively weak. This feasibility trial will provide evidence about whether it is feasible to recruit and retain young people to a full RCT to assess the effectiveness and cost-effectiveness of an exercise intervention for depression. TRIAL REGISTRATION: ISRCTN, ISRCTN66452702 . Registered 9 April 2020.

Circulating leptin levels are associated with adiposity in survivors of childhood brain tumors.

Survivors of Childhood Brain Tumors (SCBT) are at a higher risk of developing cardiovascular disease and type 2 diabetes compared to the general population. Adiposity is an important risk factor for the development of these outcomes, and identifying biomarkers of adiposity may help the stratification of survivors based on their cardiovascular risk or allow for early screening and interventions to improve cardiometabolic outcomes. Leptin is an adipokine that positively correlates with the adipose mass in the general population and is a predictor of adverse cardiometabolic outcomes, yet its association with adiposity in SCBT has not been studied. The aim of this study was to determine if leptin levels are associated with the adipose mass in SCBT, and to define its predictors. This cross-sectional study included 74 SCBT (n = 32 females) with 126 non-cancer controls (n = 59 females). Total adiposity was measured using Bioelectrical Impendence Analysis (BIA) and central adiposity was measured using waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR). We used multivariable linear regression analysis to determine if leptin predicts adiposity in SCBT and adjusted for age, sex, puberty, and cancer status. Leptin correlated strongly with total (p < 0.001) and central (WHR p = 0.001; WHtR p < 0.001) adiposity in SCBT and non-cancer controls. In conclusion, leptin is a potential biomarker for adiposity in SCBT, and further investigation is needed to clarify if leptin is a predictor of future cardiometabolic risk in SCBT.

Adjuvant statin therapy for oesophageal adenocarcinoma: the STAT-ROC feasibility study.

BACKGROUND: Statins inhibit proliferative signalling in oesophageal adenocarcinoma (OAC) and their use is associated with better survival in observational studies. The present study was undertaken to examine the feasibility of assessing adjuvant statin therapy in patients with operable OAC in a phase III RCT. METHODS: For this multicentre, double-blind, parallel-group, randomized, placebo-controlled feasibility trial, adults with OAC (including Siewert I-II lesions) who had undergone oesophagectomy were centrally allocated (1 : 1) to simvastatin 40 mg or matching placebo by block randomization, stratified by centre. Participants, clinicians and investigators were blinded to treatment allocation. Patients received treatment for up to 1 year. Feasibility outcomes were recruitment, retention, drug absorption, adherence, safety, quality of life, generalizability and survival. RESULTS: A total of 120 patients were assessed for eligibility at four centres, of whom 32 (26·7 per cent) were randomized, 16 in each group. Seven patients withdrew. Participants allocated to simvastatin had lower low-density lipoprotein cholesterol levels by 3 months (adjusted mean difference -0·83 (95 per cent c.i. -1·4 to -0·22) mmol/l; P = 0·009). Median adherence to medication was greater than 90 per cent between 3 and 12 months' follow-up. Adverse events were similar between the groups. Quality-of-life data were complete for 98·3 per cent of questionnaire items. Cardiovascular disease, diabetes and aspirin use were more prevalent in the non-randomized group, whereas tumour site, stage and grade were similar between groups. Survival estimates were imprecise. CONCLUSION: This RCT supports the conduct and informs the design considerations for a future phase III trial of adjuvant statin therapy in patients with OAC. Registration number: ISRCTN98060456 (www.isrctn/com).

