Mapping the inflammatory process in neonatal lung disease

Chronic lung disease (CLD) of prematurity is a significant complication of preterm birth in which the neutrophil appears to be the key cell of inflammation. Lack of resolution of neutrophilic inflammation, due to delayed or dysregulated neutrophil apoptosis, is thought to be an important component of the pathogenesis of CLD. In this thesis, I sought to examine the inflammatory process in the lungs of ventilated newborn infants. I have established a reliable method for the use of flow cytometry, a technique not previously reported in the study of neonatal bronchoalveolar lavage (BAL) samples, and have described both the cellular and supernatant components of BAL from term and preterm infants, paying particular attention to the role of infection. I found higher peak neutrophil counts in infants developing CLD, as well as more immature, monocyte-like, macrophages and higher rates of detection of microbial DNA when compared to term infants and infants whose respiratory distress syndrome resolved. I focused more specifically on the role of neutrophil apoptosis in CLD and sought to understand the mechanism for the delay in neutrophil apoptosis in newborn infants and how this may impact on lung disease. BAL supernatants from term infants showed more pro-apoptotic activity against adult neutrophils than BAL from preterm infants. I found a delay in apoptosis in lung neutrophils in preterm infants and confirmed this delay in blood neutrophils of term infants compared to adults. I have shown that this delay might be due to differential expression of anti-apoptotic proteins Bcl-xl and Mcl-1 between cord and adult neutrophils, which has not previously been described.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Mapping the inflammatory process in neonatal lung disease

Chronic lung disease (CLD) of prematurity is a significant complication of preterm birth in which the neutrophil appears to be the key cell of inflammation. Lack of resolution of neutrophilic inflammation, due to delayed or dysregulated neutrophil apoptosis, is thought to be an important component of the pathogenesis of CLD. In this thesis, I sought to examine the inflammatory process in the lungs of ventilated newborn infants. I have established a reliable method for the use of flow cytometry, a technique not previously reported in the study of neonatal bronchoalveolar lavage (BAL) samples, and have described both the cellular and supernatant components of BAL from term and preterm infants, paying particular attention to the role of infection. I found higher peak neutrophil counts in infants developing CLD, as well as more immature, monocyte-like, macrophages and higher rates of detection of microbial DNA when compared to term infants and infants whose respiratory distress syndrome resolved. I focused more specifically on the role of neutrophil apoptosis in CLD and sought to understand the mechanism for the delay in neutrophil apoptosis in newborn infants and how this may impact on lung disease. BAL supernatants from term infants showed more pro-apoptotic activity against adult neutrophils than BAL from preterm infants. I found a delay in apoptosis in lung neutrophils in preterm infants and confirmed this delay in blood neutrophils of term infants compared to adults. I have shown that this delay might be due to differential expression of anti-apoptotic proteins Bcl-xl and Mcl-1 between cord and adult neutrophils, which has not previously been described.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Disability, hostility and everyday geographies of un/safety

