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71.
72.
Regner M Culley F Fontannaz P Hu K Morein B Lambert PH Openshaw P Siegrist CA 《Microbes and infection / Institut Pasteur》2004,6(7):666-675
To protect against human respiratory syncytial virus (hRSV)-induced bronchiolitis in early infancy, vaccines need to be designed which are effective in the neonatal period. To test the safety and efficacy of adjuvants in neonatal mice, we injected hRSV surface proteins combined with immune-stimulating complexes (ISCOMs) prepared from fractions A, C or A + C of Quillaja saponins. All were well tolerated in adults, but A + C ISCOMS proved lethal in neonates; A or C fractions alone were well tolerated by neonates up to the adult dose. hRSV-ISCOM A induced antibody responses similar to combined fractions, and potent in vitro cytotoxic T cell responses. Adult-like in vitro cytotoxicity against hRSV-infected targets and precursor cytotoxic T cell frequencies were observed within one week of neonatal priming and hRSV-ISCOM A-primed neonates showed virtually complete protection against subsequent viral challenge. hRSV challenge was associated with some pulmonary eosinophilia in both age groups, with higher IL-4 production by lung CD4+ T cells in mice primed as neonates. This was, however, accompanied by only minor (approximately 10%) and transient illness and weight loss. Thus, the identification of hRSV antigen delivery systems with an age-appropriate adjuvanticity/reactogenicity balance may be feasible even in the vulnerable early-life period. 相似文献
73.
Brett SJ Myles P Lim WS Enstone JE Bannister B Semple MG Read RC Taylor BL McMenamin J Nicholson KG Nguyen-Van-Tam JS Openshaw PJ;Influenza Clinical Information Network 《PloS one》2011,6(4):e18120
Background
Statins are drugs that are used to lower plasma cholesterol levels. Recently, contradictory claims have been made about possible additional effects of statins on progression of a variety of inflammatory disorders, including infections. We therefore examined the clinical course of patients admitted to hospital with 2009 pandemic influenza A(H1N1), who were or weren''t taking statins at time of admission.Methods
A retrospective case-control study was performed using the United Kingdom Influenza Clinical Information Network (FLU-CIN) database, containing detailed information on 1,520 patients admitted to participating hospitals with confirmed 2009 pandemic influenza A(H1N1) infection between April 2009 and January 2010. We confined our analysis to those aged over 34 years. Univariate analysis was used to calculate unadjusted odds ratios (OR) and 95 percent confidence intervals (95%CI) for factors affecting progression to severe outcome (high dependency or intensive care unit level support) or death (cases); two multivariable logistic regression models were then established for age and sex, and for age, sex, obesity and “indication for statin” (e.g., heart disease or hypercholesterolaemia).Results
We found no statistically significant association between pre-admission statin use and severity of outcome after adjustment for age and sex [adjusted OR: 0.81 (95% CI: 0.46–1.38); n = 571]. After adjustment for age, sex, obesity and indication for statin, the association between pre-admission statin use and severe outcome was not statistically significant; point estimates are compatible with a small but clinically significant protective effect of statin use [adjusted OR: 0.72 (95% CI: 0.38–1.33)].Conclusions
In this group of patients hospitalized with pandemic influenza, a significant beneficial effect of pre-admission statin use on the in-hospital course of illness was not identified. Although the database from which these observations are derived represents the largest available suitable UK hospital cohort, a larger study would be needed to confirm whether there is any benefit in this setting. 相似文献74.
Loebbermann J Schnoeller C Thornton H Durant L Sweeney NP Schuijs M O'Garra A Johansson C Openshaw PJ 《PloS one》2012,7(2):e32371
Interleukin (IL-) 10 is a pleiotropic cytokine with broad immunosuppressive functions, particularly at mucosal sites such as the intestine and lung. Here we demonstrate that infection of BALB/c mice with respiratory syncytial virus (RSV) induced IL-10 production by CD4(+) and CD8(+) T cells in the airways at later time points (e.g. day 8); a proportion of these cells also co-produced IFN-γ. Furthermore, RSV infection of IL-10(-/-) mice resulted in more severe disease with enhanced weight loss, delayed recovery and greater cell infiltration of the respiratory tract without affecting viral load. In addition, IL-10(-/-) mice had a pronounced airway neutrophilia and heightened levels of pro-inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid. Notably, the proportion of lung T cells producing IFN-γ was enhanced, suggesting that IL-10 may act in an autocrine manner to dampen effector T cell responses. Similar findings were made in mice treated with anti-IL-10R antibody and infected with RSV. Therefore, IL-10 inhibits disease and inflammation in mice infected with RSV, especially during recovery from infection. 相似文献
75.
Y Yamaguchi JA Harker B Wang PJ Openshaw JS Tregoning FJ Culley 《Journal of virology》2012,86(19):10456-10461
Severe respiratory viral infection in early life is associated with recurrent wheeze and asthma in later childhood. Neonatal immune responses tend to be skewed toward T helper 2 (Th2) responses, which may contribute to the development of a pathogenic recall response to respiratory infection. Since neonatal Th2 skewing can be modified by stimulation with Toll-like receptor (TLR) ligands, we investigated the effect of exposure to CpG oligodeoxynucleotides (TLR9 ligands) prior to neonatal respiratory syncytial virus (RSV) infection in mice. CpG preexposure was protective against enhanced disease during secondary adult RSV challenge, with a reduction in viral load and an increase in Th1 responses. A similar Th1 switch and reduction in disease were observed if CpG was administered in the interval between neonatal infection and challenge. In neonates, CpG pretreatment led to a transient increase in expression of major histocompatibility complex class II (MHCII) and CD80 on CD11c-positive cells and gamma interferon (IFN-γ) production by NK cells after RSV infection, suggesting that the protective effects may be mediated by antigen-presenting cells (APC) and NK cells. We conclude that the adverse effects of early-life respiratory viral infection on later lung health might be mitigated by conditions that promote TLR activation in the infant lung. 相似文献
76.
