Persistence of health inequalities in childhood injury in the UK: a population-based cohort study of children under 5

BACKGROUND: Injury is a significant cause of childhood death and can result in substantial long-term disability. Injuries are more common in children from socio-economically deprived families, contributing to health inequalities between the most and least affluent. However, little is known about how the relationship between injuries and deprivation has changed over time in the UK. METHODS: We conducted a cohort study of all children under 5 registered in one of 495 UK general practices that contributed medical data to The Health Improvement Network database between 1990–2009. We estimated the incidence of fractures, burns and poisonings by age, sex, socio-economic group and calendar period and adjusted incidence rate ratios (IRR) comparing the least and most socio-economically deprived areas over time. Estimates of the UK annual burden of injuries and the excess burden attributable to deprivation were derived from incidence rates. RESULTS: The cohort of 979,383 children experienced 20,804 fractures, 15,880 burns and 10,155 poisonings, equating to an incidence of 75.8/10,000 person-years (95% confidence interval 74.8–76.9) for fractures, 57.9 (57.0–58.9) for burns and 37.3 (35.6–38.0) for poisonings. Incidence rates decreased over time for burns and poisonings and increased for fractures (p<0.001 test for trend for each injury). They were significantly higher in more deprived households (IRR test for trend p<0.001 for each injury type) and these gradients persisted over time. We estimate that 865 fractures, 3,763 burns and 3,043 poisonings could be prevented each year in the UK if incidence rates could be reduced to those of the most affluent areas. CONCLUSIONS: The incidence of burns and poisonings declined between 1990 and 2009 but increased for fractures. Despite these changes, strong socio-economic inequalities persisted resulting in an estimated 9,000 additional medically-attended injuries per year in under-5s

Independent Risk Factors for Injury in Pre-School Children: Three Population-Based Nested Case-Control Studies Using Routine Primary Care Data

Background: Injuries in childhood are largely preventable yet an estimated 2,400 children die every day because of injury and violence. Despite this, the factors that contribute to injury occurrence have not been quantified at the population scale using primary care data. We used The Health Improvement Network (THIN) database to identify risk factors for thermal injury, fractures and poisoning in pre-school children in order to inform the optimal delivery of preventative strategies. Methods: We used a matched, nested case-control study design. Cases were children under 5 with a first medically recorded injury, comprising 3,649 thermal injury cases, 4,050 fracture cases and 2,193 poisoning cases, matched on general practice to 94,620 control children. Results: Younger maternal age and higher birth order increased the odds of all injuries. Children’s age of highest injury risk varied by injury type; compared with children under 1 year, thermal injuries were highest in those age 1-2 (OR = 2.43, 95%CI 2.23–2.65), poisonings in those age 2-3 (OR = 7.32, 95%CI 6.26–8.58) and fractures in those age 3-5 (OR = 3.80, 95%CI 3.42–4.23). Increasing deprivation was an important modifiable risk factor for poisonings and thermal injuries (tests for trend p#0.001) as were hazardous/harmful alcohol consumption by a household adult (OR = 1.73, 95%CI 1.26–2.38 and OR = 1.39, 95%CI 1.07–1.81 respectively) and maternal diagnosis of depression (OR = 1.45, 95%CI 1.24–1.70 and OR = 1.16, 95%CI 1.02–1.32 respectively). Fracture was not associated with these factors, however, not living in single-adult household reduced the odds of fracture (OR = 0.88, 95%CI 0.82–0.95). Conclusions: Maternal depression, hazardous/harmful adult alcohol consumption and socioeconomic deprivation represent important modifiable risk factors for thermal injury and poisoning but not fractures in preschool children. Since these risk factors can be ascertained from routine primary care records, pre-school children’s frequent visits to primary care present an opportunity to reduce injury risk by implementing effective preventative interventions from existing national guidelines

Microvertebrates preserved in mammal burrows from the Holocene of the Argentine Pampas: a taphonomic and paleoecological approach

