The NLRP3 inflammasome is implicated in the processing of the pro-inflammatory cytokine interleukin 1β. Inflammatory disorders associated with the activation of the NLRP3 inflammasome - IL-1 axis are ...termed autoinflammatory diseases. Gout is an autoinflammatory disease, which is triggered by the deposition of monosodium urate crystals of precipitated uric acid. It is characterized by recurrent attacks of inflammation due to the activation of phagocytic cells that try to clear the crystals. NLRP3 inflammasome-mediated IL-1β production plays a key role in the manifestation of the disease. Currently, the best approach to treat gout is to reduce uric acid concentration by targeting xanthine oxidase or uric acid transporters, or to use non-steroidal anti-inflammatory drugs. Nevertheless, most of these treatments are not effective enough and may results in side effects. During the past decades, our knowledge has greatly improved about the molecular mechanisms of NLRP3 activation. This knowledge enables and urges scientists to discover or design drugs that target pathways of NLRP3 inflammasome activation, or more preferentially, NLRP3 inflammasome itself. In this review, we discuss the already available drugs and products, that target the diverse pathways of the NLRP3 - IL-1β axis, and the future therapeutic perspectives.
Innate immune responses in the ageing lung Boe, D. M.; Boule, L. A.; Kovacs, E. J.
Clinical and experimental immunology,
January 2017, Volume:
187, Issue:
1
Journal Article
Peer reviewed
Open access
Summary
The world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the ...global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age‐related dysfunction of the immune system resulting from low‐grade chronic inflammation known as ‘inflamm‐ageing’. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life‐threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age‐related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age‐specific therapies to address lung infections in such a vulnerable population.
The elderly are a growing demographic at high risk for respiratory infections due to innate immune dysfunction in the lungs. In this review, we examine research on age‐related changes in the response of the innate immune system to pulmonary infections.
ABSTRACT
Many scientific investigations of photometric galaxy surveys require redshift estimates, whose uncertainty properties are best encapsulated by photometric redshift (photo-z) posterior ...probability density functions (PDFs). A plethora of photo-z PDF estimation methodologies abound, producing discrepant results with no consensus on a preferred approach. We present the results of a comprehensive experiment comparing 12 photo-z algorithms applied to mock data produced for The Rubin Observatory Legacy Survey of Space and Time Dark Energy Science Collaboration. By supplying perfect prior information, in the form of the complete template library and a representative training set as inputs to each code, we demonstrate the impact of the assumptions underlying each technique on the output photo-z PDFs. In the absence of a notion of true, unbiased photo-z PDFs, we evaluate and interpret multiple metrics of the ensemble properties of the derived photo-z PDFs as well as traditional reductions to photo-z point estimates. We report systematic biases and overall over/underbreadth of the photo-z PDFs of many popular codes, which may indicate avenues for improvement in the algorithms or implementations. Furthermore, we raise attention to the limitations of established metrics for assessing photo-z PDF accuracy; though we identify the conditional density estimate loss as a promising metric of photo-z PDF performance in the case where true redshifts are available but true photo-z PDFs are not, we emphasize the need for science-specific performance metrics.
The National Institute of Oncology, Budapest conducted a single centre randomized clinical study. The OTOASOR (Optimal Treatment Of the Axilla - Surgery Or Radiotherapy) trial compares completion of ...axillary lymph node dissection (cALND) to regional nodal irradiation (RNI) in patients with sentinel lymph node metastasis (pN1sn) in stage I-II breast cancer.
Patients with primary invasive breast cancer (cN0 and cT ≤ 3 cm) were randomized before surgery for cALND (standard treatment) or RNI (investigational treatment). Sentinel lymph nodes (SN) were investigated with serial sectioning at 0.5 mm levels by hematoxylin-eosin staining. Investigational treatment arm patients received 50 Gy RNI instead of cALND. Adjuvant treatment and follow up were performed according to the actual guidelines. Between August 2002 and June 2009, 1054 patients were randomized for cALND and 1052 patients for RNI. SN was evaluated in 2073 patients and was positive in 526 patients (25.4%). 474 cases were evaluable (244 in the cALND and 230 in the RNI arm), and in the cALND group 94 of 244 patients (38.5%) who underwent completion axillary surgery has additional positive nodes. The two arms were well balanced according to the majority of main prognostic factors. Primary endpoint was axillary recurrence and secondary endpoints were overall survival (OS) and disease-free survival (DFS).