Emma L Hesketh John RP Knight Rosemary HC Wilson James PJ Chong Dawn Coverley 《Cell cycle (Georgetown, Tex.)》2015,14(3):333-341
The minichromosome maintenance complex (MCM2-7) is the putative DNA helicase in
eukaryotes, and essential for DNA replication. By applying serial extractions to mammalian
cells synchronized by release from quiescence, we reveal dynamic changes to the
sub-nuclear compartmentalization of MCM2 as cells pass through late G1 and early S phase,
identifying a brief window when MCM2 becomes transiently attached to the nuclear-matrix.
The data distinguish 3 states that correspond to loose association with chromatin prior to
DNA replication, transient highly stable binding to the nuclear-matrix coincident with
initiation, and a post-initiation phase when MCM2 remains tightly associated with
chromatin but not the nuclear-matrix. The data suggests that functional MCM complex
loading takes place at the nuclear-matrix. 相似文献
77.
78.
Apoptosis is characterized by DNA strand breaks with a 3'-OH terminus, which are analyzed by terminal deoxy(d)-UTP nick end labeling (TUNEL). Proteinase K digestion is thought to be an essential step in the TUNEL procedure. The effects of decalcifying reagents on general staining and the TUNEL assay for cartilage sections are largely unknown. The effects of these reagents on retention and integrity of DNA in chondrocytes have not been described until now. We evaluated the effects of various decalcifying solutions, including 10% EDTA, 10% citric acid, 5% trichloroacetic acid, 5% acetic acid and a commercial hydrochloric acid-based reagent, on general cartilage staining and the TUNEL assay for cartilage. The effects of proteinase K on nucleus preservation were also examined. Decalcification with 10% EDTA gave the best result for general cartilage staining. Chondrocyte DNA was retained and intact after using this reagent. Decalcification with 10% EDTA is also the safest method of decalcification if the TUNEL assay is applied to cartilage. Proteinase K digestion may have adverse effects on nucleus preservation in cartilage. Awareness of these effects is important whenever the TUNEL assay is applied. 相似文献
79.
MG Mullender NA Blom M De Kleuver JM Fock WMGC Hitters AMC Horemans CJ Kalkman JEH Pruijs RR Timmer PJ Titarsolej NC Van Haasteren Tol-de MJ Van Jager AJ Van Vught BJ Van Royen 《Scoliosis》2008,3(1):1-14
Background
Children with neuromuscular disorders with a progressive muscle weakness such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy frequently develop a progressive scoliosis. A severe scoliosis compromises respiratory function and makes sitting more difficult. Spinal surgery is considered the primary treatment option for correcting severe scoliosis in neuromuscular disorders. Surgery in this population requires a multidisciplinary approach, careful planning, dedicated surgical procedures, and specialized after care.Methods
The guideline is based on scientific evidence and expert opinions. A multidisciplinary working group representing experts from all relevant specialties performed the research. A literature search was conducted to collect scientific evidence in answer to specific questions posed by the working group. Literature was classified according to the level of evidence.Results
For most aspects of the treatment scientific evidence is scarce and only low level cohort studies were found. Nevertheless, a high degree of consensus was reached about the management of patients with scoliosis in neuromuscular disorders. This was translated into a set of recommendations, which are now officially accepted as a general guideline in the Netherlands.Conclusion
In order to optimize the treatment for scoliosis in neuromuscular disorders a Dutch guideline has been composed. This evidence-based, multidisciplinary guideline addresses conservative treatment, the preoperative, perioperative, and postoperative care of scoliosis in neuromuscular disorders. 相似文献80.
Peter JM Openshaw 《Respiratory research》2002,3(1):3
Viral bronchiolitis is the most common cause of hospitalization in infants under 6 months of age, and 70% of all cases of bronchiolitis are caused by respiratory syncytial virus (RSV). Early RSV infection is associated with respiratory problems such as asthma and wheezing later in life. RSV infection is usually spread by contaminated secretions and infects the upper then lower respiratory tracts. Infected cells release proinflammatory cytokines and chemokines, including IL-1, tumor necrosis factor-α, IL-6, and IL-8. These activate other cells and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues. The pattern of cytokine production by T lymphocytes can be biased toward 'T-helper-1' or 'T-helper-2' cytokines, depending on the local immunologic environment, infection history, and host genetics. T-helper-1 responses are generally efficient in antiviral defense, but young infants have an inherent bias toward T-helper-2 responses. The ideal intervention for RSV infection would be preventive, but the options are currently limited. Vaccines based on protein subunits, live attenuated strains of RSV, DNA vaccines, and synthetic peptides are being developed; passive antibody therapy is at present impractical in otherwise healthy children. Effective vaccines for use in neonates continue to be elusive but simply delaying infection beyond the first 6 months of life might reduce the delayed morbidity associated with infantile disease. 相似文献