Microvertebrates are a major component of many assemblages recovered from the Quaternary of the Argentine Pampas. The main goal of this paper is to analyse the taphonomic history of a Holocene microfossil bonebed, recovered from the infilling of a burrow. Evidences suggest the plains vizcacha Lagostomus maximus as the putative producer of the burrow. The assemblage includes individuals belonging to different taxa of mammals (marsupials and rodents) and reptiles (snakes). Taphonomic features suggest that the accumulation inside the burrow was related to flooding processes in the plain. The burrow was a natural trap that favoured the accumulation and preservation of remains corresponding to individuals from different sources. According to the taphonomic evidence, some individuals (Lagostomus maximus, Lestodelphys halli and Serpentes indet.) died inside the burrow, whereas others (Microcavia australis, Reithrodon auritus and Ctenomys sp.) died outside the burrow, and after a time of being exposed on the surface their remains were transported by surface run-offs into the burrow. The record of Lestodelphys halli and Serpentes indet. in the burrow produced by Lagostomus maximus could be related to a circumstantial use. Mammal burrows are a significant taphonomic mode for the late Cenozoic of the Argentine Pampas

Luminal-Applied Flagellin Is Internalized by Polarized Intestinal Epithelial Cells and Elicits Immune Responses via the TLR5 Dependent Mechanism

Bacteria release flagellin that elicits innate responses via Toll-like receptor 5 (TLR5). Here, we investigated the fate of apically administrated full length flagellin from virulent and avirulent bacteria, along with truncated recombinant flagellin proteins in intestinal epithelial cells and cellular responses. Flagellin was internalized by intestinal epithelial cell (IEC) monolayers of IEC-18. Additionally, apically applied flagellin was internalized by polarized human Caco-2BBe and T-84 cells in a TLR5 dependent mechanism. More, flagellin exposure did not affect the integrity of intestinal monolayers. With immunofluorescent staining, internalized flagellin was detected in both early endosomes as well as lysosomes. We found that apical exposure of polarized Caco-2BBe and T-84 to flagellin from purified Salmonella, Escherichia coli O83:H1 (isolate from Crohn’s lesion) or avirulent E. coli K12 induced comparable levels of basolateral IL-8 secretion. A recombinant protein representing the conserved amino (N) and carboxyl (C) domains (D) of the flagellin protein (ND1/2ECHCD2/1) induced IL-8 secretion from IEC similar to levels elicited by full-length flagellins. However, a recombinant flagellin protein containing only the D3 hypervariable region elicited no IL-8 secretion in both cell lines compared to un-stimulated controls. Silencing or blocking TLR5 in Caco-2BBe cells resulted in a lack of flagellin internalization and decreased IL-8 secretion. Furthermore, apical exposure to flagellin stimulated transepithelial migration of neutrophils and dendritic cells. The novel findings in this study show that luminal-applied flagellin is internalized by normal IEC via TLR5 and co-localizes to endosomal and lysosomal compartments where it is likely degraded as flagellin was not detected on the basolateral side of IEC cultures

The highly attenuated oncolytic recombinant vaccinia virus GLV-1h68: comparative genomic features and the contribution of F14.5L inactivation

As a new anticancer treatment option, vaccinia virus (VACV) has shown remarkable antitumor activities (oncolysis) in preclinical studies, but potential infection of other organs remains a safety concern. We present here genome comparisons between the de novo sequence of GLV-1h68, a recombinant VACV, and other VACVs. The identified differences in open reading frames (ORFs) include genes encoding host-range selection, virulence and immune modulation proteins, e.g., ankyrin-like proteins, serine proteinase inhibitor SPI-2/CrmA, tumor necrosis factor (TNF) receptor homolog CrmC, semaphorin-like and interleukin-1 receptor homolog proteins. Phylogenetic analyses indicate that GLV-1h68 is closest to Lister strains but has lost several ORFs present in its parental LIVP strain, including genes encoding CrmE and a viral Golgi anti-apoptotic protein, v-GAAP. The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma. The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L-null and revertant viruses. GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism

