Seronegative spondyloarthropathies : a review : part I: classification and differential diagnosis

The seronegative spondyloarthropathies comprise a group of non-rheumatoid disorders with similar clinical, laboratory and genetic features. Recognition of new clinical features has supported the notion that they all form part of a clinical spectrum. These features and the classification of the seronegative spondyloarthropathies are discussed in the review.peer-reviewe

Seronegative spondyloarthropathies : a review : part II: genetics and pathogenesis

In none of the spondyloarthropathies is the pathogenesis well understood. Much of the investigation into the aetio-pathogenesis of these diseases has focused on the association with HLA-B27 and the known triggering potential of certain infectious agents. In this article the author describes that the HLA linked genes which is subdivided into three groups, class I, class II and class III, which are structurally and functionally distinct from each other.peer-reviewe

Operant Conditioning of Heart Rate Changes in Curarized Rats with Brain Stimulation Reinforcement

Many learning theorists have distinguished between autonomic responses which can be conditioned using classical conditioning procedures, and skeletal responses which can be conditioned using operant or instrumental conditioning procedures. In recent years this distinction has been challenged since such autonomic responses as changes in heart rate, GSRs, vasoconstriction and vasodilation, and changes in blood pressure have all been conditioned as operants. The aim of this study was to investigate the possibility that both increases and decreases in heart rate could be conditioned in groups of curarized rats using an operant conditioning procedure with brain stimulation as the reinforcement for the heart rate changes. Curarized rats were used in order to markedly reduce the possibility of skeletal mediation of the heart rate changes which were conditioned. Brain stimulation was used since it has been found to have powerful reinforcing effects for more typical operant responses. A feedback stimulus was presented to the rats during the curare conditioning sessions whenever they were emitting criterion heart rates, i.e. heart rates which if sustained for a fixed number of beats would be followed by the brain stimulation. Two groups of six rats were used, one group being reinforced for heart rate increases, and one for decreases. All rats were given four curare conditioning sessions during which heart rate changes were reinforced. During the first curare conditioning session no evidence of operant conditioning of heart rate changes was found. On the three later conditioning sessions significant differences were found in the heart rates of the two groups, with the group reinforced for heart rate increases showing the higher heart rate. There was also some evidence of an extinction effect during the later curare sessions in that the heart rates of the two groups which diverged during condition­ing, tended to converge during extinction. The results of this experiment show that changes in heart rate can be conditioned in curarized rats using an operant conditioning procedure with brain stimulation as the reinforcement for the heart rate changes. In a second experiment three rats were used in an attempt to first condition a heart rate change in one direction, and then to reinforce heart rate changes in the opposite direction. Although the three rats showed good acquisition of the initial heart rate change none of them showed any evidence of acquisition of the heart rate change in the opposite direction. The results from these three rats suggest that heart rate reversals will only be conditioned with great difficulty

Epistemology and Social Work: Integrating theory, research and practice through philosophical pragmatism

Debates regarding theory and practice in social work have often avoided detailed discussion regarding the nature of knowledge itself and the various ways this can be created. As a result, positivistic conceptions of knowledge are still assumed by many to be axiomatic, such that context-dependent and practitioner-oriented approaches to knowledge creation and use are assumed to lack epistemological rigor and credibility. By drawing on epistemology, this theoretical paper outlines the case for a renewed approach to knowledge definition, creation and use within social work by reference to pragmatism. Pragmatism has the potential to act as an organizing theoretical framework, taking account of the role of both ontology and epistemology, acting as a functional methodology for the further enhancement of practice-based knowledge

Effect of atorvastatin on asthma control and airway inflammation: a randomised controlled trial

