Envelope Determinants of Equine Lentiviral Vaccine Protection

Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection. © 2013 Craigo et al

My time; your time; the time of living with myeloma

Abstract of a poster presentation presented at the Joint Meeting of the COSA 39th Annual Scientific Meeting and IPOS 14th World Congress of Psycho-Oncology, 13-15 November 2012, Brisbane Convention and Exhibition Centre

Survey of rehabilitation support for children 0-15 years in a rural part of Kenya

Abstract Purpose: Information regarding the nature, availability and distribution of rehabilitation services for children with disabilities across developing countries is scarce, and data that do exist are of variable quality. If planning and development are to progress, information about service provision is vital. The aim was to establish the scope and nature of rehabilitation support available to children with disabilities (0-15 years) and their families in rural Kenya. Method: A comprehensive sample comprising service provision in the health and special education sectors was established. Non-governmental and community-based organisations were also included. A survey of rehabilitation services was conducted through examination of service-related documentation and key informant interviews with the heads of services. Results: Rehabilitation comprised hospital-based occupational therapy, physiotherapy and orthopaedic technology; and seven special education establishments plus an education assessment resource centre. There was one non-government organisation and one community-based organisation relevant to children with disabilities. Activities focused on assessment, diagnosis and raising community awareness. Provision was challenged by inadequate staffing, resources and transport. Government funding was supplemented variously by donations and self-sufficiency initiatives. Rehabilitation approaches appeared to be informed by professional background of practitioner, rather than the needs of child. Service documentation revealed use of inconsistent recording methods. Conclusions: The data highlight the challenges of rehabilitation, demanding greater investment in personnel and their training, more material resources, improved access to the community and better recording mechanisms. Implications for Rehabilitation There needs to be greater investment in rehabilitation provision in developing countries. Consideration of community-based initiatives is required to support better access for all. In order to argue the case for improved resources, better skills and mechanisms for recording, monitoring and evaluating practice are needed

Transdermal uptake of diethyl phthalate and di(n-butyl) phthalate directly from air: Experimental verification

Background: Fundamental considerations indicate that, for certain phthalate esters, dermal absorption from air is an uptake pathway that is comparable to or larger than inhalation. Yet this pathway has not been experimentally evaluated and has been largely overlooked when assessing uptake of phthalate esters. Objectives: This study investigated transdermal uptake, directly from air, of diethyl phthalate (DEP) and di(n-butyl) phthalate (DnBP) in humans. Methods: In a series of experiments, six human participants were exposed for six hours in a chamber containing deliberately elevated air concentrations of DEP and DnBP. The participants either wore a hood and breathed air with phthalate concentrations substantially below those in the chamber or did not wear a hood and breathed chamber air. All urinations were collected from initiation of exposure until 54 hours later. Metabolites of DEP and DnBP were measured in these samples and extrapolated to parent phthalate intakes, corrected for background and hood air exposures. Results: For DEP the median dermal uptake directly from air was 4.0 µg/(µg/m3 in air) compared with an inhalation intake of 3.8 µg/(µg/m3 in air). For DnBP the median dermal uptake from air was 3.1 µg/(µg/m3 in air) compared with an inhalation intake of 3.9 µg/(µg/m3 in air). Conclusions: This study shows that dermal uptake directly from air can be a meaningful exposure pathway for DEP and DnBP. For other semivolatile organic compounds (SVOCs) whose molecular weight and Kow are in the appropriate range, direct absorption from air is also anticipated to be significant

Genomic signatures of population decline in the malaria mosquito Anopheles gambiae

Population genomic features such as nucleotide diversity and linkage disequilibrium are expected to be strongly shaped by changes in population size, and might therefore be useful for monitoring the success of a control campaign. In the Kilifi district of Kenya, there has been a marked decline in the abundance of the malaria vector Anopheles gambiae subsequent to the rollout of insecticide-treated bed nets. To investigate whether this decline left a detectable population genomic signature, simulations were performed to compare the effect of population crashes on nucleotide diversity, Tajima's D, and linkage disequilibrium (as measured by the population recombination parameter ρ). Linkage disequilibrium and ρ were estimated for An. gambiae from Kilifi, and compared them to values for Anopheles arabiensis and Anopheles merus at the same location, and for An. gambiae in a location 200 km from Kilifi. In the first simulations ρ changed more rapidly after a population crash than the other statistics, and therefore is a more sensitive indicator of recent population decline. In the empirical data, linkage disequilibrium extends 100-1000 times further, and ρ is 100-1000 times smaller, for the Kilifi population of An. gambiae than for any of the other populations. There were also significant runs of homozygosity in many of the individual An. gambiae mosquitoes from Kilifi. These results support the hypothesis that the recent decline in An. gambiae was driven by the rollout of bed nets. Measuring population genomic parameters in a small sample of individuals before, during and after vector or pest control may be a valuable method of tracking the effectiveness of interventions

Maternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat

Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. Results: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. Conclusions: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children

New Physics in Bs -> J/psi phi: a General Analysis

Recently, the CDF and D0 collaborations measured indirect CP violation in Bs -> J/psi phi and found a hint of a signal. If taken at face value, this can be interpreted as a nonzero phase of Bs-Bsbar mixing (beta_s), in disagreement with the standard model, which predicts that beta_s ~= 0. In this paper, we argue that this analysis may be incomplete. In particular, there can be new physics (NP) in the bbar -> sbar c cbar decay. If so, the value of beta_s is different than for the case in which NP is assumed to be present only in the mixing. We have examined several models of NP and found that, indeed, there can be significant contributions to the decay. These effects are consistent with measurements in B -> J/psi K* and Bd -> J/psi Ks. Due to the NP in the decay, polarization-dependent indirect CP asymmetries and triple-product asymmetries are predicted in Bs -> J/psi phi.Comment: 28 pages, JHEP, no figures. Considerable changes made. Abstract and main text of paper modified to alter presentation. Appendix added. References added. Conclusions unchanged

The use of percutaneous coronary intervention in black and white veterans with acute myocardial infarction

BACKGROUND: It is uncertain whether black white differences in the use of percutaneous coronary intervention (PCI) persist in the era of drug eluting stents. The purpose of this study is to determine if black veterans with acute myocardial infarction (AMI) are less likely to receive PCI than their white counterparts. METHODS: This study included 680 black and 3529 white veterans who were admitted to Veterans Health Administration (VHA) medical centers between July 2003 and August 2004. Information for this study was collected as part of the VHA External Peer Review Program for quality monitoring and improvement for a variety of medical conditions and procedures, including AMI. In addition, Department of Veterans Affairs workload files were used to determine PCI utilization after hospital discharge. Standard statistical methods including the Chi-square, 2 sample t-test, and logistic regression with a cluster correction for medical center were used to assess the association between race and the use of PCI ≤ 30 days from admission. RESULTS: Black patients were younger, more often had diabetes mellitus, renal disease, or dementia and less often had lipid disorders, previous coronary artery bypass surgery, or chronic obstructive pulmonary disease than their white counterparts. Equal proportions of blacks and whites underwent cardiac catheterization ≤ 30 days after admission, but the former were less likely to undergo PCI (32% vs. 40%, p < 0.0001). This difference persisted after multivariate adjustment, although measures of the extent of coronary artery disease were not available. CONCLUSION: Given the equivalent use of cardiac catheterization, it is possible that less extensive or minimal coronary artery disease in black patients could account for the observed difference