This paper connects relational theorising within geographies of disability and geographies of fear of violent crime (FOVC) to explore how disabled people navigate fear and experience of hostility in their everyday lives in Ireland. Drawing on a two year qualitative study with people with a range of impairments, we explore the human and non-human components of assemblages â in particular, encounters with others, assistive supports and â objectsâ of disability, and the physical environment â that give rise to diverse affectual and sensory geographies of un/safety. Disabled people have multiple understandings of un/safety that are contingent, embodied and emplaced, and have highly developed spatial strategies which they deploy as they navigate and respond to fears about hostility in different temporal-spatial contexts. We suggest that relational thinking has the potential to unfix binary assumptions about spaces as safe or unsafe, and to challenge dominant constructions of disabled subjectivities as inherently vulnerable. This includes expanding our attention beyond the public sphere as a site where most fear of violent crime is situated and recognising the agentic potential of disabled people as they negotiate and (re)author safety in space.Este artículo conecta la teorización relacional dentro de las geografías de la discapacidad y las geografías del miedo a los delitos violentos (FOVC, siglas en inglés) para explorar cómo las personas discapacitadas navegan por el miedo y la experiencia de la hostilidad en su vida cotidiana en Irlanda. Basándonos en un estudio cualitativo de dos años con personas con una variedad de discapacidades, exploramos los componentes humanos y no humanos de los ensamblajes, en particular, los encuentros con otros, los apoyos de asistencia y los ‘objetos’ de la discapacidad, y el entorno físico, que abren diversas geografías afectivas y sensoriales de la inseguridad. Las personas discapacitadas tienen múltiples entendimientos de inseguridad que son contingentes, incorporados y emplazados, y tienen estrategias espaciales altamente desarrolladas que despliegan mientras navegan y responden a los temores sobre la hostilidad en diferentes contextos espacio-temporales. Sugerimos que el pensamiento relacional tiene el potencial de deshacer los supuestos binarios sobre los espacios como seguros o inseguros, y desafiar las construcciones dominantes de subjetividades discapacitadas como inherentemente vulnerables. Esto incluye expandir nuestra atención más allá de la esfera pública como un sitio donde se ubica la mayor parte del miedo al crimen violento y reconocer la agencia potencial de las personas discapacitadas mientras negocian y (re) escriben la seguridad en el espacio.Cet article connecte les théorisations relationnelles au sein de la géographie du handicap et de la géographie de la peur du crime violent (aussi appelé FOVC en anglais) pour explorer la manière dont les personnes en situation de handicap traversent les peurs et les expériences d’hostilité dans leurs vies quotidiennes en Irlande. En nous appuyant sur une étude qualitative de deux ans avec des personnes en diverses situations de handicaps, nous explorons les éléments d’assemblages humains et non-humains, en particulier les rencontres avec les autres, les soutiens et les « objets » d’assistance pour les handicaps, et l’environnement physique, qui donnent lieu à une variété de géographies affectives et sensorielles de l’insécurité et de la sécurité. Les personnes en situation de handicap ont des interprétations multiples de l’insécurité et de la sécurité qui sont dépendantes, concrètes et mises en place. Elles ont également des stratégies spatiales très développées qu’elles déploient quand elles traversent et répondent à leurs peurs concernant l’hostilité dans des contextes temporels et spatiaux différents. Nous suggérons que le raisonnement relationnel a le potentiel de démonter les hypothèses binaires relatives aux espaces et qui les définissent comme dangereux ou non, et de remettre en question les constructions dominantes des subjectivités qui conçoivent les personnes en situation de handicap comme étant fondamentalement vulnérables. Cela inclut l’élargissement de notre attention au-delà de la sphère publique en tant que lieu où se trouve la majorité de la peur du crime violent, et l’admission du potentiel d’agentivité des personnes en situation de handicap tandis qu’elles négocient et (re-)créent une sécurité spatiale

Saying it out loud: how Rights theory frames and shapes practice for students with ID in a university setting

This paper tells the story of the development of a rights-based education programme for students with intellectual disability (ID) in one Irish university, the University College Cork (UCC). It explores how the philosophy underpinning the programme has emerged from an instinctive response to the segregation and isolation of people with ID into a more clearly articulated commitment to a model of provision based on a commitment to human rights. This represents a paradigm shift in how we view and work with people with ID and marks a break from traditional paternalistic and charity-based approaches to provision. Articulating what we are doing and why we are doing it, is vital for developing communities of inclusive practice who are sustained by an ongoing process of reflection, disruption, and reimagining

