Regulation of human neutrophil apoptosis by nitric oxide and peroxynitrite

Apoptosis of inflammatory cells is a critical event in the resolution of inflammation, as failure to undergo this form of cell death leads to increased tissue damage and exacerbation of the inflammatory response. Prolonged survival of the neutrophilic granulocyte has been implicated in the pathogenesis of many chronic inflammatory conditions. Many factors are able to influence the rate of apoptosis in neutrophils. Among these is the signalling molecule, nitric oxide (NO), which possesses both anti-apoptotic and pro-apoptotic properties in many cell types, depending on the concentration and flux of NO, and also the source from which NO is derived.Characterisation of the NO-related species generated by four 'NO-donating' compounds, spermine diazeniumdiolate (SPER/NO), diethylamine diazeniumdiolate (DEA/NO), 1,2,3,4-oxatriazolium, 5-amino-3- (3,4-dichlorophenyl)-chloride (GEA 3162) and 3-morpholinosydnonime (SIN-1) was carried out. It was demonstrated that the diazeniumdiolates, SPER/NO and DEA/NO both spontaneously liberated free NO in aqueous solution at physiological temperature and pH. In contrast, both GEA 3162 and SIN-1 produced NO and superoxide anion (O2") concomitantly, that rapidly react to form the powerful oxidant species, peroxynitrite (ONOO"). These two compounds should therefore be considered ONOO" donors rather than NO donors.Apoptosis studies demonstrated the biphasic pro- and anti-apoptotic effects of pure NO donors, SPER/NO and DEA/NO, and the pro-apoptotic effects of ONOO" donors, GEA 3162 and SIN-1, in human neutrophils. Low concentrations of the pure NO donors delayed the rate of neutrophil apoptosis, while high concentrations of all compounds tested accelerated cell death. Time course analyses of four independent events of apoptosis revealed that morphological and biochemical parameters of neutrophil apoptosis may proceed independently of internucleosomal DNA fragmentation, which has long been considered a key hallmark of apoptosis and is frequently used as the sole criterion for assessment of this form of cell death. Treatment with high concentrations of ONOO" donors and, to a lesser extent, with the longer-lasting pure NO donor, SPER/NO, induced morphological and cell surface (CD 16 shedding and phosphatidylserine exposure) changes characteristic of neutrophil apoptosis, but paradoxically inhibited internucleosomal DNA fragmentation, as measured by propidium iodide intercalation and gel electrophoresis. In contrast, treatment with the short-lasting NO donor, DEA/NO, produced no such inhibition. An oxidation reaction was shown to be responsible for the suppression of the DNA fragmentation pathway, as the reducing agent, dithiothreitol, restored DNA fragmentation back to control levels. However, GEA 3162-mediated inhibition of DNA fragmentation did not occur upstream or at the level of degradation of inhibitor of caspase-activated DNase (ICAD/DFF45), as Western blotting showed breakdown of this protein was enhanced rather than inhibited in GEA 3162-treated neutrophils.Therefore, NO can exert either pro- or anti-apoptotic effects on human neutrophil apoptosis, depending on its concentration and flux, whereas only proapoptotic effects are achieved with ONOO" donors. Cell death promoted by ONOO" or SPER/NO is independent of an increase in internucleosomal DNA fragmentation; this process is inhibited via an oxidative mechanism, but not through inhibition of ICAD/DFF45 breakdown or upstream mechanisms. Thus, NO and ONOO" are able to modulate the rate of neutrophil apoptosis, which may have implications for chronic inflammatory conditions

