52 research outputs found
New Research on the Importance of Cystic Fibrosis Transmembrane Conductance Regulator Function for Optimal Neutrophil Activity
Despite tremendous recent advances in our understanding of the molecular and cellular basis of cystic fibrosis (CF), there remains a paradox of why recruited neutrophils fail to eradicate bacterial infections in the airways of individuals with CF. The focus of this chapter is on new research authenticating the CF neutrophil as a key player in disease pathogenesis. Studies specifying intrinsic abnormalities due to a lack of cystic fibrosis transmembrane conductance regulator (CFTR) function, along with reports indicating reprogrammed cell activity secondary to chronic bacterial infection and inflammation, will be discussed
State-of-the-art drug detection in sport
The use and abuse of performance enhancing drugs (doping) is rife in professional sport. The detection of doping is an extremely important task because it ensures athletes’ safety. It also maintains standards of acceptable training practices, whatever they are determined to be. In 2007, successes and key challenges in doping detection involved anabolic steroids and peptide hormones. Genetic doping is expected in the not too distant future, and will present new difficulties for current detection practices </p
The differences in attitudes and beliefs among smokers and ex-smokers regarding the benefits of smoking cessation in Ireland
Introduction: Smoking-related diseases account for almost 5,500 deaths per year in Ireland and cost the Irish economy €1-2 billion per year. Some 50% of all smokers will die of a smoking-related disease, and smokers on average die 10 years younger than non-smokers. The aim of this project was to assess attitudes and beliefs regarding smoking cessation in both smokers and ex-smokers.
Methods: The study took place in Beaumont Hospital, Dublin. Patients who were smokers or ex-smokers were identified from the inpatient wards and respiratory outpatient department (OPD), and interviewed using a standardised questionnaire. Data regarding underlying medical history was acquired from medical records.
Results: A total of 104 patients were included, comprising 50 smokers and 54 ex-smokers. There were no differences in gender or medical history. Ex-smokers were slightly older, with a mean age of 66.5 years compared to 56.9 years in smokers (p=0.0017). Current smokers had a longer smoking history; 39.14 years compared to 32.9 years in ex-smokers (p=0.047). Smokers reported lower expectations regarding the benefits of smoking cessation than the ex-smokers; only 60% believed that there would be a short-term health benefit and only 74% believed that quitting was worthwhile compared to 88.9% and 94.4%, respectively, in the ex-smoking group (p=0.0025/p=0.01).
Conclusion: There is significant variation among smokers and ex-smokers regarding attitudes to smoking cessation; this is despite receiving the same smoking cessation advice and having low Fagerstrom scores.</p
Alpha-1 antitrypsin deficiency: current therapy and emerging targets
Introduction: Alpha1 antitrypsin deficiency (AATD), a common hereditary disorder affecting mainly lungs, liver and skin has been the focus of some of the most exciting therapeutic approaches in medicine in the past 5 years. In this review, we discuss the therapies presently available for the different manifestations of AATD and new therapies in the pipeline.
Areas covered: We review therapeutic options for the individual lung, liver and skin manifestations of AATD along with approaches which aim to treat all three. Along with this renewed interest in treating AATD come challenges. How is AAT best delivered to the lung? What is the desired level of AAT in the circulation and lungs which therapeutics should aim to provide? Will treating the liver disease increase the potential for lung disease? Are there treatments to target the underlying genetic defect with the potential to prevent all aspects of AATDrelated disease?
Expert opinion: With a relatively small population able to participate in clinical studies, increased awareness and diagnosis of AATD is urgently needed. Better, more sensitive clinical parameters will assist in the generation of acceptable and robust evidence of therapeutic effect for current and emerging treatments.</p
Reply to Blot et al. and to Inoue et al.
We thank Blot and colleagues for their interest in our article and for raising an important question regarding the suitability of IL-6 as a therapeutic target in coronavirus disease (COVID-19).In their correspondence, Blot and colleagues provide data on IL-6 levels measured in patients with a diagnosis of COVID-19 versus non–COVID-19 pneumonia. Although we believe the data presented by Blot and colleagues are valid, we suggest that the IL-6 levels depicted are, by virtue of sample timing, processing methodology, and patient severity of disease, not comparable to ours and should be interpreted in context.</p
Measurement of the unfolded protein response (UPR) in monocytes.