Background Statins are inhibitors of the rate-limiting enzyme, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, in cholesterol biosynthesis. As such, they have been widely used in clinical practice as cholesterol lowering agents to reduce morbidity and mortality from coronary artery disease. There is evidence from clinical studies and in vitro experiments that statins have additional anti-inflammatory properties in atherosclerotic disease, which are unrelated to their lipid lowering activity. Clinical studies have previously suggested that statins might show a beneficial clinical effect in inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Furthermore, preliminary data obtained in models of pulmonary inflammation suggest that the effects manifest in rheumatoid patients can be achieved also in asthma. A proof of concept study was designed to test the hypothesis that atorvastatin improves asthma control and airway inflammation in adults with asthma. Methods Fifty four adults with allergic asthma were recruited to a 22-week crossover randomised controlled trial comparing the effect on asthma control and airway inflammation of oral atorvastatin 40 mg daily with that of a matched placebo. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow. Secondary outcomes included spirometry, asthma control questionnaire (ACQ) score, asthma quality of life questionnaire (AQLQ), provocation concentration to methacholine (PC20) and inflammatory markers: exhaled nitric oxide, sputum differential cell count, sputum supernatant and serum inflammatory markers such as interleukin-6 (IL-6), IL-5, IL-8, sICAM-1, TNF-α, leukotriene B4 (LTB4) and high sensitivity C-reactive protein (hsCRP), and blood lymphocyte proliferation. Results At 8 weeks, the change in mean morning PEF, as compared with baseline, did not differ between the atorvastatin and placebo treatment periods [mean difference -0.5 L/min, 95% CI -10.6 to 9.6, p=0.921]. No statistically significant effect of atorvastatin was seen in evening PEF, or methacholine responsiveness (PC20). Out of all spirometry results, only post-salbutamol FVC showed a statistically significant result, which was slightly lower in the atorvastatin group [treatment difference -0.1L, 95% CI -0.2 to 0.0, p=0.037]. There was also no change in ACQ or AQLQ. No change was seen in exhaled nitric oxide. The total cell counts recovered from sputum were similar after atorvastatin compared to after placebo treatment. After 8 weeks, the mean absolute and relative sputum macrophage count was significantly reduced after atorvastatin compared to placebo [mean absolute difference -44.9x104 cells, 95% CI -80.1 to -9.7, p=0.029]. There was a reciprocal increase in the relative proportion of sputum neutrophils [mean proportion difference 13.1%, 95% CI 1.8 to 24.4, p=0.025], but there were no significant changes in the absolute count of these cells or the counts and proportions of the other sputum cell phenotypes under atorvastatin treatment. The sputum concentrations of inflammatory cytokines and mediators were similar after atorvastatin compared to after placebo treatment other than LTB4 which was significantly reduced [mean difference -88.1 pg/mL, 95% CI -156.4 to -19.9, p=0.014]. No significant difference was seen in the concentration of any serum marker of inflammation between atorvastatin and placebo treatment periods. The change in hsCRP was of borderline significance [mean difference -0.65 mg/L, 95% CI -1.38 to 0.09, p=0.082], but there were no changes in sICAM-1, TNF-α, IL-5, IL-6 and IL-8. There was no significant difference in lymphocyte proliferation. The biochemical effects of atorvastatin therapy were reflected in significant reduction in concentration of serum lipids; cholesterol (mean difference -1.71 mmol/l, 95% CI -1.94 to -1.48 p<0.0001), and HDL-cholesterol (mean difference -0.14 mmol/l, 95% CI -0.26 to -0.02 p=0.026), but not triglycerides. There were significant, albeit modest, increases in mean bilirubin, AST and ALT. There was no difference in compliance, assessed by number of tablets returned and by biochemical results. There was no correlation between changes in LTB4 or IL-8 and sputum macrophage count, sputum neutrophil count, or PEF. The only correlation observed between the variables that were compared was between sputum macrophages and neutrophils. Adverse event rates were similar in patients taking atorvastatin compared with placebo. Equal numbers of patients were lost to follow-up in both arms of the study. One patient died of unrelated causes while taking the placebo medication. Conclusions There were no clinically important improvements in a range of clinical indices of asthma control after eight weeks of treatment with atorvastatin despite expected changes in serum lipids. There were however changes in airway inflammation and in particular, a reduction in the absolute sputum macrophage count after atorvastatin compared to placebo and an associated reduction in sputum LTB4 and a trend towards lower CRP. The lack of any evidence of clinical benefit of atorvastatin in allergic asthma confirms and extends the findings of a smaller randomised placebo controlled crossover trial of simvastatin in 16 subjects with asthma, which showed no change in clinical outcomes or inflammatory markers. It is unlikely that altering duration of treatment, washout period or type of statin used would have changed the outcome of the study. However, as all patients were receiving inhaled corticosteroid as part of their asthma therapy, it is possible that this may have masked any modest anti-inflammatory effects of the statin. Baseline asthma inflammation may also have been too low to show any significant improvement. Despite the postulated anti-inflammatory actions of statins, it seems that they may not be appropriate for the inflammatory phenotype associated with atopic asthma. The reduction in alveolar macrophage count found in patients with allergic asthma may however have relevance to the treatment of chronic lung diseases such as COPD in which alveolar macrophage function has been implicated in the pathogenesis

