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.

Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers.

In view of the evidence that cognitive deficits in schizophrenia are critically important for long-term outcome, it is essential to establish the effects that the various antipsychotic compounds have on cognition, particularly second-generation drugs. This parallel group, placebo-controlled study aimed to compare the effects in healthy volunteers (n = 128) of acute doses of the atypical antipsychotics amisulpride (300 mg) and risperidone (3 mg) to those of chlorpromazine (100 mg) on tests thought relevant to the schizophrenic process: auditory and visual latent inhibition, prepulse inhibition of the acoustic startle response, executive function and eye movements. The drugs tested were not found to affect auditory latent inhibition, prepulse inhibition or executive functioning as measured by the Cambridge Neuropsychological Test Battery and the FAS test of verbal fluency. However, risperidone disrupted and amisulpride showed a trend to disrupt visual latent inhibition. Although amisulpride did not affect eye movements, both risperidone and chlorpromazine decreased peak saccadic velocity and increased antisaccade error rates, which, in the risperidone group, correlated with drug-induced akathisia. It was concluded that single doses of these drugs appear to have little effect on cognition, but may affect eye movement parameters in accordance with the amount of sedation and akathisia they produce. The effect risperidone had on latent inhibition is likely to relate to its serotonergic properties. Furthermore, as the trend for disrupted visual latent inhibition following amisulpride was similar in nature to that which would be expected with amphetamine, it was concluded that its behaviour in this model is consistent with its preferential presynaptic dopamine antagonistic activity in low dose and its efficacy in the negative symptoms of schizophrenia.

Test stimulus characteristics determine the perceived speed of the dynamic motion aftereffect

Using a speed-matching task, we measured the speed tuning of the dynamic motion aftereVect (MAE). The results of our Wrst experiment, in which we co-varied dot speed in the adaptation and test stimuli, revealed a speed tuning function. We sought to tease apart what contribution, if any, the test stimulus makes towards the observed speed tuning. This was examined by independently manipulating dot speed in the adaptation and test stimuli, and measuring the eVect this had on the perceived speed of the dynamic MAE. The results revealed that the speed tuning of the dynamic MAE is determined, not by the speed of the adaptation stimulus, but by the local motion characteristics of the dynamic test stimulus. The role of the test stimulus in determining the perceived speed of the dynamic MAE was conWrmed by showing that, if one uses a test stimulus containing two sources of local speed information, observers report seeing a transparent MAE; this is despite the fact that adaptation is induced using a single-speed stimulus. Thus while the adaptation stimulus necessarily determines perceived direction of the dynamic MAE, its perceived speed is determined by the test stimulus. This dissociation of speed and direction supports the notion that the processing of these two visual attributes may be partially independent.

Pullout test correlations and in-place strength assessment - the European Concrete Frame Building Project

A full-scale, seven-story, reinforced concrete building frame was constructed in-place at the Building Research Establishment's Cardington Laboratory, which encompassed a range of different concrete mixtures and advanced construction techniques. This provided an opportunity to assess in-place nondestructive test methods, namely the pullout test, and more specifically the Danish version, which has been known as the Lok test, on a systematic basis during the construction of the building. It was used in conjunction with both standard and temperature-matched cube specimens to assess its practicality and accuracy under site conditions. Strength correlations were determined using linear and power function regression analysis. Strength predictions from these were found to be in very good agreement with the compressive strengths of temperature-matched cube specimens. When a general correlation is used, however, estimates for compressive strength are likely to have 95% confidence limits of around '20% of the mean value of four results.

Eye movements and neurocognitive function in treatment resistant schizophrenia: a pilot study.

Objectives: It is increasingly important to develop predictors of treatment response and outcome in schizophrenia. Neuropsychological impairments, particularly those reflecting frontal lobe function, appear to predict poor outcome. Eye movement abnormalities probably also reflect frontal lobe deficits. We wished to see if these two aspects of schizophrenia were correlated and whether they could distinguish a treatment resistant from a treatment responsive group. Methods: Ten treatment resistant schizophrenic patients were compared with ten treatment responsive patients on three eye movement paradigms (reflexive saccades, antisaccades and smooth pursuit), clinical psychopathology (BPRS, SANS and CGI) and a neuropsychological test battery designed to detect frontal lobe dysfunction. Ten aged-matched controls also carried out the eye movement tasks. Results: Both treatment responsive (p = 0.038) and treatment resistant (p = 0.007) patients differed significantly from controls on the antisaccade task. The treatment resistant group had a higher error rate than the treatment responsive group, but the difference was not statistically significant. Similar poor neuropsychological test performance was found in both groups. Conclusions: To demonstrate the biological differences characteristic of treatment resistance, larger sample sizes and wider differences in outcome between the two groups are necessary.

Role of creatine supplementation on exercise-induced cardiovascular function and oxidative stress

Many degenerative diseases are associated with increased oxidative stress. Creatine has the potential to act as an indirect and direct antioxidant; however, limited data exist to evaluate the antioxidant capabdities of creatine supplementation within in vivo human systems. This study aimed to investigate the effects of oral creatine supplementation on markers of oxidative stress and antioxidant defenses following exhaustive cycling exercise. Following preliminary testing and two additional familiarization sessions, 18 active males repeated two exhaustive incremental cycling trials (T1 and T2) separated by exactly 7 days. The subjects were assigned, in a double-blind manner, to receive either 20 g of creatine (Cr) or a placebo (P) for the 5 days preceding T2. Breath-by-breath respiratory data and heart rate were continually recorded throughout the exercise protocol and blood samples were obtained at rest (preexercise), at the end of exercise (postexercise), and the day following exercise (post24 h). Serum hypdroperoxide concentrations were elevated at postexercise by 17 +/- 5% above preexercise values (p = 0.030). However, supplementation did not influence lipid peroxidation (serum hypdroperoxide concentrations), resistance of low density lipoprotein to oxidative stress (t(1/2max) LDL oxidation) and plasma concentrations of non-enzymatic antioxidants (retinol, alpha-carotene, beta-carotene, alpha-tocopherol, gamma-tocopherol, lycopene and vitamin Q. Heart rate and oxygen uptake responses to exercise were not affected by supplementation. These findings suggest that short-term creatine supplementation does not enhance non-enzymatic antioxidant defence or protect against lipid peroxidation induced by exhaustive cycling in healthy males.

