An experience of attempting to apply the randomised controlled trial (RCT) design in a ‘real world’ community-based clinical setting – one family therapist’s current journey. Context, 99, 6-9.

This paper describes an early career researcher's expereince of using randomised controlled trial methodology to investigarte the effectiveness of psychotherapeutic interventions for traumatised families in a 'real world' setting.

Synthesis and in Vitro and in Vivo Evaluation of a Series of Dihydroisocoumarin Derivatives Conjugated with Fatty Acids, Alcohols, and Amines as Potential Anticancer Agents

In this paper, we report the synthesis and biological activity of a series of dihydroisocoumarin analogues Conjugated with fatty acids, alcohols, or amines, of varying hydrocarbon chain length and degree of unsaturation, to (he dihydroisocoumarins, kigelin and mellein, at the C-7 and C-8 positions on the core dihydroisocoumarin structure. These compounds were evaluated for their antiproliferative activity against human breast cancer (MCF-7 and MDA-MB-468) and melanoma cells (SK-MEL-28 and Malme-3M) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Two compounds Conjugated with gamma-linolenyl alcohol (18:3 n-6) demonstrated potent antiproliferative activity in vitro with one of these 4-hydroxy-3-oxo-1.3-dihydro-isobenzofuran-5-carboxylic acid octadeca-6,9,12-trienyl ester, demonstrating significant antitumor activity in vivo ill a number of human tumor xenograft models.

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes:results of the MRC AML15 trial

Two hundred eighty-five patients, median age 42, with PML-RARa-positive acute promyelocytic leukaemia were randomised to Ara-C-containing 'Medical Research Council (MRC) Chemotherapy'+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified 'Spanish') therapy. MRC treatment comprised four courses with ATRA in courses 1-2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1-3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P10 × 10(9)/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

Development and Single-Laboratory Validation of a Pseudofunctional Biosensor Immunoassay for the Detection of the Okadaic Acid Group of Toxins

A rapid analytical optical biosensor-based immunoassay was developed and validated for the detection of okadaic acid (OA) and its structurally related toxins from shellfish matrix. The assay utilizes a monoclonal antibody which binds to the OA group of toxins in order of their toxicities, resulting in a pseudofunctional assay. Single-laboratory validation of the assay for quantitative detection of OA determined that it has an action limit of 120 mu g/kg, a limit of detection of 31 mu g/kg, and a working range of 31-174 mu g/kg. The midpoint on the standard matrix calibration curve is 80 mu g/kg, half the current regulatory limit. Inter- and intra-assay studies of negative mussel samples spiked with various OA concentrations produced average coefficient of variation (CV) and standard deviation (SD) values of 7.9 and 10.1, respectively. The assay was also validated to confirm the ability to accurately codetect and quantify dinophysistoxin-1 (DTX-1), DTX-2, and DTX-3 from shellfish matrix. Alkaline hydrolysis was not required for the detection of DTX-3 from matrix. Excellent correlations with the data generated by the biosensor method and liquid chromatography/tandem mass spectrometry (LC/MS/MS) were obtained using a certified reference material (R-2 = 0.99), laboratory reference material, and naturally contaminated mussel samples (R-2 = 0.97). This new procedure could be used as a rapid screening procedure replacing animal-based tests for DSP toxins.

Multicenter Randomized Controlled Trial of Withdrawal of Inhaled Corticosteroids in Cystic Fibrosis

Rationale: Lung inflammation and injury is critical in cystic fibrosis. An ideal antiinflammatory agent has not been identified but inhaled corticosteroids are widely used despite lack of evidence.

Objectives: To test the safety of withdrawal of inhaled corticosteroids with the hypothesis this would not be associated with an earlier onset of acute chest exacerbations.

Methods: Multicenter randomized double-blind placebo-controlled trial in 18 pediatric and adult UK centers. Eligibility criteria included age > 6.0 yr, FEV1 ? 40% predicted, and corticosteroid use > 3 mo. During the 2-mo run-in period, all patients received fluticasone; they then took either fluticasone or placebo for 6 mo.