In mammalian cells, the primary function of the endoplasmic reticulum (ER) is to synthesize and assemble membrane and secreted proteins. As the main site of protein folding and posttranslational modification in the cell, the ER operates a highly conserved quality control system to ensure only correctly assembled proteins exit the ER and misfolded and unfolded proteins are retained for disposal. Any disruption in the equilibrium of the ER engages a multifaceted intracellular signaling pathway termed the unfolded protein response (UPR) to restore normal conditions in the cell. A variety of pathological conditions can induce activation of the UPR, including neurodegenerative disorders such as Parkinson's disease, metabolic disorders such as atherosclerosis, and conformational disorders such as cystic fibrosis. Conformational disorders are characterized by mutations that modify the final structure of a protein and any cells that express abnormal protein risk functional impairment. The monocyte is an important and long-lived immune cell and acts as a key immunological orchestrator, dictating the intensity and duration of the host immune response. Monocytes expressing misfolded or unfolded protein may exhibit UPR activation and this can compromise the host immune system. Here, we describe in detail methods and protocols for the examination of UPR activation in peripheral blood monocytes. This guide should provide new investigators to the field with a broad understanding of the tools required to investigate the UPR in the monocyte.</p
SZ alpha-1 antitrypsin deficiency and pulmonary disease: more like MZ, not like ZZ
The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is associated with COPD regardless of smoking. Heterozygous MZ-AATD is recognised as a moderate deficiency state, increasing the risk of COPD only among smokers. The risk attributable to SZ-AATD remains debated. We compared 486 AATD-registry participants, to determine whether SZ-AATD was associated with pulmonary outcomes more comparable to MZ-AATD or ZZ-AATD. We found no significant differences between MZ and SZ individuals regardless of never-smoking/ever-smoking (p>0.05 for all). ZZ-AATD was associated with lower FEV1pp than SZ, regardless of never-smoking/ever-smoking, as well as an increased OR of lung-index status and visually defined emphysema on CT (p≤0.002 for all). In our registry cohort SZ-AATD is associated with a risk of lung disease comparable to MZ, not ZZ-AATD. </p
Toll-like receptors as therapeutic targets in cystic fibrosis.
Background: Toll-like receptors (TLRs) are pattern recognition receptors that act as a first-line of defence in the innate immune response by recognising and responding to conserved molecular patterns in microbial factors and endogenous danger signals. Cystic fibrosis (CF)-affected airways represent a milieu potentially rich in TLR agonists and the chronic inflammatory phenotype evident in CF airway epithelial cells is probably due in large part to activation of TLRs. Objective/methods: To examine the prospects of developing novel therapies for CF by targeting TLRs. We outline the expression and function of TLRs and explore the therapeutic potential of naturally-occurring and synthetic TLR inhibitors for CF. Results/conclusion: Modulation of TLRs has therapeutic potential for the inflammatory lung manifestations of CF
Pitfalls and caveats in α1-antitrypsin deficiency testing: a guide for clinicians
α1-antitrypsin deficiency (AATD) remains the only readily identified genetic cause of chronic obstructive pulmonary disease (COPD). Furthermore, there is growing evidence that even a moderate deficiency increases the risk of lung disease among smokers. Despite these facts, the uptake of testing for AATD in at-risk populations remains low for many reasons, and a lack of clarity among clinicians regarding the most appropriate diagnostic techniques presents a major deterrent. This Personal View addresses the benefits of diagnosis, the technical basis of the available diagnostic methods, and possible clinical confounders for each test. We include a series of unusual cases encountered at our National Centre of Expertise to provide context. The topics covered should equip clinicians with the core knowledge required to confidently assess patients for AATD
TLR3 Sensing of Viral Infection
Viral infection is detected by the innate immune system which mounts a rapid semi-selective defence involving inflammation and production of type 1 interferons. Several sensors, both cell surface and intracellular, exist to detect different types of viral motifs. Double-stranded RNA viruses and dsRNA replication intermediates are detected by tolllike receptor 3 (TLR3) as well as by retinoid-inducible gene 1 (RIG-I) like receptors. Binding of dsRNA or its synthetic analogue poly I:C to TLR3 recruits the adaptor protein TRIF and stimulates distinct pathways leading to activation of interferon regulatory factor (IRF) and NF-KB. Here, we review the signalling cascades initiated by TLR3 and the modulation of these pathways.</p
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