Pepsin measured in induced sputum - a test for pulmonary aspiration in children?

Purpose The purpose of this study was to investigate if pepsin measured in sputum is a useful marker of pulmonary aspiration secondary to gastroesophageal reflux (GER) in children. It is possible that the induced sputum procedure could cause GER and invalidate the results. The hypothesis stated that healthy children (those without history of respiratory or gastroesophageal symptoms) would not have pepsin detected in induced sputum. Methods Children attending surgical outpatients in the Royal Belfast Hospital for Sick Children (Belfast, Northern Ireland) were recruited. After spirometry, sputum was obtained by induction with hypertonic 3% saline. Spirometry was repeated, and complications were noted. An “in-house” enzyme-linked immunosorbent assay was used to measure pepsin concentration in sputum. The lower limit of detection of pepsin was 1.19 ng/mL. Results Children (n = 21) aged 4 to 16 years were recruited. Twenty children completed the study. No adverse effects were reported. Pepsin was detected in 17 (85%) of 20 sputum samples. Conclusions The act of sputum induction appears to induce physiologic GER in a healthy childhood population. The analysis of pepsin in sputum obtained by sputum induction is therefore not useful in the investigation of reflux-related respiratory disease.

Validity of a 1 minute walk test for children with cerebral palsy.

The concurrent validity of a 1 minute walk test at a child's maximum walking speed was assessed in children with bilateral spastic cerebral palsy (BSCP). The distance covered during the 1 minute walk test was compared with the children's gross motor function as assessed by the Gross Motor Function Measure (GMFM). Twenty-four male and 10 female children with CP (mean age 11y, range 4 to 16y) participated in the study. Gross Motor Function Classification System (GMFCS) levels were; level I (n=3), level II (n=17), level III (n=10), and level IV (n=4). Participants had clinical diagnoses of symmetrical diplegia (n=19), asymmetrical diplegia (n=14), and quadriplegia (n=1). Results showed a significant correlation between GMFM score and the distance covered during the 1 minute walk (r=0.92; p<0.001). There was also a significant decrease in the distance walked with increasing GMFCS level (p<0.001). We concluded that the 1 minute walk test is a valid measure for assessing functional ability in children with ambulatory BSCP. Its cost-effectiveness and user friendliness make it a potentially useful tool in the clinical setting. Further study needs to address its reliability and ability to detect change over time.

A randomized clinical trial of hydroxymethylglutaryl-Coenzyme A reductase inhibition for Acute Lung Injury (The HARP study)

Rationale: There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI.

Objectives: To test whether simvastatin improves physiological and biological outcomes in ALI.

Methods: We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein.

Measurements and Main Results: Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group.

Conclusions: Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation.

Selection for cuticular melanism reveals immune function and life-history trade-offs in Spodoptera littoralis

Several insect species show an increase in cuticular melanism in response to high densities. In some species, there is evidence that this melanism is correlated with an up-regulation of certain immune system components, particularly phenoloxidase (PO) activity, and with the down-regulation of lysozyme activity, suggesting a trade-off between the two traits. As melanism has a genetic component, we selected both melanic and nonmelanic lines of the phase-polyphenic lepidopteran, Spodoptera littoralis, in order to test for a causative genetic link between melanism, PO activity and lysozyme activity, and to establish if there are any life-history costs associated with the melanic response. We found that, in fact, melanic lines had lower PO activity and higher lysozyme activity than nonmelanic lines, confirming a genetic trade-off between the two immune responses, but also indicating a genetic trade-off between melanism and PO activity. In addition, we found that lines with high PO activity had slower development rates suggesting that investment in PO, rather than in melanism, is costly.

Testing the stability of the benefit transfer function for discrete choice contingent valuation data

This paper examines the stability of the benefit transfer function across 42 recreational forests in the British Isles. A working definition of reliable function transfer is Put forward, and a suitable statistical test is provided. A novel split sample method is used to test the sensitivity of the models' log-likelihood values to the removal of contingent valuation (CV) responses collected at individual forest sites, We find that a stable function improves Our measure of transfer reliability, but not by much. We conclude that, in empirical Studies on transferability, considerations of function stability are secondary to the availability and quality of site attribute data. Modellers' can study the advantages of transfer function stability vis-a-vis the value of additional information on recreation site attributes. (c) 2008 Elsevier GmbH. All rights reserved.

Fokker-Planck equation for a test-particle weakly coupled to a magnetized plasma

We consider the derivation of a kinetic equation for a charged test particle weakly interacting with an electrostatic plasma in thermal equilibrium, subject to a uniform external magnetic field. The Liouville equation leads to a generalized master equation to second order in the `weak' interaction; a Fokker-Planck-type equation then follows as a `Markovian' approximation. It is shown that such an equation does not preserve the positivity of the distribution function f(x,v;t). By applying techniques developed in the theory of open systems, a correct Fokker-Planck equation is derived. Explicit expressions for the diffusion and drift coefficients, depending on the magnetic field, are obtained.