ANTECEDENTES: Las estatinas inhiben las señalizaciones proliferativas en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC) y su uso se asocia con mejor supervivencia en estudios observacionales. El presente estudio se llevó a cabo para examinar la viabilidad de evaluar el tratamiento adyuvante con estatinas en pacientes con OAC operable en un ensayo aleatorizado y controlado de fase III. MÉTODOS: En este ensayo de viabilidad controlado por placebo, aleatorizado, de grupos paralelos, doble ciego y multicéntrico, los pacientes adultos con OAC (incluyendo lesiones Siewert I/II) que fueron sometidos a esofaguectomía se asignaron de forma centralizada (1:1) a tratamiento con simvastatina 40 mg o placebo equivalente mediante aleatorización en bloques, estratificados por centro. Los participantes, los clínicos y los investigadores desconocían la asignación del tratamiento. Los pacientes recibieron el tratamiento hasta un año. Los resultados de viabilidad fueron reclutamiento, retención, absorción del fármaco, adherencia, seguridad, calidad de vida, generalización, y supervivencia. RESULTADOS: Un total de 120 pacientes fueron evaluados para elegibilidad en 4 centros, de los cuales 32 (26,7%) fueron aleatorizados, 16 en cada grupo. Siete pacientes abandonaron el ensayo. Los pacientes asignados a tratamiento con simvastatina tenían niveles de colesterol LDL más bajos a los 3 meses (diferencia media ajustada, −0,83 mmol/L, i.c. del 95% −1,4 a −0,22, P = 0,009). La mediana de la adherencia a la medicación fue mayor del 90% entre los 3-12 meses de seguimiento. Los eventos adversos fueron similares entre los grupos. Los datos de calidad de vida estaban completos en el 98,3% de las preguntas del cuestionario. Enfermedad cardiovascular, diabetes y uso de aspirina eran más prevalentes en el grupo no aleatorizado, mientras que la localización del tumor, el estadio y el grado fueron similares entre los grupos. Las estimaciones de supervivencia fueron imprecisas. CONCLUSIÓN: Este RCT apoya la realización e informa de las consideraciones de diseño para un futuro ensayo de fase III de tratamiento adyuvante con estatinas en pacientes con OAC.

Contamination in complex healthcare trials: the falls in care homes (FinCH) study experience.

BACKGROUND: Trials are at risk of contamination bias which can occur when participants in the control group are inadvertently exposed to the intervention. This is a particular risk in rehabilitation studies where it is easy for trial interventions to be either intentionally or inadvertently adopted in control settings. The Falls in Care Homes (FinCH) trial is used in this paper as an example of a large randomised controlled trial of a complex intervention to explore the potential risks of contamination bias. We outline the FinCH trial design, present the potential risks from contamination bias, and the strategies used in the design of the trial to minimise or mitigate against this. The FinCH trial was a multi-centre randomised controlled trial, with embedded process evaluation, which evaluated whether systematic training in the use of the Guide to Action Tool for Care Homes reduced falls in care home residents. Data were collected from a number of sources to explore contamination in the FinCH trial. Where specific procedures were adopted to reduce risk of, or mitigate against, contamination, this was recorded. Data were collected from study e-mails, meetings with clinicians, research assistant and clinician network communications, and an embedded process evaluation in six intervention care homes. During the FinCH trial, there were six new falls prevention initiatives implemented outside the study which could have contaminated our intervention and findings. Methods used to minimise contamination were: cluster randomisation at the level of care home; engagement with the clinical community to highlight the risks of early adoption; establishing local collaborators in each site familiar with the local context; signing agreements with NHS falls specialists that they would maintain confidentiality regarding details of the intervention; opening additional research sites; and by raising awareness about the importance of contamination in research among participants. CONCLUSION: Complex rehabilitation trials are at risk of contamination bias. The potential for contamination bias in studies can be minimized by strengthening collaboration and dialogue with the clinical community. Researchers should recognise that clinicians may contaminate a study through lack of research expertise.

Bariatric interventions in obesity treatment and prevention in pediatric acute lymphoblastic leukemia: a systematic review and meta-analysis.

Most children are surviving acute lymphoblastic leukemia (ALL) today. Yet, the emergence of cardiometabolic comorbidities in this population may impact long-term outcomes including the quality of life and lifespan. Obesity is a major driver of cardiometabolic disorders in the general population, and in ALL patients it is associated with increased risk of hypertension, dysglycemia, and febrile neutropenia when compared with lean ALL patients undergoing therapy. This systematic review aims to assess the current evidence for bariatric interventions to manage obesity in children with ALL. The primary outcome for this systematic review was the change in BMI z-score with implementation of the interventions studied. Literature searches were conducted in several databases. Ten publications addressing the study question were included in this review, and five studies were used in the meta-analysis to assess the impact of the bariatric interventions on obesity. The BMI z-score did not change significantly with the interventions. However, the quality of evidence was low, which precluded the recommendation of their use. In conclusion, prospective, rigorous, adequately powered, and high-quality longitudinal studies are urgently needed to deliver effective lifestyle interventions to children with ALL to treat and prevent obesity. These interventions, if successful, may improves cardiometabolic health outcomes and enhance the quality of life and life expectancy in children with ALL.

