Bronchial inflammation in alpha-1-antitrypsin deficiency

Chronic bronchitis was first recognised as a disabling disorder in 1808. It is often a feature of chronic obstructive pulmonary disease, and recent studies have shown that the neutrophil and in particular neutrophil elastase, released by activated neutrophils, is implicated in the pathogenesis of chronic bronchitis including the facilitation of bacterial colonisation. The degree of neutrophil influx has been shown to be associated, not only with worse lung function, but also the rate of progression of airflow obstruction. Many patients with chronic bronchitis are colonised with bacteria in the stable clinical state but it is not known how this affects upper airways inflammation, disease progression, frequency of exacerbations, or quality of life. Secretory leukoprotease inhabitor is thought to be the most critical anti-elastase in the upper airways whereas alpha-1-antitrypsin is thought to be less important, although more important at the alveolar level protecting against the development of emphysema. Patients with homozygous PiZ alpha-1-antitrypsin deficiency have decreased circulating (15-20% normal) and alveolar concentrations of alpha-1-antitrypsin which facilitate the development of early onset and rapidly progressive emphysema. About 30-40 % of these patients also have chronic bronchitis although the nature of the upper airways inflammation has not been studied. There have been few studies assessing the complex interplay of inflammatory cells and appropriate mediators in patients with chronic bronchitis. The first study in this thesis investigated patients with chronic bronchitis and a wide spectrum of neutrophil influx to assess the relationships between: neutrophil influx (as reflected by sputum myeloperoxidase concentration) and the chemoattractants interleukin 8 and leulcotriene B4; active neutrophil elastase and the chemoattractants (interleukin 8 and leukotriene B4), its own inhabitor secretory leukoprotease inhibitor, and bronchial protein leak (leakage of albumin from serum into the airways); and finally FEV1 (% predicted) and myeloperoxidase, interleukin 8 and leukotriene B4, secretory leukoprotease inhibitor, and bronchial protein leak. The results showed that both interleukin 8 and leukotriene B4 correlate with the degree of neutrophil influx and elastase activity, although the relationship with interleukin 8 and neutrophil influx appeared to be curvilinear. Elastase activity that exceeded 50nM was associated with decreased levels of secretory leukoprotease inhabitor and increased levels of bronchial protein leak. Patients with chronic bronchitis without alpha-1- antitrypsin deficiency showed a negative correlation between FEV1 (% predicted) and myeloperoxidase, interlexikin 8 and leukotriene B4, and bronchial protein leak. Although the interrelationships were often significant, they were complex, and further understanding the interaction of various mediators will require the development of specific antagonists and appropriately designed intervention studies. The second study investigated the effect of bacterial colonisation, bacterial load, and bacteria themselves on upper airways inflammation in patients with chronic bronchitis. The third study assessed upper airways inflammation in patients with chronic bronchitis with and without PiZ alpha-1-antitrypsin deficiency in the stable clinical state, to determine the importance of alpha-1-antitrypsin in the upper airways and the effects of continued smoking. The final study assessed upper airways inflammation in patients with and without alpha-1-antitrypsin deficiency during an acute exacerbation. This study revealed that there was excessive upper airways inflammation in patients with alpha-1-antitrypsin deficiency which was probably due to the low baseline alpha-1-antitrypsin levels and the reduced acute phase respons

Effect of expectoration on inflammation in induced sputum in α-1-antitrypsin deficiency

SummaryIt is unclear how chronic expectoration influences airway inflammation in patients with chronic lung disease. The aim of this study was to investigate factors influencing inflammation in induced sputum samples, including, in particular, chronic sputum production. Myeloperoxidase, interleukin-8, leukotriene B4 (LTB4), neutrophil elastase, secretory leukoprotease inhibitor (SLPI) and protein leakage were compared in induced sputum samples from 48 patients (36 with chronic expectoration) with COPD (with and without alpha-1-antitrypsin deficiency; AATD), 9 individuals with AATD but without lung disease and 14 healthy controls. There were no differences in inflammation in induced sputum samples from healthy control subjects and from AATD deficient patients with normal lung function but without chronic expectoration (P>0.05). Inflammation in induced sputum from AATD patients with airflow obstruction and chronic sputum expectoration was significantly greater than for similar patients who did not expectorate: Interleukin-8 (P<0.01), elastase activity (P=0.01), and protein leakage (P<0.01). The presence of spontaneous sputum expectoration in AATD patients with airflow obstruction was associated with increased neutrophilic airway inflammation in induced sputum samples. The presence of chronic expectoration in some patients will clearly complicate interpretation of studies employing sputum induction where this feature has not been identified