Reducing SSI rates for women birthing by caesarean section

Surgical site infections (SSIs) are the most common type of nosocomial infection, accounting for up to 20% of all hospitalacquired infections in Europe (European Centre for Disease Prevention and Control [ECDPC], 2013). There are varying SSI rates reported across the UK. In 2016, Public Health Wales reported an overall 14-day SSI rate for women undergoing caesarean section of 4.35% — 83% of which were superficial infections and 92.5% were detected after discharge (PHW, 2016). From 2015–2016, Aneurin Bevan University Health Board (ABUHB) services experienced an increase in the SSI rate for women birthing by caesarean section from 3.07% to 5.86% respectively. Therefore, a multifaceted approach to quality improvement (ABUHB organisational method) was adopted throughout the duration of 2017, with a view to implement by 2018. The aim was to reduce SSIs for women birthing by caesarean section in ABUHB. Interventions included the use of evidence-based practice and guidelines, education and engagement among clinicians, patients and staff, and the gradual implementation of Leukomed® Sorbact® (Essity) post-operative dressings

The risk of infection by African swine fever virus in European swine through boar movement and legal trade of pigs and pig meat

African swine fever (ASF) is currently spreading westwards throughout Europe and eastwards into China, with cases occurring in both wild boar and domestic pigs. A generic risk assessment framework is used to determine the probability of first infection with ASF virus (ASFV) at a fine spatial scale across European Union Member States. The framework aims to assist risk managers across Europe with their ASF surveillance and intervention activities. Performing the risk assessment at a fine spatial scale allows for hot-spot surveillance, which can aid risk managers by directing surveillance or intervention resources at those areas or pathways deemed most at risk, and hence enables prioritization of limited resources. We use 2018 cases of ASF to estimate prevalence of the disease in both wild boar and pig populations and compute the risk of initial infection for 2019 at a 100 km2 cell resolution via three potential pathways: legal trade in live pigs, natural movement of wild boar, and legal trade in pig meat products. We consider the number of pigs, boar and amount of pig meat entering our area of interest, the prevalence of the disease in the origin country, the probability of exposure of susceptible pigs or boar in the area of interest to introduced infected pigs, boar, or meat from an infected pig, and the probability of transmission to susceptible animals. We provide maps across Europe indicating regions at highest risk of initial infection. Results indicate that the risk of ASF in 2019 was predominantly focused on those regions which already had numerous cases in 2018 (Poland, Lithuania, Hungary, Romania, and Latvia). The riskiest pathway for ASFV transmission to pigs was the movement of wild boar for Eastern European countries and legal trade of pigs for Western European countries. New infections are more likely to occur in wild boar rather than pigs, for both the pig meat and wild boar movement pathways. Our results provide an opportunity to focus surveillance activities and thus increase our ability to detect ASF introductions earlier, a necessary requirement if we are to successfully control the spread of this devastating disease for the pig industry

A generic framework for spatial quantitative risk assessments of infectious diseases : lumpy skin disease case study

The increase in availability of spatial data and the technological advances to handle such data allow for subsequent improvements in our ability to assess risk in a spatial setting. We provide a generic framework for quantitative risk assessments of disease introduction that capitalises on these new data. It can be adopted across multiple spatial scales, for any pathogen, method of transmission or location. The framework incorporates the risk of initial infection in a previously uninfected location due to registered movement (e.g. trade) and unregistered movement (e.g. daily movements of wild animals). We discuss the steps of the framework and the data required to compute it. We then outline how this framework is applied for a single pathway using lumpy skin disease as a case study, a disease which had an outbreak in the Balkans in 2016. We calculate the risk of initial infection for the rest of Europe in 2016 due to trade. We perform the risk assessment on 3 spatial scales – countries, regions within countries, and individual farms. We find that Croatia (assuming no vaccination occurred) has the highest mean probability of infection, with Italy, Hungary and Spain following. Including import detection of infected trade does reduce risk but this reduction is proportionally lower for countries with highest risk. The risk assessment results are consistent across the spatial scales, while in addition, at the finer spatial scales, it highlights specific areas or individual locations of countries on which to focus surveillance

Testing socioeconomic status and family socialization hypotheses of alcohol use in young people: A causal mediation analysis