Mean follow-up was 97 months (Q1-Q3: 80-120). Axillary recurrence was 2.0% in cALND arm vs. 1.7% in RNI arm (p = 1.00). OS at 8 years was 77.9% vs. 84.8% (p = 0.060), and DFS was 72.1% in cALND arm and 77.4% after RNI (p = 0.51). The results show that RNI is statistically not inferior to cALND treatment.
The long term follow-up results of this prospective-randomized trial suggest that RNI without cALND does not increase the risk of axillary failure in selected patients with early-stage invasive breast cancer (cT ≤ 3 cm, cN0) and pN1(sn). Axillary radiotherapy should be an alternative treatment for selected patients with sentinel lymph node metastases.
The National Child Measurement Programme (NCMP) is a child weight monitoring system in England, taking place in the first and final years of primary school. Many local authorities consider it ...important to inform parents if their child is overweight, and do so by letter alongside the offer of support and advice. Such letters have been met with mixed reactions from parents, but research seeking to better understand parents' responses is often limited by reliance on survey data and low participation rates. This study aimed to collect a broad variety of perspectives on the programme by analyzing views expressed in parent-to-parent discussions posted online.
UK-based online parenting fora were used to identify discussion threads based around the NCMP between 2010 and 2017. Thirty-one discussion threads from two parent fora were identified. Thematic analysis was used to identify themes in these data.
The primary themes identified related to (1) the legitimacy of feedback and judgement from health professionals, (2) the relative importance of collecting population level data above individual preferences, and (3) risks versus benefits of having conversations with children about weight. Most threads adopted an 'argument, counter-argument' format, providing two sides to each issue raised. Information and opinions consistent with public health messages were frequently provided, such as how data are used, that feedback is intended to be helpful, and the importance of collecting national data. There was little evidence of individual parents shifting their views in response to others' arguments.
This study provides novel insight into peer-to-peer debates about the NCMP, including the arguments parents find convincing and acceptable for and against a national programme to weigh children and provide feedback to parents about their weight. Online fora were used as an opportunity to express criticism or distress, but also to seek advice from peers regarding concerns about whether or not to opt-out. Thus, both general issues related to the legitimacy of population screening and outcomes for individual children were of concern to parents.
To investigate the reproducibility of food consumption frequencies derived from the food frequency section of the Children's Eating Habits Questionnaire (CEHQ-FFQ) that was developed and used in the ...IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) project to assess food habits in 2- to 9-year-old European children.
From a subsample of 258 children who participated in the IDEFICS baseline examination, parental questionnaires of the CEHQ were collected twice to assess reproducibility of questionnaire results from 0 to 354 days after the first examination. Weighted Cohen's kappa coefficients (κ) and Spearman's correlation coefficients (r) were calculated to assess agreement between the first and second questionnaires for each food item of the CEHQ-FFQ. Stratification was performed for sex, age group, geographical region and length of period between the first and second administrations. Fisher's Z transformation was applied to test correlation coefficients for significant differences between strata.
For all food items analysed, weighted Cohen's kappa coefficients (κ) and Spearman's correlation coefficients (r) were significant and positive (P<0.001). Reproducibility was lowest for diet soft drinks (κ=0.23, r=0.32) and highest for sweetened milk (κ=0.68, r=0.76). Correlation coefficients were comparable to those of previous studies on FFQ reproducibility in children and adults. Stratification did not reveal systematic differences in reproducibility by sex and age group. Spearman's correlation coefficients differed significantly between northern and southern European countries for 10 food items. In nine of them, the lower respective coefficient was still high enough to conclude acceptable reproducibility. As expected, longer time (>128 days) between the first and second administrations resulted in a generally lower, yet still acceptable, reproducibility.