Natural Theories of Ultra-Low Mass PNGB's: Axions and Quintessence

We consider the Wilson Line PNGB which arises in a U(1)^N gauge theory, abstracted from a latticized, periodically compactified extra dimension U(1). Planck scale breaking of the PNGB's global symmetry is suppressed, providing natural candidates for the axion and quintessence. We construct an explicit model in which the axion may be viewed as the 5th component of the U(1)_Y gauge field in a 1+4 latticized periodically compactified extra dimension. We also construct a quintessence PNGB model where the ultra-low mass arises from Planck-scale suppressed physics itself.Comment: 20 pages, fixed typo and reference

Risk factors for <i>Clostridium difficile</i> infection in hospitalized patients with community-acquired pneumonia

Objectives: Clostridium difficile infection (CDI) is strongly associated with anti-biotic treatment, and community-acquired pneumonia (CAP) is the leading indication for anti-biotic prescription in hospitals. This study assessed the incidence of and risk factors for CDI in a cohort of patients hospitalized with CAP. Methods: We analysed data from a prospective, observational cohort of patients with CAP in Edinburgh, UK. Patients with diarrhoea were systematically screened for CDI, and risk factors were determined through time-dependent survival analysis. Results: Overall, 1883 patients with CAP were included, 365 developed diarrhoea and 61 had laboratory-confirmed CDI. The risk factors for CDI were: age (hazard ratio [HR], 1.06 per year; 95% confidence interval [CI], 1.03-1.08), total number of antibiotic classes received (HR, 3.01 per class; 95% CI, 2.32-3.91), duration of antibiotic therapy (HR, 1.09 per day; 95% CI, 1.00-1.19 and hospitalization status (HR, 13.1; 95% CI, 6.0-28.7). Antibiotic class was not an independent predictor of CDI when adjusted for these risk factors (P &gt; 0.05 by interaction testing).Conclusions: These data suggest that reducing the overall antibiotic burden, duration of antibiotic treatment and duration of hospital stay may reduce the incidence of CDI in patients with CAP.</p

Minimal length scales for the existence of local temperature

We review a recent approach to determine the minimal spatial length scales on which local temperature exists. After mentioning an experiment where such considerations are of relevance, we first discuss the precise definition of the existence of local temperature and its physical relevance. The approach to calculate the length scales in question considers homogenous chains of particles with nearest neighbor interactions. The entire chain is assumed to be in a thermal equilibrium state and it is analyzed when such an equilibrium state at the same time exists for a local part of it. The result yields estimates for real materials, the liability of which is discussed in the sequel. We finally consider a possibility to detect the existence or non-existence of a local thermal state in experiment.Comment: review, 13 pages, 11 figure

MicroRNA-122 and cytokeratin-18 have potential as a biomarkers of drug-induced liver injury in European and African patients on treatment for mycobacterial infection

Funding: Sarah Rupprechter was funded by the UK Medical Research Council via the Doctoral Training Programme Grant in Precision Medicine at the University of Edinburgh.Aims Patients on antituberculosis (anti‐TB) therapy are at risk of drug‐induced liver injury (DILI). MicroRNA‐122 (miR‐122) and cytokeratin‐18 (K18) are DILI biomarkers. To explore their utility in this global context, circulating miR‐122 and K18 were measured in UK and Ugandan populations on anti‐TB therapy for mycobacterial infection. Methods Healthy subjects and patients receiving anti‐TB therapy were recruited at the Royal Infirmary of Edinburgh, UK (ALISTER—ClinicalTrials.gov Identifier: NCT03211208). African patients with human immunodeficiency virus–TB coinfection were recruited at the Infectious Diseases Institute, Kampala, Uganda (SAEFRIF—NCT03982277). Serial blood samples, demographic and clinical data were collected. In ALISTER samples, MiR‐122 was quantified using polymerase chain reaction. In ALISTER and SAEFRIF samples, K18 was quantified by enzyme‐linked immunosorbent assay. Results The study had 235 participants (healthy volunteers [n = 28]; ALISTER: active TB [n = 30], latent TB [n = 88], nontuberculous mycobacterial infection [n = 25]; SAEFRIF: human immunodeficiency virus‐TB coinfection [n = 64]). In the absence of DILI, there was no difference in miR‐122 and K18 across the groups. Both miR‐122 and K18 correlated with alanine transaminase (ALT) activity (miR‐122: R = .52, 95%CI = 0.42–0.61, P 50 U/L with higher sensitivity/specificity than K18. There were 2 DILI cases: baseline ALT, 18 and 28 IU/L, peak ALT 431 and 194 IU/L; baseline K18, 58 and 219 U/L, peak K18 1247 and 3490 U/L; baseline miR‐122 4 and 17 fM, peak miR‐122 60 and 336 fM, respectively. Conclusion In patients treated with anti‐TB therapy, miR‐122 and K18 correlated with ALT and increased with DILI. Further work should determine their diagnostic and prognostic utility in this global context‐of‐use.Publisher PDFPeer reviewe