103,987 research outputs found
A new look at the pathogenesis of asthma
No full textAsthma is an inflammatory disorder of the conducting airways that has strong association with allergic sensitization. The disease is characterized by a polarized Th-2 (T-helper-2)-type T-cell response, but in general targeting this component of the disease with selective therapies has been disappointing and most therapy still relies on bronchodilators and corticosteroids rather than treating underlying disease mechanisms. With the disappointing outcomes of targeting individual Th-2 cytokines or manipulating T-cells, the time has come to re-evaluate the direction of research in this disease. A case is made that asthma has its origins in the airways themselves involving defective structural and functional behaviour of the epithelium in relation to environmental insults. Specifically, a defect in barrier function and an impaired innate immune response to viral infection may provide the substrate upon which allergic sensitization takes place. Once sensitized, the repeated allergen exposure will lead to disease persistence. These mechanisms could also be used to explain airway wall remodelling and the susceptibility of the asthmatic lung to exacerbations provoked by respiratory viruses, air pollution episodes and exposure to biologically active allergens. Variable activation of this epithelial-mesenchymal trophic unit could also lead to the emergence of different asthma phenotypes and a more targeted approach to the treatment of these. It also raises the possibility of developing treatments that increase the lung's resistance to the inhaled environment rather than concentrating all efforts on trying to suppress inflammation once it has become established.<br/
The processing of antigens delivered as DNA vaccines
No full textThe ability of DNA vaccines to provide effective immunological protection against infection and tumors depends on their ability to generate good CD4+ and CD8+ T-cell responses. Priming of these responses is a property of dendritic cells (DCs), and so the efficacy of DNA-encoded vaccines is likely to depend on the way in which the antigens they encode are processed by DCs. This processing could either be via the synthesis of the vaccine-encoded antigen by the DCs themselves or via its uptake by DCs following its synthesis in bystander cells that are unable to prime T cells. These different sources of antigen are likely to engage different antigen-processing pathways, which are the subject of this review. Understanding how to access different processing pathways in DCs may ultimately aid the rational development of plasmid-based vaccines to pathogens and to cancer
δ Orionis: Further temporal variability and evidence for small-scale structure in the interstellar medium
No full textWe report here the detection of both spatial and temporal variations in interstellar absorption in the line of sight to δ Orionis. First, we present new high-resolution (R≈110 000) observations of the interstellar D lines of Na i towards both δ Ori A and C. Comparison of these spectra highlights variations in absorption between the two stars, indicative of small-scale spatial structure in the interstellar medium in this direction over distances of less than ≈15 000 au (the projected separation of the two stars). Components with the largest Na i column densities and lowest velocity dispersions are, in general, found to be subject to the greatest differences; in fact the narrowest component detected is only observed in one of the sightlines. This effect has also been reported by Meyer & Blades. Secondly, we present new ultra-high-resolution (R≈900 000) Na i D1 observations and high-resolution (R≈110 000) Ca ii H & K observations of δ Ori A which, through ultra-high-resolution work conducted between 1994 and 2000, has been shown to exhibit a time-variable interstellar Na i absorption component. These new observations, while revealing the further reduction in intensity of the time-variable Na i absorption, indicate constant Ca ii absorption over the same period. This results in a dramatic reduction in the Na°/Ca+ abundance ratio, perhaps indicating the line of sight to be gradually probing a less-dense outer region of an absorbing filament
Priobiotics and prebiotics in inflammatory bowel disease
No full textL. Prisciandaro, G.S. Howarth and M.S. Geierhttp://trove.nla.gov.au/work/3181956
A peptide filtering relation quantifies MHC class I peptide optimization
No full textMajor Histocompatibility Complex (MHC) class I molecules enable cytotoxic T lymphocytes to destroy virus-infected or cancerous cells, thereby preventing disease progression. MHC class I molecules provide a snapshot of the contents of a cell by binding to protein fragments arising from intracellular protein turnover and presenting these fragments at the cell surface. Competing fragments (peptides) are selected for cell-surface presentation on the basis of their ability to form a stable complex with MHC class I, by a process known as peptide optimization. A better understanding of the optimization process is important for our understanding of immunodominance, the predominance of some T lymphocyte specificities over others, which can determine the efficacy of an immune response, the danger of immune evasion, and the success of vaccination strategies. In this paper we present a dynamical systems model of peptide optimization by MHC class I. We incorporate the chaperone molecule tapasin, which has been shown to enhance peptide optimization to different extents for different MHC class I alleles. Using a combination of published and novel experimental data to parameterize the model, we arrive at a relation of peptide filtering, which quantifies peptide optimization as a function of peptide supply and peptide unbinding rates. From this relation, we find that tapasin enhances peptide unbinding to improve peptide optimization without significantly delaying the transit of MHC to the cell surface, and differences in peptide optimization across MHC class I alleles can be explained by allele-specific differences in peptide binding. Importantly, our filtering relation may be used to dynamically predict the cell surface abundance of any number of competing peptides by MHC class I alleles, providing a quantitative basis to investigate viral infection or disease at the cellular level. We exemplify this by simulating optimization of the distribution of peptides derived from Human Immunodeficiency Virus Gag-Pol polyprotein
