The role of adenosine in chondrocyte death in murine osteoarthritis and in a murine chondrocyte cell line

SummaryObjectiveTo investigate the role of adenosine in chondrocyte death in murine osteoarthritis (OA).Methods5′-Nucleotidase (5′NT) generates adenosine. Enzyme activity was measured histochemically in normal murine and osteoarthritic STR/ort strain tibial cartilage. Adenosine-mediated cell death was investigated in MC615 chondrocyte cultures. Adenosine receptors (ARs) were assessed by reverse transcriptase polymerase chain reaction (RT-PCR). Cellular uptake of [3H] adenosine was measured with or without the inhibitor, nitrobenzylthioinosine (NBTI). Cell death was assessed by cell counting and DNA laddering following selective receptor stimulation, or after modulating adenosine metabolism with adenosine deaminase (ADA) or adenosine kinase (AK) inhibitors [erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and Iodotubericidin (Itub)], or with homocysteine (HC). Markers of apoptosis were assessed by Western blotting. Cell studies were validated by incubating normal murine knee joints in a medium containing adenosine and metabolic inhibitors. Apoptotic chondrocytes were identified with the TUNEL reaction.Results5′NT activity in STR/ort tibial cartilage increased with development of OA, especially close to OA lesions. Adenosine induced MC615 cell death in the presence of ADA inhibition (100μM EHNA), or 1mM HC, or both. Adenosine uptake, mediated by NBTI-sensitive adenosine transporters, was required for cell death. ARs were expressed (A2b>A2a>A1) but were not involved in mediating cell death. Cell death involved the activation of caspase-3 and DNA fragmentation and was prevented by inhibiting caspase activity. However, neither caspase-8 nor caspase-9 was detected. Adenosine+EHNA induced chondrocyte apoptosis in normal murine knee joints.ConclusionIncreased adenosine production may induce chondrocyte apoptosis and play a role in OA in STR/ort mice

Characterising non-urgent users of the emergency department (ED): A retrospective analysis of routine ED data

Background The pressures of patient demand on emergency departments (EDs) continue to be reported worldwide, with an associated negative impact on ED crowding and waiting times. It has also been reported that a proportion of attendances to EDs in different international systems could be managed in settings such as primary care. This study used routine ED data to define, measure and profile non-urgent ED attendances that were suitable for management in alternative, non-emergency settings. Methods We undertook a retrospective analysis of three years of Hospital Episode and Statistics Accident Emergency (HES A&E) data for one large region in England, United Kingdom (April 1st 2011 to March 31st 2014). Data was collected on all adult (>16 years) ED attendances from each of the 19 EDs in the region. A validated process based definition of nonurgent attendance was refined for this study and applied to the data. Using summary statistics non-urgent attenders were examined by variables hypothesised to influence them as follows: age at arrival, time of day and day of week and mode of arrival. Odds ratios were calculated to compare non-urgent attenders between groups. Results There were 3,667,601 first time attendances to EDs, of which 554,564 were defined as nonurgent (15.1%). Non-urgent attendances were significantly more likely to present out of hours than in hours (OR = 1.19, 95% CI: 1.18 to 1.20, P<0.001). The odds of a non-urgent attendance were significantly higher for younger patients (aged 16–44) compared to those aged 45–64 (odds ratio: 1.42, 95% CI: 1.41 to 1.43, P<0.001) and the over 65’s (odds ratio: 3.81, 95% CI: 3.78 to 3.85, P<0.001). Younger patients were significantly more likely to attend non-urgently out of hours compared to the 45–64’s (OR = 1.24, 95% CI: 1.22 to 1.25, P<0.001) and the 65+’s (OR = 1.38, 95% CI: 1.35 to 1.40, P<0.001). 110,605/554,564 (19.9%) of the non-urgent attendances arrived by ambulance, increasing significantly out of hours versus in hours (OR = 2.12, 95% CI: 2.09 to 2.15, P<0.001). Conclusions Younger adults are significantly more likely as older counterparts to use the ED to obtain healthcare that could be provided in a less urgent setting and also more likely to do this out of hours. Alternative services are required to manage non-urgent demand, currently being borne by the ED and the ambulance service, particularly in out of hours