Obesity and muscle-macrophage crosstalk in humans and mice: A systematic review.

Obesity is associated with the production of inflammatory cytokines that are implicated in insulin resistance (IR), and if not addressed, can lead to type 2 diabetes (T2D). The role of the immune system in skeletal muscle (SM) inflammation and insulin sensitivity is not yet well characterized. As SM IR is an important determinant of glycaemia, it is critical that the muscle-immune phenotype is mapped to help design interventions to target T2D. This systematic review synthesized the evidence for SM macrophage content and phenotype in humans and murine models of obesity, and the association of muscle macrophage content and phenotype with IR. Results were synthesized narratively, as we were unable to conduct a meta-analysis. We included 28 studies (n=10 human, n=18 murine), and all studies detected macrophage markers in SM. Macrophage content was positively associated with IR. In humans and mice, there was variability in muscle macrophage content and phenotype in obesity. Overall certainty in the evidence was low due to heterogeneity in detection methods and incompleteness of data reporting. Macrophages are detected in human and murine SM in obesity and a positive association between macrophage content and IR is noted; however, the standardization of markers, detection methods, and reporting of study details is warranted to accurately characterize macrophages and improve the potential for creating specific and targeted immune-based therapies in obesity.

Traditional knowledge-based lifestyle interventions in the prevention of obesity and type 2 diabetes in Indigenous children in Canada: a systematic review protocol.

BACKGROUND: Approximately 50% of all youth-onset type 2 diabetes mellitus (T2DM) in Canada occurs in Indigenous children. In adults, cardiovascular disease is one of the leading causes of mortality in First Nations communities, and diabetes is a significant contributor to the risk of developing this disorder. The early onset of diabetes may predispose these children to premature cardiovascular disease and influence their longevity and quality of life. As a result, the implementation of culturally tailored obesity and T2DM primary prevention programs is vital. This systematic review aims to assess the effectiveness of existing traditional knowledge-based lifestyle intervention programs on preventing obesity and T2DM in Indigenous children in Canada. METHODS: We will conduct database searches in MEDLINE, Embase, PsycINFO, SPORTDiscus, CINAHL, Web of Science, Cochrane Database of Systematic Reviews, and the Cochrane Controlled Register of Trials. We will also conduct grey literature searches of central repository of trials ( ClinicalTrials.gov ), ProQuest Dissertations, Theses A&I, and Indigenous studies portal research tools. Reviewers will independently review titles, abstracts, and full-text articles retrieved from databases to assess potentially eligible studies, and relevant articles will be assessed for risk of bias and quality. The primary outcomes include the change in body mass index z-scores or a diagnosis of diabetes. The secondary outcomes include the change in measures of adiposity as well as lifestyle and metabolic profiles. A meta-analysis will be performed if two or more studies have used similar study designs, comparable intervention techniques , similar populations and measured similar outcomes. DISCUSSION: This review will provide a summary of current interventions to prevent obesity and T2DM in Indigenous children in Canada and help determine the gaps in the literature so that interventions can be developed to control the surge in pediatric T2DM in Indigenous communities. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017072781.

Tri-ponderal mass index in survivors of childhood brain tumors: A cross-sectional study.

Survivors of childhood brain tumors (SCBT) face a higher risk of cardiometabolic disorders and premature mortality compared to the general population. Excess adiposity is a known risk factor for these comorbidities. However, while SCBT have higher adiposity compared to healthy controls, measuring adiposity in clinical practice involves access to specialized equipment and may impact busy clinical services. Tri-ponderal Mass Index (TMI; kg/m3) may be a superior measure of adiposity when compared to Body Mass Index (BMI; kg/m2). However, its use in determining adiposity in SCBT has not been assessed. This study aims to validate TMI as a clinical measure of adiposity in SCBT. This was a cross-sectional study including 44 SCBT (n = 20 female) and 137 (n = 64 female) non-cancer control children, 5-17 years of age. BMI and TMI were calculated from height and weight measurements. Fat mass percentage was assessed using bioelectrical impedance analysis and waist to hip and waist to height ratios were used to assess central adiposity. Regression analyses were adjusted for age, sex, puberty and treatment. TMI demonstrated strong correlations to measures of total and central adiposity and predicted adiposity in SCBT and non-cancer controls, with stronger trends in the latter group. TMI may serve as a reliable clinical measure of adiposity in both SCBT and healthy children.

