ABSTRACT
Background and objective
Influenza A viruses (IAV) cause respiratory tract infections that can be fatal when the virus spreads to the alveolar space (i.e. alveolitis), and this is mainly ...observed with highly pathogenic strains. Reactive oxygen species (ROS) production by the NOX2 NADPH oxidase in endosomes has been directly implicated in IAV pathology. Recently, we demonstrated that treatment with a novel endosome‐targeted NOX2 oxidase inhibitor, cholestanol‐conjugated gp91dsTAT (Cgp91ds‐TAT), attenuated airway inflammation and viral replication to infection with a low pathogenic influenza A viral strain. Here, we determined whether suppression of endosome NOX2 oxidase prevents the lung inflammation following infection with a highly pathogenic IAV strain.
Methods
C57Bl/6 mice were intranasally treated with either DMSO vehicle (2%) or Cgp91ds‐TAT (0.2 mg/kg/day) 1 day prior to infection with the high pathogenicity PR8 IAV strain (500 PFU/mouse). At Day 3 post‐infection, mice were culled for the evaluation of airway and lung inflammation, viral titres and ROS generation.
Results
PR8 infection resulted in a marked degree of airway inflammation, epithelial denudation, alveolitis and inflammatory cell ROS production. Cgp91ds‐TAT treatment significantly attenuated airway inflammation, including neutrophil influx, the degree of alveolitis and inflammatory cell ROS generation. Importantly, the anti‐inflammatory phenotype affected by Cgp91ds‐TAT significantly enhanced the clearance of lung viral mRNA following PR8 infection.
Conclusion
Endosomal NOX2 oxidase promotes pathogenic lung inflammation to IAV infection. The localized delivery of endosomal NOX2 oxidase inhibitors is a novel therapeutic strategy against IAV, which has the potential to limit the pathogenesis caused during epidemics and pandemics.
Lung inflammation to influenza A virus (IAV) infection can be fatal when the virus spreads to the alveolar space. We demonstrated that pathogenic inflammation to IAV is promoted by endosomally located NOX2 oxidase and that targeted inhibition of the reactive oxygen species (ROS) generated by this enzyme suppressed this inflammation and improved viral clearance.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Reactive oxygen species (ROS) promote growth factor signalling including for VEGF-A and have potent angiogenic and tumourigenic properties. However, the precise enzymatic source of ROS generation, ...the subcellular localization of ROS production and cellular targets
that influence tumour-promoting processes, are largely undefined. Here, using mRNA microarrays, we show increased gene expression for NOX2, the catalytic subunit of the ROS-generating NADPH oxidase enzyme, in human primary prostate cancer compared to non-malignant tissue. In addition, NOX4 gene expression was markedly elevated in human metastatic prostate cancers, but not in primary prostate tumours. Using a syngeneic, orthotopic mouse model of prostate cancer the genetic deletion of NOX2 (i.e. NOX2
mouse) resulted in reduced angiogenesis and an almost complete failure in tumour development. Furthermore, pharmacological inhibition of NOX2 oxidase suppressed established prostate tumours in mice. In isolated endothelial cells, and in human normal and prostate cancer cells, NOX2 co-located to varying degrees with early endosome markers including EEA1, Appl1 and Rab5A and the late endosome marker Rab7A, and this correlated with significant VEGF-A-dependent ROS production within acidified endosomal compartments and endothelial cell proliferation that was NOX2 oxidase- and hydrogen peroxide dependent. We concluded that NOX2 oxidase expression and endosomal ROS production were important for prostate cancer growth and that this was required to positively regulate the VEGF pathway. The research provides a paradigm for limiting tumour growth through a better understanding of NOX2 oxidase's effect on VEGF signalling and how controlling the development of tumour vasculature can limit prostate tumour development and metastasis.
