The transcytosis of antigens across the gut epithelium by microfold cells (M cells) is important for the induction of efficient immune responses to some mucosal antigens in Peyer's patches. Recently, ...substantial progress has been made in our understanding of the factors that influence the development and function of M cells. This review highlights these important advances, with particular emphasis on: the host genes which control the functional maturation of M cells; how this knowledge has led to the rapid advance in our understanding of M-cell biology in the steady state and during aging; molecules expressed on M cells which appear to be used as "immunosurveillance" receptors to sample pathogenic microorganisms in the gut; how certain pathogens appear to exploit M cells to infect the host; and finally how this knowledge has been used to specifically target antigens to M cells to attempt to improve the efficacy of mucosal vaccines.
Human rhinovirus (HRV) infection is an important trigger of exacerbations of chronic obstructive pulmonary disease (COPD) but its role in determining exacerbation frequency phenotype or the ...time-course of HRV infection in naturally occurring exacerbations is unknown. Sputum samples from 77 patients were analysed by real-time quantitative PCR for both HRV (388 samples), and Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (89 samples). Patients recorded worsening of respiratory symptoms on daily diary cards, from which exacerbations were identified. HRV prevalence and load at exacerbation presentation were significantly higher than in the stable state (prevalence 53.3% versus 17.2%, respectively; p<0.001) but 0% by day 35 post-exacerbation. HRV load was higher in patients with cold symptoms (p=0.046) or sore throats (p=0.006) than those without. 73% of bacterium-negative but HRV-positive exacerbations were bacterium-positive by day 14. Patients with HRV detected at exacerbation had a higher exacerbation frequency (interquartile range) of 3.01 (2.02-5.30) per year compared with patients without HRV (2.51 (2.00-3.51)) (p=0.038). HRV prevalence and load increased at COPD exacerbation, and resolved during recovery. Frequent exacerbators were more likely to experience HRV infection. Secondary bacterial infection is common after HRV infection, and provides a possible mechanism for exacerbation recurrence and a potential target for novel therapies.
One of the new models for thinking the production of art in a new decolonialised art history might be the artist colony. Certainly, in Australia, one of the revolutions Aboriginal art has brought ...about lies in the way it takes place in a series of artist colonies: self-identifying and -regulating cultural centres that have little or nothing to do with any imagined national art. Australian artists have been involved with any number of artist colonies throughout the nineteenth and twentieth centuries, not just in Australia but around the world. This article will address just one: the Abbey Art Centre in New Barnet, just outside of London. Owned by gallerist and ethnographic art collector William Ohly, the complex of studios operated from the late 1940s until the late 1950s as the base for a generation of Australian artists and art historians, who enjoyed an entrée into the English art scene offered to no others either before or after. In particular, we examine the artists Robert Klippel, James Gleeson and Mary Webb, who stayed between 1947 and 1949, and the art historian Bernard Smith, who stayed between 1949 and 1950.
Isolated lymphoid follicles (ILFs) develop after birth in the small and large intestines (SI and LI) and represent a dynamic response of the gut immune system to the microbiota. Despite their ...similarities, ILF development in the SI and LI differs on a number of levels. We show that unlike ILF in the SI, the microbiota inhibits ILF development in the colon as conventionalization of germ-free mice reduced colonic ILFs. From this, we identified a novel mechanism regulating colonic ILF development through the action of interleukin (IL)-25 on IL-23 and its ability to modulate T regulatory cell (Treg) differentiation. Colonic ILF develop in the absence of a number of factors required for the development of their SI counterparts and can be specifically suppressed by factors other than IL-25. However, IL-23 is the only factor identified that specifically promotes colonic ILFs without affecting SI-ILF development. Both IL-23 and ILFs are associated with inflammatory bowel disease, suggesting that disruption to this pathway may have an important role in the breakdown of microbiota-immune homeostasis.
Abstract Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be ...painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165 a and VEGF-A165 b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165 a is upregulated and predominates over the VEGF-A165 b isoform. We show here that in rats and mice VEGF-A165 a and VEGF-A165 b have opposing effects on pain, and that blocking the proximal splicing event – leading to the preferential expression of VEGF-A165 b over VEGF165 a – prevents pain in vivo. VEGF-A165 a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165 b blocks the effect of VEGF-A165 a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxx a compared to VEGF-Axxx b, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxx a expression and reversed associated neuropathic pain. Exogenous VEGF-A165 b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxx a/VEGF-Axxx b balance by targeting alternative RNA splicing may be a new analgesic strategy.
Chronic obstructive pulmonary disease (COPD) is associated with a 2-3-fold increase in the risk of ischaemic heart disease, stroke and sudden death. The mechanisms responsible for this association ...are not clear and appear to be independent of smoking history.
We test the hypothesis that patients with COPD have increased arterial stiffness and blood pressure in comparison with age and smoking matched controls.
In a prospective case control study, we recruited 102 patients with COPD and 103 healthy controls matched for age and smoking status. Patients were assessed by clinical history and spirometry, with arterial stiffness and blood pressure determined using radial artery applanation tonometry and sphygmomanometry.