Paediatric emergency department utilisation rates and maternal migration status in the Born in Bradford cohort: A cross-sectional study

Background Globally, international migration is increasing. Population growth, along with other demographic changes, may be expected to put new pressures on healthcare systems. Some studies across Europe suggest that emergency departments (EDs) are used more, and differently, by migrants compared to non-migrant populations, which may be a result of unfamiliarity with the healthcare systems and difficulties accessing primary healthcare. However, little evidence exists to understand how migrant parents, who are typically young and of childbearing age, utilise EDs for their children. This study aimed to examine the association between paediatric ED utilisation in the first 5 years of life and maternal migration status in the Born in Bradford (BiB) cohort study. Methods and findings We analysed linked data from the BiB study—an ongoing, multi-ethnic prospective birth cohort study in Bradford. Bradford is a large, ethnically diverse city in the north of England. In 2017, more than a third of births in Bradford were to mothers who were born outside the UK. Between March 2007 and December 2010, pregnant women were recruited to BiB during routine antenatal care, and the children born to these mothers have been, and continue to be, followed over time to assess how social, genetic, environmental, and behavioural factors impact on health from childhood to adulthood. Data analysed in this study included baseline questionnaire data from BiB mothers, and Bradford Royal Infirmary ED episode data for their children. Main outcomes were likelihood of paediatric ED use (no visits versus at least 1 ED visit in the first 5 years of life) and ED utilisation rates (number and frequency of ED visits) for children who have accessed the ED. The main explanatory variable was mother’s migrant status (foreign-born versus UK/Irish-born). Multivariable analyses (logistic and zero-truncated negative binomial regression) were conducted adjusting for socio-demographic and socio-economic factors. The final dataset included 10,168 children born between April 2007 and June 2011, of whom 35.6% were born to migrant mothers. Foreign-born mothers originated from South Asia (28.6%), Europe/Central Asia (3.2%), Africa (2.1%), East Asia/Pacific (1.1%), and the Middle East (0.6%). At recruitment the mothers ranged in age from 15 to 49 years old. Overall, 3,104 (30.5%) children had at least 1 ED visit in the first 5 years of life, with the highest proportion of visits being in the first year of life (36.7%). The proportion of children who visited the ED at least once was lower for children of migrant mothers as compared to children of non-migrant mothers (29.4% versus 31.2%). Children of migrant mothers were found to be less likely to visit the ED (odds ratio 0.88 [95% CI 0.80 to 0.97], p = 0.012). However, among children who visited the ED, the utilisation rate was significantly higher for children of migrant mothers (incidence rate ratio [IRR] 1.19 [95% CI 1.01 to 1.40], p = 0.040). Utilisation rates were higher for children born to mothers from Europe (IRR 1.71 [95% CI 1.07 to 2.71], p = 0.024) and established migrants (≥5 years living in UK) (IRR 1.24 [95% CI 1.02 to 1.51], p = 0.032) compared to UK/Irish-born mothers. Important limitations include being unable to measure children’s underlying health status and the urgency of ED attendance, as well as the analysis being limited by missing data. Conclusions In this study we observed that there is no higher likelihood of first paediatric ED attendance in the first 5 years of life for children in the BiB cohort for migrant mothers. However, among ED users, children of migrant mothers attend the service more frequently than children of UK/Irish-born mothers. Our findings show that patterns of ED utilisation differ by mother’s region of origin and time since arrival in the UK

Actual and potential distribution of an invasive canola pest, Meligethes viridescens (Coleoptera: Nitidulidae), in Canada

Meligethes viridescens (Fabricius), bronzed or rape blossom beetle, is a widespread and common pest of oilseed rape [Brassica napus L. and Brassica rapa L. (Brassicaceae)] in the western Palaearctic subregion. The establishment of M. viridescens in eastern North America has raised concern that its presence is a potential risk to the Canadian canola industry, especially to the prairie ecozone of western Canada where up to 4 million ha of summer canola (B. napus and B. rapa) are grown annually. Study of museum specimens indicated that M. viridescens was first recorded in Nova Scotia in 1947. Field surveys indicated that, as of 2001, M. viridescens was established as far west as Saint-Hyacinthe, Quebec. A CLIMEXTM model for M. viridescens in Europe was developed and validated with actual distribution records. In Canada the model predicted that once introduced, M. viridescens would readily survive in the canola-growing areas. The actual distribution of M. viridescens in eastern Canada matched the predicted distribution well. The westward dispersal to and establishment of M. viridescens in canola-growing areas of Ontario and western Canada, particularly southern Manitoba, appear to be inevitable. Establishment in these areas presents the risk of substantial production losses to canola producer