A three-year-old Holstein-Friesian cow presented at University College Dublin Veterinary Hospital with clinical signs of chronic weight loss, abnormal stance, slight arching of the back and increased ...left cranioventral lung sounds. Traumatic reticulitis, following the ingestion of a foreign body, was suspected. Radiographs showed the presence of a wire that had perforated the diaphragm and penetrated cranially into the thorax. Ultrasonographic findings included hyperechogenic areas mainly cranioventrally on the left side of the thorax as well as changes indicative of lung consolidation. A standing left thoracotomy to remove the wire was successfully performed under standing sedation and regional anaesthesia. This involved the removal of a portion of the sixth rib to facilitate surgical access. A drainage tube was placed in order to manage the subsequent temporary unilateral pneumothorax. The cow recovered very well postsurgery, went back to the farm and calved four months later.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Hashimoto Thyroiditis (H.T.) is a destructive autoimmune thyroid condition whose precise molecular pathogenesis remains unclear. ret/PTC-1 is a chimeric transcript which has been described in ...autoimmune thyroid disease (AITD) and thyroid neoplasia. The purpose of this study was to observe the immunogenic effect exposure to H.T. and control lymphocyte supernatant would have on normal (Nthy-ori) and ret/PTC-1 (TPC-1) expressing thyroid cell line models.
A 2 x 2 matrix comprising Nthy-ori and TPC-1 cell lines and H.T. and control lymphocyte supernatant was designed and utilised as follows; activated lymphocytic supernatant from a H.T. and normal control were co-cultured with a cell line derived from normal thyroid (Nthy-ori) and also a cell line derived from a papillary thyroid carcinoma that endogenously expresses ret/PTC-1 (TPC-1). The co-cultures were harvested at 0, 6 and 18 hour time points. Gene expression analysis was performed on RNA extracted from thyrocytes using TaqMan Immune profiling Low-Density Arrays (Applied Biosystems, CA, USA) comprising gene expression markers for 93 immune related targets plus 3 endogenous controls. Stimulation of the normal thyroid cell line model with activated T cell supernatant from the H.T. donor yielded global up-regulation of immune targets when compared with control supernatant stimulation. In particular, a cohort of targets (granzyme B, CD3, CD25, CD152, CD45) associated with cytotoxic cell death; T cell receptor (TCR) and T cell signaling were up-regulated in the normal cell line model. When the ret/PTC-1 expressing thyroid cell line was co-cultured with H.T. lymphocyte supernatant, in comparison to control supernatant stimulation, down-regulation of the same subset of immune targets was seen.
Co-culturing H.T. lymphocyte supernatant with a normal thyroid cell line model leads to over-expression of a subset of targets which could contribute to the pathogenesis of H.T. via cytotoxic cell death and TCR signalling. Stimulation of the ret/PTC-1 positive cell line with the same stimulus led to a down-regulated shift in the gene expression pattern of the cohort of immune targets. We hypothesize that ret/PTC-1 activation may dampen immunogenic responses in the thyroid, which could possibly facilitate papillary thyroid carcinoma development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives:
To examine agreement between patients, caregivers, and clinicians regarding prognosis communication and to examine patients' and caregivers' desire for prognostic information.
Design: ...Cross‐sectional survey.
Setting: Participants' homes.
Participants: Two hundred fourteen persons aged 60 and older with a limited life expectancy secondary to cancer, congestive heart failure, or chronic obstructive pulmonary disease; caregivers; and clinicians.
Measurements: Patient–clinician and caregiver–clinician agreement about the occurrence of prognosis discussions and patient and caregiver desire for prognostic information.
Results: In 46% of patient/clinician and 34% of caregiver/clinician pairs, the clinician reported saying that the patient could die of the underlying disease, whereas the patient or caregiver reported no discussion. In 23% of patient/clinician and 30% of patient/caregiver pairs, the clinician reported discussing an approximate life expectancy, whereas the patient or caregiver reported no discussion. Of 205 patients who reported no life expectancy discussion, 40% did not want this discussion. Whereas 83% of those believing they had 1 year or less to live wanted to discuss prognosis, 79% of those believing they had 1 to 2 years, 53% of those believing they had 2 to 5 years, and 50% of those believing they had more than 5 years or who were unwilling to answer wanted this discussion (P=.007).