The effect of cannabis exposure on pubertal outcomes: a systematic review.

PURPOSE: Several countries are legalizing the use of medicinal cannabis and easing restrictions on its recreational use. While adults have been the primary target of these initiatives, expanding access to cannabis will likely lead to increased use by children. While the effects of cannabis on pediatric neuropsychological and mental health outcomes have been broadly studied, there are limited data on the physical health effects of cannabis, including endocrine health. Animal studies have shown that chronic cannabis use leads to delayed sexual maturation; however, its effects on pubertal outcomes in children are not well studied. This systematic review aimed to assess the effect of cannabis use on pubertal timing and tempo in children. METHODS: We conducted a systematic review with literature searches in MEDLINE, Embase, Cochrane Database of Systematic Reviews, Central, PsycINFO, CINAHL, Web of Science, and SPORTDiscus from inception to February 2018. A gray literature search was also completed in Clinicaltrials.gov and ProQuest Dissertations and Theses A&I. The primary outcome was pubertal timing, while secondary outcomes included pubertal tempo and final height and weight. We had no restrictions on date or language of publication of papers. Two reviewers independently assessed records for eligibility, with a third reviewer resolving disagreements. RESULTS: Our database and gray literature searches identified 759 records. A total of 29 full-text papers were assessed for eligibility. However, all studies were ultimately excluded as they did not meet the eligibility criteria. CONCLUSION: Our results highlight a significant gap in existing literature regarding the effects of cannabis use on puberty. Adequately powered longitudinal studies are urgently needed to provide pediatricians and other health care providers with high-quality information on the potential effects of cannabis on the physical health of children. PROSPECTIVE REGISTRAR OF SYSTEMATIC REVIEWS REGISTRATION: PROSPERO no.: CRD42018089397.

Community-based treatment for chronic hepatitis C in drug users: high rates of compliance with therapy despite ongoing drug use.

BACKGROUND: Chronic hepatitis C infection is common in drug users. Treatment of injectors is possible under controlled conditions, but many have not yet been included in treatment programmes as there are concerns about their ability to comply with therapy. It is not known which factors influence compliance. AIM: To examine the hypothesis that active drug users would comply with anti-viral therapy if treatment was delivered in a convenient manner. METHODS: We established a community-based treatment programme and offered anti-viral therapy to all drug users who wanted it. Few pre-treatment requirements were imposed and, by design, compliance with therapy was reviewed after 50 patients had completed treatment. RESULTS: Of the 441 patients who were known to be HCV RNA positive and attended the specialist addiction services during the period of this study, eighty three patients considered therapy. Twenty patients did not undergo treatment: 14 declined and 6 had medical conditions that precluded it. In 60 episodes (58 patients) where treatment had been completed, compliance was greater than 80% and homelessness, active illicit drug use and pre-treatment antidepressant therapy were not associated with noncompliance. In 25 of 49 treatment episodes that were assessed 6 months after treatment cessation, a sustained virological response (51%) was seen. CONCLUSION: Active drug users using illicit drugs can be successfully treated in community-based clinics.

Gender differences in plantar loading during three soccer-specific tasks.

OBJECTIVE: Examine the effect of gender on plantar loading during three football-specific tasks. DESIGN: Thirty-four athletes (17 men, 17 women) ran an agility course five times while wearing the Nike Vitoria hard ground cleat. Plantar loading data were recorded during a side cut, a cross-over cut and a forward acceleration task using Pedar-X insoles. SETTING: Controlled laboratory study. PARTICIPANTS: No history of lower extremity injury in the past 6 months, no previous foot or ankle surgery, not currently wearing foot orthotics and play a cleated sport at least two times per week. MAIN OUTCOME MEASUREMENTS: Contact area, maximum force and the force-time integral (FTI) in the medial and lateral midfoot, medial, middle and lateral forefoot as well as the hallux. A univariate ANCOVA (alpha = 0.05) was performed on each dependent variable (covariate was course speed). RESULTS: Significant gender differences existed in the force and force-time integral beneath the lateral midfoot and forefoot during the cross-over cut task as well as in the middle forefoot during the side cut task with the men demonstrating an increased force. No significant differences existed in the loading on the medial side of the foot during any tasks. CONCLUSIONS: The results of this study indicate that the increase in plantar loading on the lateral portion of the midfoot and forefoot in men could be one possible explanation for the increased incidence of fifth metatarsal stress fractures in men. Gender differences in loading patterns need to be considered when comparing different movements as well as different footwear conditions.