Measurements and Main Results: Fluticasone group: n = 84, median age 14.6 yr, mean (SD) FEV1 76% (18); placebo group: n = 87, median age 15.8 yr, mean (SD) FEV1 76% (18). There was no difference in time to first exacerbation (primary outcome) with hazard ratio (95% confidence interval) of 1.07 (0.68 to 1.70) for fluticasone versus placebo. There was no effect of age, atopy, corticosteroid dose, FEV1, or Pseudomonas aeruginosa status. There was no change in lung function or differences in antibiotic or rescue bronchodilator use. Fewer patients in the fluticasone group withdrew from the study due to lung-related adverse events (9 vs. 15%); with a relative risk (95% confidence interval) of 0.59 (0.23–1.48) fluticasone versus placebo.

Conclusions: In this study population (applicable to 40% of patients with cystic fibrosis in the UK), it appears safe to consider stopping inhaled corticosteroids. Potential advantages will be to reduce the drug burden on patients, reduce adverse effects, and make financial savings.

Neostigmine antagonism of rocuronium block during anesthesia with sevoflurane, isoflurane or propofol

Purpose: To examine the influence of continuing administration of sevoflurane or isoflurane during reversal of rocuronium induced neuromuscular block with neostigmine. Methods: One hundred and twenty patients, divided into three equal groups, were randomly allocated to maintenance of anesthesia with sevoflurane, isoflurane or propofol. Neuromuscular block was induced with rocuronium and monitored using train-of-four (TOF) stimulation of the ulnar nerve and recording the force of contraction of the adductor pollicis muscle. Neostigmine was administered when the first response in TOF had recovered to 25%. At this time the volatile agent administration was stopped or propofol dosage reduced in half the patients in each group (n = 20 in each group). The times to attain TOF ratio of 0.8, and the number of patients attaining this end point within 15 min were recorded. Results: The times (mean ± SD) to recovery of the TOF ratio to 0.8 were 12.0 ± 5.5 and 6.8 ± 2.3 min in the sevoflurane continued and sevoflurane stopped groups, 9.0 ± 8.3 and 5.5 ± 3.0 min in the isoflurane continued and isoflurane stopped groups, and 5.2 ± 2.8 and 4.7 ±1.5 min in the propofol continued and propofol stopped groups (P <0.5- 01). Only 9 and 15 patients in the sevoflurane and isoflurane continued groups respectively had attained a TOF ratio of 0.8 within 15 min (P <0.001 for sevoflurane). Conclusions: The continued administration of sevoflurane, and to a smaller extent isoflurane, results in delay in attaining adequate antagonism of rocuronium induced neuromuscular block.

Enhanced surface attachment of protein-type targeting ligands to poly(lactide-co-glycolide) nanoparticles using variable expression of polymeric acid functionality

The density of reactive carboxyl groups on the surface of poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) was modulated using a combination of high-molecular weight (MW) encapped and low MW non-encapped PLGA. Carboxyl groups were activated using carbodiimide chemistry and conjugated to bovine serum albumin and a model polyclonal antibody. Activation of carboxyl,groups in solution-phase PLGA prior to NP formation was compared with a postformation activation of peripheral carboxyl groups on intact NP. Activation before or after NP formation did not influence conjugation efficiency to NP prepared using 100% of the low-MW PLGA. The effect of steric stabilization using poly(vinyl alcohol) reduced conjugation of a polyclonal antibody from 62 mu g/(mg NP) to 32 mu g/(mg NP), but enhanced particulate stability. Increasing the amount of a high-MW PLGA also reduced Conjugation, with the activation post-formation still superior to the preformation approach. Drug release studies showed that high proportions of high-MW PLGA in the NP produced a longer sustained release profile of a model drug (celecoxib). It can be concluded that activating intact PLGA NP is superior to activating component parts prior to NP formation. Also, high MW PLGA could be used to prolong drug release, but at the expense of conjugation efficiency on to the NP surface. (C) 2008 Wiley Periodicals, Inc. J Biomed Mater Res 87A: 873-884, 2008

The carbenoid approach to peptide synthesis

A different approach to the synthesis of dipeptides is described based on the formation of the (NHCHRCONH)-C-1-(CHRCO)-C-2 bond by carbenoid N-H insertion, rather than the formation of the peptide bond itself. Thus decomposition of triethyl diazophosphonoacetate catalysed by rhodium(Ii) acetate in the presence of N-protected amino acid amides 8 gives the phosphonates 9, Subsequent Wadsworth-Emmons reaction of 9 with aldehydes in the presence of DBU gives dehydro dipeptides 10. The reaction has been extended to a simple two-step procedure, without the isolation of the intermediate phosphonate. for conversion of a range of amino acid amides 11 into dehydro dipepides 12 and to an N-methylamide 11h, and for conversion of a dipeptide: to tripeptide (13-14). Direct conversion, by using methyl diazophenylacetate, of amino acid amides to phenylglycine-containing dipeptides 19 proceeds in good chemical yield, but with poor diastereoselectivity.