Expression and modulation of an NADPH oxidase in mammalian astrocytes

Amyloid β peptides generate oxidative stress in hippocampal astrocytes through a mechanism sensitive to inhibitors of the NADPH oxidase [diphenylene iodonium (DPI) and apocynin]. Seeking evidence for the expression and function of the enzyme in primary hippocampal astrocytes, we confirmed the expression of the subunits of the phagocyte NADPH oxidase by Western blot analysis and by immunofluorescence and coexpression with the astrocyte-specific marker glial fibrillary acidic protein both in cultures and in vivo. Functional assays using lucigenin luminescence, dihydroethidine, or dicarboxyfluorescein fluorescence to measure the production of reactive oxygen species (ROS) demonstrated DPI and apocynin-sensitive ROS generation in response to the phorbol ester PMA and to raised [Ca2+]c after application of ionomycin or P2u receptor activation. Stimulation by PMA but not Ca2+ was inhibited by the protein kinase C (PKC) inhibitors staurosporine and hispidin. Responses were absent in transgenic mice lacking gp91phox. Expression of gp91phox and p67phox was increased in reactive astrocytes, which showed increased rates of both resting and stimulated ROS generation. NADPH oxidase activity was modulated by intracellular pH, suppressed by intracellular alkalinization, and enhanced by acidification. The protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone suppressed basal ROS generation but markedly increased PMA-stimulated ROS generation. This was independent of mitochondrial ROS production, because it was unaffected by mitochondrial depolarization with rotenone and oligomycin. Thus, the NADPH oxidase is expressed in astrocytes and is functional, activated by PKC and intracellular calcium, modulated by pHi, and upregulated by astrocyte activation. The astrocytic NADPH oxidase is likely to play important roles in CNS physiology and pathology

Long-distance sound propagation over discontinuous impedances

A calculation method is presented for sound propagation over an impedance discontinuity in flat ground with a homogeneous, still atmosphere. The method is based on an approximate solution to a two dimensional boundary integral equation formulation of the problem, which expresses the wave field as the solution for homogeneous ground plus an integral over half of the boundary. Through recognizing this integral as a generalized Fourier integral, asymptotic methods are applied to evaluate the part of the integral most expensive to compute by numerical quadrature. Single frequency excess attenuation results for propagation from a point source above rigid ground to a receiver above absorbing ground are discussed. The results are applied, with air attenuation and A-weighting, to a notional jet engine noise source. Simple trends are noted

Sound fields near building facades: comparison of finite and semi-infinite reflectors on a rigid ground plane

The sound field in front of, and close to a building facade is relevant to the measurement and prediction of environmental noise and sound insulation. For simplicity it is often assumed that the facade can be treated as a semi-infinite reflector, however in the low-frequency range (50–200 Hz) this is no longer appropriate as the wavelengths are similar or larger than the facade dimensions. Scale model measurements and predictions using integral equation methods have been used to investigate the effect of diffraction on the sound field in front of finite size reflectors. For the situation that is commonly encountered in front of building facades, the results indicate that diffraction effects are only likely to be significant in the low-frequency range (50–200 Hz) when the façade dimensions are less than 5 m. This assumes that there is a point source close to the ground and microphones at a height of 1.2 or 1.5 m, at a distance between 1 and 2 m in front of the façade. © 2008 Elsevier Ltd. All rights reserved

Public Health Education in Medical Schools – The Impact of the COVID-19 Pandemic

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Exploring threshold concepts in population health

Background: Doctors are increasingly expected to improve the health and well-being of populations, as well as to care for individuals. However, despite extensive efforts to integrate population health into undergraduate programmes, engaging students in such learning is notoriously challenging. Threshold concepts are transformative, integrative, irreversible and fundamental to understanding a discipline. Grasping such concepts requires learners to cross a liminal space, which often involves struggle. Methods: We employed a form of transactional curriculum enquiry, involving qualitative and quantitative methods, with experienced population health medical educators to identify and explore threshold and troublesome concepts in population health. Results: Attributing causality, inequalities in health and doctors’ responsibility for populations not just individuals were the concepts most participants thought were threshold. The value of qualitative research, health as politically and socially determined and not taking evidence at face value were the concepts ranked as most troublesome for learners. Participants found the notions of threshold and troublesome concepts helpful and empowering. They described ways these new ideas would influence how they taught population health. Discussion: Transactional curriculum enquiry can offer insights into which population health concepts may be threshold and troublesome. The number of such concepts identified in this study may help explain why students often struggle to engage in population health learning. Understanding which concepts are threshold and particularly which are troublesome can help teachers to better support learners and can also inform curriculum design. If our students are to … take responsibility for populations as well as individuals … it is vital that they cross these fundamental thresholds in learning