A comparison of cleat types during two football-specific tasks on FieldTurf.

OBJECTIVE: To examine the effect of different cleat plate configurations on plantar pressure during two tasks. DESIGN: Thirty-six athletes ran an agility course 5 times while wearing 4 different types of Nike Vitoria cleats: (1) bladed, (2) elliptical firm ground, (3) hard ground and (4) turf. Plantar pressure data were recorded during a side cut and a cross cut using Pedar-X insoles. SETTING: Controlled laboratory study PARTICIPANTS: No history of lower extremity injury in the past 6 months, no previous foot or ankle surgery, not currently wearing foot orthotics and play a cleated sport at least twice a week. MAIN OUTCOME MEASUREMENTS: Total foot contact time, contact area, maximum force, peak pressure and the force-time integral (FTI) in the medial, middle and lateral regions of the forefoot were collected. A 1x4 ANOVA (alpha = 0.05) was performed on each dependent variable. A Bonferroni adjustment was conducted (alpha = 0.008). RESULTS: In the cross cut task, statistical differences between cleats were observed in three variables: total foot peak pressure, lateral forefoot FTI, and lateral forefoot normalised maximum force. In the side cut task, statistical differences between cleats were observed in 4 variables: total foot peak pressure, the medial and middle forefoot FTI, and the medial and middle forefoot normalised maximum force. CONCLUSIONS: Significant differences in forefoot loading patterns existed between cleat types. Based on the results of this study, it might be beneficial to increase the forefoot cushioning in cleats in an attempt to decrease loading in these regions of the foot.

Effects of fexofenadine and desloratadine on subjective and objective measures of nasal congestion in seasonal allergic rhinitis.

BACKGROUND: In vitro studies have shown much higher H1-receptor antagonist potency with desloratadine (DL) compared to fexofenadine (FEX), although it is unclear whether this has any clinical relevance on disease control parameters in seasonal allergic rhinitis (SAR), especially for nasal congestion. OBJECTIVE: To compare the relative efficacy between presently recommended doses of DL and FEX on daily measurements of peak nasal inspiratory flow (PNIF) and nasal symptoms in SAR. METHODS: Forty-nine patients with SAR were randomized into a double-blind, placebo-controlled cross-over study during the grass pollen season, comparing 2 weeks of once daily treatment with (a) 180 mg FEX or (b) 5 mg DL, taken in the morning. There was a 7-10 day placebo run-in and washout prior to each randomized treatment. Measurements were made in the morning (AM) and in the evening (PM) for PNIF (the primary outcome variable), nasal and eye symptoms. The average of AM/PM values were used for analysis. RESULTS: There were significant (P < 0.05) improvements, compared to placebo, with FEX and DL, for PNIF, nasal blockage, nasal irritation, and total nasal symptoms, but not nasal discharge or eye symptoms. There were no significant differences between active treatments. Values for PNIF (L/min) for mean placebo baseline, mean difference from baseline (95% CI for difference) were 126, 10 (4-16) for FEX; and 122, 11 (4-17) for DL. The mean difference (95% CI) between FEX vs. DL was 1 L/min (-7-8). Values for total nasal symptoms (out of 12) were: 3.2, 0.7 (0.2-1.2) for FEX; and 3.4, 0.9 (0.3-1.5) for DL, and for nasal blockage (out of 3) were: 1.1, 0.2 (0.1-0.4) for FEX; and 1.2, 0.3 (0.1-0.5) for DL. The mean difference (95% CI) in total nasal symptoms and nasal blockage between FEX vs. DL was 0.1 (-0.6-0.8) and 0.1 (-0.2-0.3), respectively. CONCLUSIONS: Recommended once daily doses of fexofenadine and desloratadine were equally effective in improving nasal peak flow and nasal symptoms in SAR.