Introduction: The effect of socioeconomic status on adolescent substance abuse may be mediated by family socialization practices. However, traditional mediation analysis using a product or difference method is susceptible to bias when assumptions are not addressed. We aimed to use a potential outcomes framework to assess assumptions of exposure‐mediator interaction and of no confounding of the results. Method: We revisited a traditional mediation analysis with a multiple mediator causal mediation approach using data from 17,761 Norwegian young people (13–18 years), 51% female. Data were collected through a print questionnaire. Socioeconomic status was operationalized as parental education and employment status (employed or receiving welfare); drinking behavior as the frequency of alcohol consumption and frequency of intoxication in the past year; and socialization practices as general parenting measures, alcohol‐related parental permissiveness, and parent drinking behavior. Results: There was no consistent evidence of exposure‐mediator interaction. Formal sensitivity analysis of mediator‐outcome confounding was not possible in the multiple mediator model, and this analysis supported the hypothesis that socioeconomic status effects on adolescent substance abuse are fully mediated by family socialization practices, with apparently stronger effects in younger age groups observed in plots. Conclusion: We found that the effect of socioeconomic status on adolescent substance abuse was fully mediated by family socialization practices. While our analysis provides more rigorous support for causal inferences than past work, we could not completely rule out the possibility of unmeasured confounding

Clinical relevance of biomarkers of oxidative stress

SIGNIFICANCE Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. CRITICAL ISSUES The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. FUTURE DIRECTIONS Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 00, 000-000

Bamboozled! Resolving deep evolutionary nodes within the phylogeny of bamboo corals (Octocorallia: Scleralcyonacea: Keratoisididae).

Keratoisididae is a globally distributed, and exclusively deep-sea, family of octocorals that contains species and genera that are polyphyletic. An alphanumeric system, based on a three-gene-region phylogeny, is widely used to describe the biodiversity within this family. That phylogeny identified 12 major groups although it did not have enough signal to explore the relationships among groups. Using increased phylogenomic resolution generated from Ultraconserved Elements and exons (i.e. conserved elements), we aim to resolve deeper nodes within the family and investigate the relationships among those predefined groups. In total, 109 libraries of conserved elements were generated from individuals representing both the genetic and morphological diversity of our keratoisidids. In addition, the conserved element data of 12 individuals from previous studies were included. Our taxon sampling included 11 of the 12 keratoisidid groups. We present two phylogenies, constructed from a 75% (231 loci) and 50% (1729 loci) taxon occupancy matrix respectively, using both Maximum Likelihood and Multiple Species Coalescence methods. These trees were congruent at deep nodes. As expected, S1 keratoisidids were recovered as a well-supported sister clade to the rest of the bamboo corals. S1 corals do not share the same mitochondrial gene arrangement found in other members of Keratoisididae. All other bamboo corals were recovered within two major clades. Clade I comprises individuals assigned to alphanumeric groups B1, C1, D1&D2, F1, H1, I4, and J3 while Clade II contains representatives from A1, I1, and M1. By combining genomics with already published morphological data, we provide evidence that group H1 is not monophyletic, and that the division between other groups - D1 and D2, and A1 and M1 - needs to be reconsidered. Overall, there is a lack of robust morphological markers within Keratoisididae, but subtle characters such as sclerite microstructure and ornamentation seem to be shared within groups and warrant further investigation as taxonomically diagnostic characters

A nationwide survey of confidence and knowledge of assessment and management oral conditions amongst a sample of physicians, United Kingdom

Objective: This study aimed to assess current confidence and knowledge of oral conditions amongst a sample of UK physicians and doctors in training programmes using a web-based survey. Results: 131 survey responses were analysed for doctors from FY1 to consultant grade working within medical specialties. 36.6% and 35.9% of those surveyed expressed that they felt confident diagnosing and managing oral conditions respectively. The median knowledge score was 60%; 65.6% correctly identified the image that demonstrated a squamous cell carcinoma. 91.6% reported that they felt they needed additional training in the diagnosis and management of oral conditions. Neither confidence nor knowledge were affected by grade, specialty, or region of practice