Mapping the inflammatory process in neonatal lung disease

Chronic lung disease (CLD) of prematurity is a significant complication of preterm birth in which the neutrophil appears to be the key cell of inflammation. Lack of resolution of neutrophilic inflammation, due to delayed or dysregulated neutrophil apoptosis, is thought to be an important component of the pathogenesis of CLD. In this thesis, I sought to examine the inflammatory process in the lungs of ventilated newborn infants. I have established a reliable method for the use of flow cytometry, a technique not previously reported in the study of neonatal bronchoalveolar lavage (BAL) samples, and have described both the cellular and supernatant components of BAL from term and preterm infants, paying particular attention to the role of infection. I found higher peak neutrophil counts in infants developing CLD, as well as more immature, monocyte-like, macrophages and higher rates of detection of microbial DNA when compared to term infants and infants whose respiratory distress syndrome resolved. I focused more specifically on the role of neutrophil apoptosis in CLD and sought to understand the mechanism for the delay in neutrophil apoptosis in newborn infants and how this may impact on lung disease. BAL supernatants from term infants showed more pro-apoptotic activity against adult neutrophils than BAL from preterm infants. I found a delay in apoptosis in lung neutrophils in preterm infants and confirmed this delay in blood neutrophils of term infants compared to adults. I have shown that this delay might be due to differential expression of anti-apoptotic proteins Bcl-xl and Mcl-1 between cord and adult neutrophils, which has not previously been described

Antibiotic resistance among clinical Ureaplasma Isolates Recovered from Neonates in England and Wales between 2007 and 2013

Ureaplasma spp. are associated with numerous clinical sequelae with treatment options being limited due to patient and pathogen factors. This report examines the prevalence and mechanisms of antibiotic resistance among clinical strains isolated from 95 neonates, 32 women attending a sexual health clinic, and 3 patients under investigation for immunological disorders, between 2007 and 2013 in England and Wales. MICs were determined by using broth microdilution assays, and a subset of isolates were compared using the broth microdilution method and the Mycoplasma IST2 assay. The underlying molecular mechanisms for resistance were determined for all resistant isolates. Three isolates carried the tet(M) tetracycline resistance gene (2.3%; confidence interval [CI], 0.49 to 6.86%); two isolates were ciprofloxacin resistant (1.5%; CI, 0.07 to 5.79%) but sensitive to levofloxacin and moxifloxacin, while no resistance was seen to any macrolides tested. The MIC values for chloramphenicol were universally low (2 μg/ml), while inherently high-level MIC values for gentamicin were seen (44 to 66 μg/ml). The Mycoplasma IST2 assay identified a number of false positives for ciprofloxacin resistance, as the method does not conform to international testing guidelines. While antibiotic resistance among Ureaplasma isolates remains low, continued surveillance is essential to monitor trends and threats from importation of resistant clones

Growth of HIV-exposed uninfected infants in the first 6 months of life in South Africa: The IeDEA-SA collaboration

BACKGROUND: HIV-exposed uninfected (HEU) infants are a growing population in sub-Saharan Africa especially with the increasing coverage of more effective prevention of mother-to-child transmission (PMTCT) antiretroviral therapy regimens. This study describes the characteristics of South African HEU infants, investigates factors impacting birth weight and assesses their growth within the first 28 weeks of life. METHODS: This is a retrospective cohort based on routine clinical data from two South African PMTCT programmes. Data were collected between 2007 and 2013. Linear regression assessed factors affecting birth weight-for-age z-scores (WAZ) while growth (longitudinal WAZ) was assessed using mixed effects models. RESULTS: We assessed the growth of 2621 HEU infants (median birth WAZ was -0.65 (IQR -1.46; 0.0) and 51% were male). The feeding modalities practised were as follows: 0.5% exclusive breastfeeding, 7.9% breastfeeding with unknown exclusivity, 0.08% mixed breastfeeding and 89.2% formula feeding. Mothers with CD4 <200 cells/μl delivered infants with a lower birth WAZ (adjusted ß -0.253 [95% CI -0.043; -0.072], p = 0.006) compared to mothers with aCD4 ≥500 cells/μl. Similarly, mothers who did not receive antiretroviral drugs delivered infants with a lower birth WAZ (adjusted ß -0.39 [95% CI -0.67; -0.11], p = 0.007) compared to mothers who received antenatal antiretrovirals. Infants with a birth weight <2 500g (ß 0.070 [95% CI 0.061; 0.078], p <0.0001) experienced faster growth within the first 28 weeks of life compared to infants with a birth weight ≥2 500g. Infants with any breastfeeding exposure experienced slower longitudinal growth compared to formula fed infants (adjusted ß -0.012 [95% CI 0.021; -0.003], p = 0.011). CONCLUSION: Less severe maternal disease and the use of antiretrovirals positively impacts birth weight in this cohort of South African HEU infants. Formula feeding was common with breastfed infants experiencing marginally slower longitudinal growth