Persistent airway T-lymphocyte activation in chronic corticosteroid-treated symptomatic asthma
No full textBackground: A small proportion of patients with asthma have persistent symptoms despite regular treatment with high-dose inhaled and/or oral corticosteroids. There is little information regarding immunopathology in such patients.Objective: To compare airway inflammatory changes in subjects with chronic corticosteroid-dependent symptomatic asthma (n = 5) and subjects with asthma that was clinically well controlled on inhaled corticosteroid therapy (n = 9). Subjects in the corticosteroid-dependent group were receiving long-term treatment with oral prednisolone and high-dose inhaled corticosteroids.Methods: Subjects underwent fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and bronchial biopsy. T-lymphocytes subsets and activation markers in BAL fluid and peripheral blood were determined by FACS analysis. Bronchial biopsies were stained immunohistochemically, and numbers of inflammatory cells quantitated. Inflammatory mediators in BAL fluid were measured by immunoassay.Results: There was significantly greater expression of CD25 (P = .02) and HLA-DR (P = .04) by BAL fluid T-lymphocytes in corticosteroid-treated symptomatic asthmatics. In bronchial biopsies there were no significant differences between the two groups in the numbers of AA1+ cells (mast cells), EG2+ cells (eosinophils) or MT1+ T-lymphocytes. Levels of albumin, histamine, tryptase, and eosinophil cationic protein in BAL fluid did not differ significantly between groups.Conclusions: Chronic corticosteroid-treated symptomatic asthma is associated with persistent airway T-lymphocyte activation. This, however, is not necessarily accompanied by the recruitment and activation of inflammatory cells within the airways
Letter, [Author unclear] to Paulina T. Merritt
No full textHandwritten letter to Paulina Merritt from an unknown author, October 1, 1876.
Human response to simulated intermittent railway-induced building vibration
No full textThis paper reports two whole-body vibration experiments. The first experiment was conducted to determine the manner in which annoyance caused by railway-induced building vibration depends on how frequently trains pass. It also investigated how annoyance depends on the magnitude of the vibration. The second experiment was conducted to confirm that the relation between the number of passing trains and the magnitude of vibration could be used to predict conditions which will cause similar annoyance. Forty-eight seated subjects experienced simulations of vertical vibration recorded in a house during the passage of a nearby train and assessed the stimuli on a seven-point scale. Annoyance increased with an increase in the number of passing trains and with increasing magnitude of vibration. The findings of the first study were employed to determine a trade-off between the number of passing trains. N, and the magnitude of the vibration, V. The relation was determined as approximately N ∝ V-4 for equal annoyance. This was confirmed by the results of the second experiment in which r.m.s. evaluation of the vibration (i.e., N ∝ V-2) was found to be less satisfactory. The relation (V4N = constant) for equal annoyance is consistent with the use of the vibration dose value (∫t=0
t=T a4(t) dt) 1 4 proposed for vibration assessment.</p
Subjective reaction to vertical mechanical shocks of various waveforms
No full textTwo laboratory studies have been conducted to assess the discomfort caused to seated male subjects by exposures to vertical whole-body mechanical shocks. The first experiment was designed to obtain judgements of the discomfort of single "up" or "down" damped sinusoidal impulses. Sixteen subjects used the method of magnitude estimation to indicate the discomfort produced by damped sine waves at nominal frequencies of 1, 4 and 16 Hz, with damping ratios of 0·125, 0·250 and 0·707 and vibration dose values ranging from 0·6 to 4·0 m s-1·75. Analysis was also conducted to determine whether the growth of discomfort with increasing magnitude was influenced by frequency, duration or direction of motion. The results suggested that a single frequency weighting and a single duration weighting is appropriate at all magnitudes. Analysis was also conducted to determine whether the discomfort depends on the frequency, duration and direction of shocks when they are presented at a constant vibration dose value using frequency weighting Wb. There was no difference between the discomfort caused by "up" and "down" shocks of the same vibration dose value, but the Wb frequency weighting slightly underestimated sensitivity to low-frequency shocks. The second experiment sought to compare two methods of evaluating stimuli containing between one and 16 repeated shocks. The vibration dose value [∫o T a4(t) dt] 1 4 and a measure of dose related to "energy", [∫o T a2(t) dt] 1 2, were employed to predict the reduction in shock magnitude required to counteract any increased discomfort with a greater number of shocks. Subjects employed the method of paired comparison. Judgements of the relative discomfort of the stimuli presented in pairs indicated that the vibration dose value provided the more accurate method of evaluating the discomfort of the shocks.</p
Comparative study of the T-lymphocite subsets in the nasal mucosa of perennial and seasonal rhinitics
No full textComparative study of the T-lymphocite subsets in the nasal mucosa of perennial and seasonal rhinitic
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