Functional management of ankle sprains: what volume and intensity of walking is undertaken in the first week postinjury:what volume and intensity of walking is undertaken in the first week postinjury

BACKGROUND: Acute ankle sprains are usually managed functionally, with advice to undertake progressive weight-bearing and walking. Mechanical loading is an important modular of tissue repair; therefore, the clinical effectiveness of walking after ankle sprain may be dose dependent. The intensity, magnitude and duration of load associated with current functional treatments for ankle sprain are unclear.

AIM: To describe physical activity (PA) in the first week after ankle sprain and to compare results with a healthy control group.

METHODS: Participants (16-65 years) with an acute ankle sprain were randomised into two groups (standard or exercise). Both groups were advised to apply ice and compression, and walk within the limits of pain. The exercise group undertook additional therapeutic exercises. PA was measured using an activPAL accelerometer, worn for 7 days after injury. Comparisons were made with a non-injured control group.

RESULTS: The standard group were significantly less active (1.2 ± 0.4 h activity/day; 5621 ± 2294 steps/day) than the exercise (1.7 ± 0 .7 h/day, p=0.04; 7886 ± 3075 steps/day, p=0.03) and non-injured control groups (1.7 ± 0.4 h/day, p=0.02; 8844 ± 2185 steps/day, p=0.002). Also, compared with the non-injured control group, the standard and exercise groups spent less time in moderate (38.3 ± 12.7 min/day vs 14.5 ± 11.4 min/day, p=0.001 and 22.5 ± 15.9 min/day, p=0.003) and high-intensity activity (4.1 ± 6.9 min/day vs 0.1 ± 0.1 min/day, p=0.001 and 0.62 ± 1.0 min/day p=0.005).

CONCLUSION: PA patterns are reduced in the first week after ankle sprain, which is partly ameliorated with addition of therapeutic exercises. This study represents the first step towards developing evidence-based walking prescription after acute ankle sprain.

Hydrothermal synthesis and characterization of ZSM-5 coatings on a molybdenum support and scale-up for application in micro reactors

A procedure has been developed to grow ZSM-5 crystals in situ on a molybdenum (Mo) support. The high heat conductivity (138 W/mK) and high mechanical stability at elevated temperatures of the Mo support allow the application of ZSM-5 coatings in micro reactors for high temperature processes involving large heat effects. The effect of the synthesis mixture composition on ZSM-5 coverage and on the uniformity of the ZSNI-5 coatings was investigated on plates of 10 X 10 mm(2). Ratios of H2O/Si = 50, SUAI = 25, and TPA/Al = 2.0 were found to be optimal for the formation of uniform coatings of 6 g/m(2) at a temperature of 150 degrees C and a synthesis time of 48 h. Scaling up of the synthesis procedure on 72 Mo plates of 40 x 9.8 x 0.1 mm 3 resulted in a uniform coverage of 14.8 +/- 0.4 g/m(2). The low deviation per individual plate (

Novel low-temperature photocatalytic titania films produced by plasma-assisted reactive dc magnetron sputtering

Robust, active, anatase titania films, 250 nm thick, are deposited onto glass at low temperatures, i.e., 2.0 for the photocatalytic mineralization of stearic acid. These films are typically 6.9 times more active than a sample of commercial self-cleaning glass, comprising a 15 nm layer of fitania deposited by CVD, mainly because they are much thicker and, therefore, absorb more of the incident UV light. The most active of the films tested comprised particles of P25, but lacked any significant physical robustness. Similar results, but much more quickly obtained, were generated using a photocatalyst- sensitive ink, based on the redox dye, resazurin, Rz. All fitania films tested, including those produced by magnetrom sputtering exhibited photo-induced superhydrophilicity. The possible future application of PAR-DG-MS for producing very active photocatalytic films on substrates not renowned for their high temperature stabilities, such as plastics, is noted. (c) 2006 Elsevier B.V All rights reserved.