Coronary artery brachytherapy.

Coronary artery disease is the leading cause of mortality in the West with over 1.2 million angioplasties performed annually. Despite the introduction of stents, restenosis occurs in 30-40% of vessels, which until recently has only been treated effectively by coronary artery bypass surgery. Coronary artery brachytherapy appears to provide an alternative, less invasive remedy. The mechanisms of restenosis and how these are inhibited by radiation are described here. The practicalities of radiation delivery and the history of the development of intravascular radiation as an effective clinical tool are outlined. Finally, the pitfalls of the current technology and the areas in which future research must be targeted for the field to develop are discussed.

Airway and systemic effects of hydrofluoroalkane fluticasone and beclomethasone in patients with asthma.

BACKGROUND: With the transition to hydrofluoroalkane-134a propellants in metered dose inhalers, it is important to consider the efficacy and safety profiles of formulations containing inhaled corticosteroids. We examined the airway and systemic effects of hydrofluoroalkane-134a fluticasone propionate (FLU-HFA) and beclomethasone dipropionate (BEC-HFA) at recommended labelled doses. METHODS: Twenty mild to moderate asthmatics were randomised in crossover fashion to receive 6 weeks of 500 micro g/day followed by 1000 micro g/day FLU-HFA and BEC-HFA. Measurements were made at baseline after placebo run in and washout, and after each randomised treatment. The primary airway outcome for benefit was the dose of methacholine provoking a fall in forced expiratory volume in 1 second (FEV(1)) of 20% or more (methacholine PD(20)) and for systemic adverse effects was overnight urinary cortisol/creatinine (OUCC). RESULTS: For mean responses, both doses of BEC-HFA and FLU-HFA produced significant improvements in PD(20) compared with baseline. The improvement was not significantly greater with 1000 micro g/day FLU-HFA versus BEC-HFA, a 1.69 fold difference (95% CI 0.94 to 3.04). Both doses of BEC-HFA but not FLU-HFA caused significant suppression of OUCC compared with baseline, with significantly (p<0.05) lower values at 1000 micro g/day for BEC-HFA versus FLU-HFA (1.97 fold difference (95% CI 1.28 to 3.02)). CONCLUSION: There was no difference in the airway and systemic effects in patients with mild to moderate asthma between FLU-HFA and BEC-HFA at a dose of 500 micro g/day. At 1000 micro g/day there was increased systemic bioactivity with BEC-HFA compared with FLU-HFA, without any gain in airway efficacy.

Influence of monocaprin on the permeability of a diacidic drug BTA-243 across Caco-2 cell monolayers and everted gut sacs.

This study explores the potential of the monoglyceride monocaprin as an enhancer of the epithelial permeability of the beta(3)-adrenoceptor agonist BTA-243, as an approach to improving the bioavailability of this drug. The permeabilities of BTA-243 and mannitol (paracellular marker) in Caco-2 cell monolayer and everted gut sac models in aqueous buffer (pH 6.8) in the presence of 1.3 and 2.0 mM monocaprin were compared with control (monocaprin-free) solutions over a period of 1 h. The transepithelial electrical resistance (TEER) of the Caco-2 cell monolayers was measured at regular time intervals throughout the experiment and after a recovery period of 30 h. Toxicological damage to the biological models associated with exposure to monocaprin was assessed by scanning electron microscopy and by the measurement of lactate dehydrogenase (LDH) release from everted gut sacs. The permeability of BTA-243 in epithelial monolayers was enhanced in the presence of 1.3 and 2.0 mM monocaprin. Measurements of TEER and mannitol permeability showed partial recovery of barrier properties after a 30 h period following exposure to 1.3 mM monocaprin. No structural damage was evident in these monolayers. Enhancement of Caco-2 permeability to BTA-243 by 2.0 mM monocaprin was significantly greater than by 1.3 mM but was irreversible; monolayers failed to recover their barrier properties after 30 h and changes in their gross morphology were observed. The mucosal to serosal transfer of BTA-243 in everted gut sac was enhanced but to a lesser extent than in the Caco-2 model. LDH release from everted gut sacs exposed to monocaprin was significantly less than that after exposure to Triton X-100, a nonionic surfactant known to cause membrane disruption.