Results indicate that the CEHQ-FFQ gives reproducible estimates of the consumption frequency of 43 food items from 14 food groups in European children.
The present study aimed to assess the uptake of the common nonsteroidal anti-inflammatories ibuprofen, ketoprofen and diclofenac by lettuce, radishes, and tomatoes. The influence of multiple routes ...of exposures (soil, water, vapor) of the pharmaceuticals were invstigated. The impact of accumulated pharmaceuticals active ingredients on the vegetable quality as the carbohydrate, amino acid, volatile organic aroma, and fatty acid methyl ester content were also investigated. The determination of the pharmaceutical active ingredients and vegetable quality compounds was performed by gas chromatography. For all of the vegetables, the diclofenac bioconcentration factor was the highest, as the concentration was between 31 and 118 ng·g
−1
. Ibuprofen was easily accumulated in radishes and lettuce, with levels between 6 and 58 and 11 and 73 ng·g
−1
, respectively. Higher concentrations of the pharmaceutical active ingredients were determined when the soil was artificially contaminated. The average values of bioconcentration factors considering studied pharmaceuticals active ingredients were in the following order: diclofenac > ibuprofen > ketoprofen. Considering the impact upon the vegetable carbohydrate content, a decreasing tendency in percentage values was observed for the carbohydrate concentration in radishes and tomatoes treated by pharmaceuticals through contaminated soil and water. Similarly, the volatile organic aroma compounds decreased from 7% to 36% compared with the controls when the vegetables were cultivated in contaminated conditions.
Introduction: Studies such as IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) seek to compare data across several different countries. ...Therefore, it is important to confirm that body composition indices, which are subject to intra- and inter-individual variation, are measured using a standardised protocol that maximises their reliability and reduces error in analyses. Objective: To describe the standardisation and reliability of anthropometric measurements. Both intra- and inter-observer variability of skinfold thickness (triceps, subscapular, biceps, suprailiac) and circumference (neck, arm, waist, hip) measurements were investigated in five different countries. Methods: Central training for fieldwork personnel was carried out, followed by local training in each centre involving the whole survey staff. All technical devices and procedures were standardised. As part of the standardisation process, at least 20 children participated in the intra- and inter-observer reliability test in each centre. A total of 125 children 2–5 years of age and 164 children 6–9 years of age took part in this study, with a mean age of 5.4 (±1.2) years. Results: The intra-observer technical error of measurement (TEM) was between 0.12 and 0.47mm for skinfold thickness and between 0.09 and 1.24cm for circumference measurements. Intra-observer reliability was 97.7% for skinfold thickness (triceps, subscapular, biceps, suprailiac) and 94.7% for circumferences (neck, arm, waist, hip). Inter-observer TEMs for skinfold thicknesses were between 0.13 and 0.97mm and for circumferences between 0.18 and 1.01cm. Inter-observer agreement as assessed by the coefficient of reliability for repeated measurements of skinfold thickness and circumferences was above 88% in all countries. Conclusion: In epidemiological surveys it is essential to standardise the methodology and train the participating staff in order to decrease measurement error. In the framework of the IDEFICS study, acceptable intra- and inter-observer agreement was achieved for all the measurements.
Biogas production technologies commonly involve the use of natural anaerobic consortia of microbes. The objective of this study was to elucidate the importance of hydrogen in this complex microbial ...food chain. Novel laboratory biogas reactor prototypes were designed and constructed. The fates of pure hydrogen-producing cultures of Caldicellulosiruptor saccharolyticus and Enterobacter cloacae were followed in time in thermophilic and mesophilic natural biogas-producing communities, respectively. Molecular biological techniques were applied to study the altered ecosystems. A systematic study in 5-litre CSTR digesters revealed that a key fermentation parameter in the maintenance of an altered population balance is the loading rate of total organic solids. Intensification of the biogas production was observed and the results corroborate that the enhanced biogas productivity is associated with the increased abundance of the hydrogen producers. Fermentation parameters did not indicate signs of failure in the biogas production process. Rational construction of more efficient and sustainable biogas-producing microbial consortia is proposed.
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