Patients with COPD had increased arterial stiffness compared with matched controls, with elevated augmentation pressure (17 (1) vs 14 (1) mm Hg; p = 0.005) and a reduced time to wave reflection (131 (1) vs 137 (2) ms; p = 0.004). These differences were associated with increases in both diastolic (82 (1) vs 78 (1) mm Hg; p = 0.005) and systolic blood pressure (147 (2) vs 132 (2) mm Hg; p<0.001). Serum C reactive protein concentrations were threefold higher in patients (6.1 (0.9) vs 2.3 (0.4) mg/l; p = 0.001). Data are presented as mean (SEM).
Patients with COPD have increased arterial stiffness and blood pressure in comparison with controls matched for age and smoking status. We speculate that increased systemic inflammation and vascular dysfunction could potentially explain the excess cardiovascular morbidity and mortality associated with COPD.
The transcytosis of antigens across the follicle-associated epithelium (FAE) of Peyer's patches by microfold cells (M cells) is important for the induction of efficient immune responses to mucosal ...antigens. The mucosal immune response is compromised by ageing, but effects on M cells were unknown. We show that M-cell density in the FAE of aged mice was dramatically reduced. As a consequence, aged Peyer's patches were significantly deficient in their ability to transcytose particulate lumenal antigen across the FAE. Ageing specifically impaired the expression of Spi-B and the downstream functional maturation of M cells. Ageing also dramatically impaired C-C motif chemokine ligand 20 expression by the FAE. As a consequence, fewer B cells were attracted towards the FAE, potentially reducing their ability to promote M-cell maturation. Our study demonstrates that ageing dramatically impedes the functional maturation of M cells, revealing an important ageing-related defect in the mucosal immune system's ability to sample lumenal antigens.
The Origins, Spectral Interpretation, Resource Identification, and Security Regolith Explorer(OSIRISREx) mission observed the The Origins, Spectral Interpretation, Resource Identification, and ...Security‐Regolith Explorer (OSIRIS‐REx) mission observed the Moon during the spacecraft's Earth gravity assist in 2017. From the spacecraft view, the lunar phase was 42°, and the in‐view hemisphere was dominated by anorthositic highlands terrain. Lunar spectra obtained by the OSIRIS‐REx Visible and InfraRed Spectrometer show evidence of several candidate absorption features. We observe the 2.8‐μm hydration band, confirming the spectral results from other missions, but detected in full‐disk spectra. We also tentatively identify weak spectral features near 0.9 and 1.3 μm, consistent with lunar regolith containing a mixture of plagioclase and orthopyroxene minerals, as expected for highlands terrain.
Purinergic signalling regulates airway defence mechanisms, suggesting that extracellular purines could serve as airway inflammation biomarkers in cystic fibrosis (CF). The purines adenosine ...triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and adenosine were measured in sputum from 21 adults (spontaneously expectorated from seven CF patients, induced from 14 healthy controls) to assess normal values and CF-associated changes. Subsequently, purine levels were measured in bronchoalveolar lavage fluid (BALF) from 37 children (25 CF patients, 12 disease controls) and compared with neutrophil counts, presence of airway infection and lung function. To noninvasively assess airway purines, ATP levels were measured using luminometry in exhaled breath condensate (EBC) from 14 children with CF and 14 healthy controls, then 14 CF children during a pulmonary exacerbation. Both ATP and AMP were elevated in sputum and BALF from CF subjects compared with controls. In BALF, ATP and AMP levels were inversely related to lung function and strongly correlated with neutrophil counts. In EBC, ATP levels were increased in CF relative to controls and decreased after treatment of CF pulmonary exacerbation. The purines adenosine triphosphate and adenosine monophosphate are candidate biomarkers of neutrophilic airways inflammation. Measurement of purines in sputum or exhaled breath condensate may provide a relatively simple and noninvasive method to track this inflammation.
Summary We applied the 2008 National Osteoporosis Foundation (NOF) Guidelines to Framingham Osteoporosis Study participants and found nearly one half of Caucasian postmenopausal women and one sixth ...of men aged 50 years and older would be recommended for osteoporosis treatment. Given the high proportion of persons recommended for treatment, NOF Guidelines may need to be re-evaluated with respect to budget impact. Introduction Little is known about the public health impact of the NOF Guidelines. Therefore, we determined the proportion of US Caucasians recommended for treatment of osteoporosis according to NOF Guidelines (2003 and 2008). Methods One thousand nine hundred and forty-six postmenopausal women and 1,681 men aged ≥50 years from the Framingham Study with information on bone mineral density (1987-2001) were included. Information on clinical predictors was used to estimate the 10-year probability of hip and major osteoporotic fracture by FRAX® (version 3.0). Results Overall proportion of women meeting treatment criterion was less when the 2008 NOF Guidelines were applied (41.1%) compared with 2003 Guidelines (47.8%). The proportion of women aged <65 years meeting treatment criterion was much less when applying 2008 Guidelines (23.1% in 2003, 8.3% in 2008), whereas the proportion of women aged >75 years increased slightly (78.3% in 2003, 86.0% in 2008). Seventeen percent of men aged ≥50 years met treatment criterion (2.5% aged 50-64 years, 49.8% aged >75 years). Conclusions Nearly one half of Caucasian postmenopausal women and one sixth of men aged 50 years and older would be recommended for osteoporosis treatment according to 2008 NOF Guidelines. Given the high proportion of persons recommended for treatment, NOF Guidelines may need to be re-evaluated with respect to budget impact.
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