Monitoring the South African National Antiretroviral Treatment Programme, 2003-2007: the IeDEA Southern Africa collaboration.

OBJECTIVES: To introduce the combined South African cohorts of the International epidemiologic Databases to Evaluate AIDS Southern Africa (IeDEA-SA) collaboration as reflecting the South African national antiretroviral treatment (ART) programme; to characterise patients accessing these services; and to describe changes in services and patients from 2003 to 2007. DESIGN AND SETTING: Multi-cohort study of 11 ART programmes in Gauteng, Western Cape, Free State and KwaZulu-Natal. SUBJECTS: Adults and children (<16 years old) who initiated ART with > or =3 antiretroviral drugs before 2008. RESULTS: Most sites were offering free treatment to adults and children in the public sector, ranging from 264 to 17,835 patients per site. Among 45,383 adults and 6,198 children combined, median age (interquartile range) was 35.0 years (29.8-41.4) and 42.5 months (14.7-82.5), respectively. Of adults, 68% were female. The median CD4 cell count was 102 cells/microl (44-164) and was lower among males than females (86, 34-150 v. 110, 50-169, p<0.001). Median CD4% among children was 12% (7-17.7). Between 2003 and 2007, enrolment increased 11-fold in adults and 3-fold in children. Median CD4 count at enrolment increased for all adults (67-111 cells/microl, p<0.001) and for those in stage IV (39-89 cells/microl, p<0.001). Among children <5 years, baseline CD4% increased over time (11.5-16.0%, p<0.001). CONCLUSIONS: IeDEA-SA provides a unique opportunity to report on the national ART programme. The study describes dramatically increased enrolment over time. Late diagnosis and ART initiation, especially of men and children, need attention. Investment in sentinel sites will ensure good individual-level data while freeing most sites to continue with simplified reporting

Relationship of Proteinases and Proteinase Inhibitors with Microbial Presence in Chronic Lung Disease of Prematurity

Background: A proteolytic imbalance has been implicated in the development of “classical” chronic lung disease of prematurity (CLD). However, in “new” CLD this pattern has changed. This study examines the longitudinal relationship between neutrophil proteinases and their inhibitors in ventilated preterm infants and their relationship to microbial colonisation. Methods: Serial bronchoalveolar lavage fluid was obtained from ventilated newborn preterm infants. Neutrophil elastase (NE) activity, cell counts, metalloproteinase (MMP)-9, MMP-9/TIMP-1 complex, SerpinB1 concentration and percentage of SerpinB1 and α1-antitrypsin (AAT) in complex with elastase were measured. The presence of microbial genes was examined using PCR for 16S rRNA genes. Results: Statistically more infants who developed CLD had NE activity in at least one sample (10/20) compared with infants with resolved respiratory distress syndrome (RDS) (2/17). However, NE activity was present in a minority of samples, occurring as episodic peaks. Peak levels of MMP-9, MMP-9/TIMP-1 complex, percentage of AAT and SerpinB1 in complex and cell counts were all statistically greater in infants developing CLD than in infants with resolved RDS. Peak values frequently occurred as episodic spikes and strong temporal relationships were noted between all markers. The peak values for all variables were significantly correlated to each other. The presence of bacterial 16S rRNA genes was associated with the development of CLD and with elevated elastase and MMP-9. Conclusion: NE activity and MMP-9 appear to be important in the development of “new” CLD with both proteinase and inhibitor concentrations increasing episodically, possibly in response to postnatal infection