Surfactant protein-D and pulmonary host defense

Surfactant protein-D (SP-D) participates in the innate response to inhaled microorganisms and organic antigens, and contributes to immune and inflammatory regulation within the lung. SP-D is synthesized and secreted by alveolar and bronchiolar epithelial cells, but is also expressed by epithelial cells lining various exocrine ducts and the mucosa of the gastrointestinal and genitourinary tracts. SP-D, a collagenous calcium-dependent lectin (or collectin), binds to surface glycoconjugates expressed by a wide variety of microorganisms, and to oligosaccharides associated with the surface of various complex organic antigens. SP-D also specifically interacts with glycoconjugates and other molecules expressed on the surface of macrophages, neutrophils, and lymphocytes. In addition, SP-D binds to specific surfactant-associated lipids and can influence the organization of lipid mixtures containing phosphatidylinositol in vitro. Consistent with these diverse in vitro activities is the observation that SP-D-deficient transgenic mice show abnormal accumulations of surfactant lipids, and respond abnormally to challenge with respiratory viruses and bacterial lipopolysaccharides. The phenotype of macrophages isolated from the lungs of SP-D-deficient mice is altered, and there is circumstantial evidence that abnormal oxidant metabolism and/or increased metalloproteinase expression contributes to the development of emphysema. The expression of SP-D is increased in response to many forms of lung injury, and deficient accumulation of appropriately oligomerized SP-D might contribute to the pathogenesis of a variety of human lung diseases

Dynamics of Adrenal Steroids Are Related to Variations in Th1 and Treg Populations during Mycobacterium tuberculosis Infection in HIV Positive Persons

Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS

Virulence in Murine Model Shows the Existence of Two Distinct Populations of Brazilian Vaccinia virus Strains

Brazilian Vaccinia virus had been isolated from sentinel mice, rodents and recently from humans, cows and calves during outbreaks on dairy farms in several rural areas in Brazil, leading to high economic and social impact. Some phylogenetic studies have demonstrated the existence of two different populations of Brazilian Vaccinia virus strains circulating in nature, but little is known about their biological characteristics. Therefore, our goal was to study the virulence pattern of seven Brazilian Vaccinia virus strains. Infected BALB/c mice were monitored for morbidity, mortality and viral replication in organs as trachea, lungs, heart, kidneys, liver, brain and spleen. Based on the virulence potential, the Brazilian Vaccinia virus strains were grouped into two groups. One group contained GP1V, VBH, SAV and BAV which caused disease and death in infected mice and the second one included ARAV, GP2V and PSTV which did not cause any clinical signals or death in infected BALB/c mice. The subdivision of Brazilian Vaccinia virus strains into two groups is in agreement with previous genetic studies. Those data reinforce the existence of different populations circulating in Brazil regarding the genetic and virulence characteristics

Vaccine Potential of Nipah Virus-Like Particles

Nipah virus (NiV) was first recognized in 1998 in a zoonotic disease outbreak associated with highly lethal febrile encephalitis in humans and a predominantly respiratory disease in pigs. Periodic deadly outbreaks, documentation of person-to-person transmission, and the potential of this virus as an agent of agroterror reinforce the need for effective means of therapy and prevention. In this report, we describe the vaccine potential of NiV virus-like particles (NiV VLPs) composed of three NiV proteins G, F and M. Co-expression of these proteins under optimized conditions resulted in quantifiable amounts of VLPs with many virus-like/vaccine desirable properties including some not previously described for VLPs of any paramyxovirus: The particles were fusogenic, inducing syncytia formation; PCR array analysis showed NiV VLP-induced activation of innate immune defense pathways; the surface structure of NiV VLPs imaged by cryoelectron microscopy was dense, ordered, and repetitive, and consistent with similarly derived structure of paramyxovirus measles virus. The VLPs were composed of all the three viral proteins as designed, and their intracellular processing also appeared similar to NiV virions. The size, morphology and surface composition of the VLPs were consistent with the parental virus, and importantly, they retained their antigenic potential. Finally, these particles, formulated without adjuvant, were able to induce neutralizing antibody response in Balb/c mice. These findings indicate vaccine potential of these particles and will be the basis for undertaking future protective efficacy studies in animal models of NiV disease