Metastatic melanoma:A regional review and future directions

Aims and background. The incidence of malignant melanoma has risen steadily over recent decades. NCI data from 2005-2007 have suggested that 1.93% of individuals born today in the US will develop melanoma at some stage. Approximately 15% of patients with MM either present with metastatic disease or develop metastases during the course of their illness. Unfortunately, metastatic MM remains a challenge with limited treatment options, and median overall survival is 6-9 months. Methods. We reviewed our data for the treatment of metastatic MM over a period of four years. Data from all patients with metastatic MM treated with systemic therapy without clinical trials from 2006 to 2009 were reviewed. Response rate was determined as per RECIST criteria. Results. Sixty four patients were treated with one or more lines of cytotoxic therapy. Median age was 62 years (range, 23-82) with 53% males. Primary site of the disease was the skin in 75%, mucosal in 12.5%, ocular in 9.4% and nodal with an occult primary in 3.1%. Visceral metastases were present in 75% of patients at the start of treatment, including pulmonary (39.6%) and hepatic (34.4%). All patients were screened for brain metastases, which were present in 26.5% of patients. ECOG performance status was 0 in 7.8%, 1 in 68.7%, 2 in 9.4% and undocumented in the remaining 14%. Patients without brain metastases received single agent DTIC as first line; those with brain metastases received temozolomide. Response rate was 7% for DTIC and 28% for temozolomide, with median progression-free survival of 2.4 and 3.2 months, respectively. Seven patients who received DTIC are alive on follow-up, 2 have ongoing stable disease post-DTIC at 41 months and 18 months. Second line therapy with vinblastine was given to 21 patients (32%), with a response rate of 9.5% and median progression-free survival of 3.4 months. Median overall survival from initiation of therapy was 7.7 months for DTIC and 3.6 months for patients with brain metastases receiving temozolomide. A performance status of 2 was associated with shorter median overall survival (2.0 months). Conclusions. Our results are comparable to published data. Malignant melanoma is a disease with rising incidence and limited treatment options. These patients are best treated in the context of clinical trials as new targeted therapies are promising as future strategies. © Il Pensiero Scientifico Editore.

Correction of moderate myopia is associated with improvement in self-reported visual functioning among Mexican school-aged children.

PURPOSE: To quantify the impact on self-reported visual functioning of spectacle provision for school-aged children in Oaxaca, Mexico. METHODS: The Refractive Status Vision Profile (RSVP), a previously validated tool to measure the impact of refractive correction on visual functioning, was adapted for use in rural children and administered at baseline and 4 weeks (27.3 +/- 4.4 days) after the provision of free spectacles. Visual acuity with and without correction, age, sex, and spherical equivalent refraction were recorded at the time of follow-up. RESULTS: Among 88 children (mean age, 12 years; 55.7% girls), the median presenting acuity (uncorrected or with original spectacles), tested 4 weeks after the provision of free spectacles, was 6/9 (range, 6/6-6/120). Significant improvements in the following subscales of the RSVP were seen for the group as a whole after the provision of free spectacles: function, 11.2 points (P = 0.0001); symptoms, 14.3 points (P < 0.0001); total score, 10.3 points (P = 0.0001). After stratification by presenting vision in the better-seeing eye, children with 6/6 acuity (n = 22) did not have significant improvement in any subscale; those with acuity of 6/7.5 to 6/9 (n = 34) improved only on function (P = 0.02), symptoms (P = 0.005), and total score (P = 0.003); and those with acuity of 6/12 or worse improved on total score (P < 0.0001) and all subscales. Subjects (n = 31) with uncorrected myopia of -1.25 D or more had a mean improvement in total score of 15.9 points (P < 0.0001), whereas those with uncorrected myopia between -0.50 and -1.00 D inclusive (n = 53) had a mean improvement of 8 points (P = 0.01). CONCLUSIONS: Provision of spectacles to children in this setting had a significant impact on self-reported function, even at modest levels of baseline visual disability. The correlation between presenting vision/refraction and improvement and the failure of children 6/6 at baseline to improve offer evidence for a real effect.