Rat cerebral cortical synaptoneurosomal membranes. Structure and interactions with imidazobenzodiazepine and 1,4-dihydropyridine calcium channel drugs

Small angle x-ray scattering has been used to investigate the structure of synaptoneurosomal (SNM) membranes from rat cerebral cortex. Electron micrographs of the preparation showed SNM with classical synaptic appositions intact, other vesicles, occasional mitochondria, and some myelin. An immunoassay for myelin basic protein placed the myelin content of normal rat SNM at less than 2% by weight of the total membrane present. X-Ray diffraction patterns showed five diffraction orders with a unit cell repeat for the membrane of 71 to 78 A at higher hydration states. At lower hydration, 11 orders appeared; the unit cell repeat was 130 A, indicating that the unit cell contained two membranes. Electron density profiles for the 130-A unit cell were determined; they clearly showed the two opposed asymmetrical membranes of the SNM vesicles. SNM membrane/buffer partition coefficients (Kp) of imidazobenzodiazepine and 1,4-dihydropyridine (DHP) calcium channel drugs were measured; Kp's for DHP drugs were approximately five times higher in rabbit light sarcoplasmic reticulum than in SNM. Ro 15–1788 and the DHP BAY K 8644 bind primarily to the outer monolayer of vesicles of intact SNM membranes. Nonspecific equilibrium binding of Ro 15–1788 occurs mainly in the upper acyl chain of the bilayer in lipid extracts of SNM membrane

Non-urgent emergency department attendances in children : a retrospective observational analysis

Introduction: A significant proportion of ED attendances in children may be non-urgent attendances (NUAs), which could be better managed elsewhere. This study aimed to quantify NUAs and urgent attendances (UAs) in children to ED and determine which children present in this way and when. Methods: Dataset extracted from the CUREd research database containing linked data on the provision of care in Yorkshire and Humber. Analysis focused on children’s ED attendances (April 2014–March 2017). Summary statistics and odds ratios (OR) comparing NUAs and UAs were examined by: age, mode and time of arrival and deprivation alongside comparing summary statistics for waiting, treatment and total department times. Results: NUAs were more likely in younger children: OR for NUA in children aged 1–4 years, 0.82 (95% CI: 0.80 to 0.83), age 15 years, 0.39 (95% CI: 0.38 to 0.40), when compared with those under 1 year. NUAs were more likely to arrive out of hours (OOHs) compared with in hours: OR 1.19 (95% CI 1.18 to 1.20), and OOHs arrivals were less common in older children compared with those under 1 year: age 1–4 years, 0.87 (95% CI: 0.84 to 0.89) age 15 years, 0.66 (95% CI: 0.63 to 0.69). NUAs also spent less total time in the ED, with a median (IQR) of 98 min (60–147) compared with 127 min (80–185) for UAs. Conclusion: A substantial proportion of ED attendances in children are NUAs. Our data suggest there are particular groups of children for whom targeted interventions would be most beneficial. Children under 5 years would be such a group, particularly in providing accessible, timely care outside of usual community care opening hours

Enhancement of Anisotropy due to Fluctuations in Quasi-One-Dimensional Antiferromagnets

It is shown that the observed anisotropy of magnetization at high magnetic fields in RbMnBr3 , a quasi-one-dimensional antiferromagnet on a distorted stacked triangular lattice, is due to quantum and thermal fluctuations. These fluctuations are taken into account in the framework of linear spin-wave theory in the region of strong magnetic fields. In this region the divergent one-dimensional integrals are cut off by magnetic field and the bare easy-plane anisotropy. Logarithmical dependence on the cutoff leads to the "enhancement" of the anisotropy in magnetization. Comparison between magnetization data and our theory with parameters obtained from neutron scattering experiments has been done.Comment: 15 pages + 5 postscript figures available upon request, RevTex