Conclusion: Although clinicians report that they are discussing prognosis, patients and caregivers frequently do not corroborate these reports. Furthermore, many patients do not want prognostic information. Despite previous reports concluding that patients want full disclosure about their illness, many seriously ill older persons and caregivers may not be ready or able to receive prognostic information.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this paper we present data from three research studies on stress, coping and burnout in mental health nurses. All three studies used a range of self report questionnaires. Measures included a ...demographic checklist, the General Health Questionnaire (GHQ-28), the Maslach Burnout Inventory, the DCL Stress Scale and the Cooper Coping Skills Scale. In all, 648 ward based mental health nurses were surveyed. There were no significant differences between levels of psychological distress on GHQ Total Score, but there were differences in caseness rates. In Study 3, some 38% of nurses were found to score at or above the criterion for caseness. The main stressors for ward staff were to do with staff shortages, health service changes, poor morale and not being notified of changes before they occurred. Differences in coping skills were found across studies. The study group with the highest stress scores also had the lowest coping skills scores. This was also associated with significantly higher alcohol consumption and greater self reported sickness absence. Scores on the Maslach Burnout Inventory showed higher levels of burnout amongst nurses in Study 3. These three studies have confirmed that stress is a problem for ward based mental health nurses. Two main implications arise from this work. Firstly we need models of the stress process that are empirically based, and which help us identify the moderating variables that reduce the impact of stressors on nurses. Secondly, we need to utilise this knowledge to deliver stress management interventions for staff. We end by outlining a model which may help us both understand the process of stress causation, and move towards our goal of stress reduction.
Molecular profiling of cervical neoplasia Martin, Cara M; Astbury, Katharine; O Leary, John J
Expert review of molecular diagnostics,
03/2006, Volume:
6, Issue:
2
Journal Article
Peer reviewed
Cervical cancer, a potentially preventable disease, remains the second most common malignancy in women worldwide. Human papillomavirus is the single most important etiological agent in cervical ...cancer, contributing to neoplastic progression through the action of viral oncoproteins, mainly E6 and E7, which interfere with critical cell cycle pathways, p53 and retinoblastoma. However, evidence suggests that human papillomavirus infection alone is insufficient to induce malignant changes and that other host genetic variations are important in the development of cervical cancer. This article will discuss the latest molecular profiling techniques available and review the published literature relating to their role in the diagnosis and management of cervical dysplasia and cancer. It is hoped that these techniques will allow the detection of novel biomarkers at DNA, RNA, microRNA and protein levels, which may ultimately play a role in facilitating early disease diagnosis and in predicting response to therapies, thus allowing the development of personalized treatment strategies.
Community policing is proving effective at involving communities in law enforcement, beginning with the cop on the beat. Community policing's success in San Diego, New York City's subway and other ...cities is examined.
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CEKLJ, DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The need to address our question arises from two sources, one in Kant and the other in a certain type of response to so-called Reformed epistemology. The first source consists in a tendency to ...distinguish theoretical beliefs from practical beliefs (commitments to the world's being a certain way versus commitments to certain pictures to live by), and to treat theistic belief as mere practical belief. We trace this tendency in Kant's corpus, and compare and contrast it with Aquinas's view and a more conservative Kantian view. We reject the theistic-belief-as-mere-practical-belief view: it is bad descriptive anthropology, it embraces a misguided ideal of a fragmented self unattainable by human beings, and it will deter people from the most desirable sort of faith. The second source consists in the idea that since theistic beliefs function as answers to why-questions, their epistemic status hangs on whether they meet certain distinctively explanatory standards, whatever support they might receive from other sources. We argue that this is a non-sequitur and suggest questions for further research.
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BFBNIB, INZLJ, NMLJ, NUK, PNG, UL, UM, UPUK, ZRSKP
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