Tryptophan End-Tagging Confers Antifungal Activity on a Tick-Derived Peptide by Triggering Reactive Oxygen Species Production

WHO has identified several Candida species including Candida albicans as critical priority fungal pathogens due to greater infection prevalence and formation of recalcitrant biofilms. Novel antifungal agents are urgently needed, and antimicrobial peptides (AMPs) are being considered as potential alternatives, but inactivity in physiological salt environments, serum, and plasma often limits further therapeutic development. Tryptophan end-tagging is a strategy to overcome these limitations and is thought to selectively enhance membrane permeabilization in both fungal and bacterial plasma membranes. Here, we show that C-terminal tryptophan end-tagging of the tick-derived peptide Os-C transforms an inactive peptide into Os-C(W5), an antifungal peptide capable of preventing the formation of C. albicans biofilms. Mechanistic insight is provided by circular dichroism spectroscopy and molecular dynamics simulations, which demonstrate that tryptophan end-tagging alters the secondary structure of Os-C, while the latter reveals that end-tagging reduces interactions with, and insertion into, a model C. albicans membrane but promotes peptide aggregation on its surface. Interestingly, this leads to the induction of reactive oxygen species production rather than membrane permeabilization, and consequently, oxidative stress leads to cell wall damage. Os-C(W5) does not induce the hemolysis of human erythrocytes. Reduced cell adhesion and viability contribute to decreased biofilm extracellular matrix formation which, although reduced, is retained in the serum-containing medium. In this study, tryptophan end-tagging was identified as a promising strategy for enhancing the antifungal activity, including the biofilm inhibitory activity of Os-C against C. albicans in physiological salt environments.</p

Angle of repose and segregation in cohesive granular matter

We study the effect of fluids on the angle of repose and the segregation of granular matter poured into a silo. The experiments are conducted in two regimes where: (i) the volume fraction of the fluid is small and it forms liquid bridges between particles, and (ii) the particles are completely immersed in the fluid. The data is obtained by imaging the pile formed inside a quasi-two dimensional silo through the transparent glass side walls. In the first series of experiments, the angle of repose is observed to increase sharply with the volume fraction of the fluid and then saturates at a value that depends on the size of the particles. We systematically study the effect of viscosity by using water-glycerol mixtures to vary it over at least three orders of magnitude while keeping the surface tension almost constant. Besides surface tension, the viscosity of the fluid is observed to have an effect on the angle of repose and the extent of segregation. In case of bidisperse particles, segregation is observed to decrease and finally saturate depending on the size ratio of the particles and the viscosity of the fluid. The sharp initial change and the subsequent saturation in the extent of segregation and angle of repose occurs over similar volume fraction of the fluid. In the second series of experiments, particles are poured into a container filled with a fluid. Although the angle of repose is observed to be unchanged, segregation is observed to decrease with an increase in the viscosity of the fluid.Comment: 9 pages, 12 figure

The rate of colonization by macro-invertebrates on artificial substrate samplers

The influence of exposure time upon macro-invertebrate colonization on modified Hester-Dendy substrate samplers was investigated over a 60-day period. The duration of exposure affected the number of individuals, taxa and community diversity. The numbers of individuals colonizing the samplers reached a maximum after 39 days and then began to decrease, due to the emergence of adult insects. Coefficients of variation for the four replicate samples retrieved each sampling day fluctuated extensively throughout the study. No tendencies toward increasing or decreasing coefficients of variation were noted with increasing time of sampler exposure. The number of taxa colonizing the samplers increased throughout the study period. The community diversity index was calculated for each sampling day and this function tended to increase throughout the same period. This supports the hypothesis that an exposure period of 6 weeks, as recommended by the United States Environmental Protection Agency, may not always provide adequate opportunity for a truly representative community of macro-invertebrates to colonize multiplate samplers. Many of the taxa were collected in quite substantial proportions after periods of absence or extreme sparseness. This is attributed to the growth of periphyton and the collection of other materials that created food and new habitats suitable for the colonization of new taxa. Investigation of the relationship between ‘equitability’ and length of exposure revealed that equitability did not vary like diversity with increased time of exposure.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72073/1/j.1365-2427.1979.tb01522.x.pd