The rapid evolution of porcine reproductive and respiratory syndrome viruses (PRRSV) poses a major challenge to effective disease control since available vaccines show variable efficacy against ...divergent strains. Knowledge of the antigenic targets of virus-neutralizing antibodies that confer protection against heterologous PRRSV strains would be a catalyst for the development of next-generation vaccines. Key to discovering these epitopes is the isolation of neutralizing monoclonal antibodies (mAbs) from immune pigs. To address this need, we sought to establish systems to enable the isolation of PRRSV neutralizing porcine mAbs. We experimentally produced a cohort of immune pigs by sequential challenge infection with four heterologous PRRSV strains spanning PRRSV-1 subtypes and PRRSV species. Whilst priming with PRRSV-1 subtype 1 did not confer full protection against a subsequent infection with a PRRSV-1 subtype 3 strain, animals were protected against a subsequent PRRSV-2 infection. The infection protocol resulted in high serum neutralizing antibody titers against PRRSV-1 Olot/91 and significant neutralization of heterologous PRRSV-1/-2 strains. Enriched memory B cells isolated at the termination of the study were genetically programmed by transduction with a retroviral vector expressing the Bcl-6 transcription factor and the anti-apoptotic Bcl-xL protein, a technology we demonstrated efficiently converts porcine memory B cells into proliferating antibody-secreting cells. Pools of transduced memory B cells were cultured and supernatants containing PRRSV-specific antibodies identified by flow cytometric staining of infected MARC-145 cells and
neutralization of PRRSV-1. Collectively, these data suggest that this experimental system may be further exploited to produce a panel of PRRSV-specific mAbs, which will contribute both to our understanding of the antibody response to PRRSV and allow epitopes to be resolved that may ultimately guide the design of immunogens to induce cross-protective immunity.
Summary This socio-economic review provides an overview of the sanitation crisis in slum areas, and re-emphasizes the importance of sanitation. It highlights a lack of recognition of actual drivers ...for sanitation improvements, and the complexities in the provision of sanitation services in the context of urban slums with a mix of tenants and landlords. It elaborates how the drivers of demand for sanitation outlined in contemporary research are not universal but are rather context specific. The authors point out specific knowledge gaps for future research; for example, the need to establish a scientific basis for context-specific drivers of demand for sanitation improvements in slums, and a better understanding of associated complexities in order to set boundary conditions for achieving desired improvements.
Background/aim: A current consensus in epidemiological studies of primary angle closure (PAC) is to diagnose the condition only if the posterior (usually pigmented) trabecular meshwork is seen for ...less than 90° of the angle circumference, termed an “occludable angle.” The authors sought to assess the validity of this epidemiological classification by exploring the relation between drainage angle width, peripheral anterior synechiae (PAS) and glaucomatous optic neuropathy (GON). Methods: 918 Mongolians and 995 Chinese Singaporeans, both groups aged 40 years and older were examined in two population based surveys. Gonioscopic angle width was graded in five categories (0 = closed to 4 = wide open) according the scheme described by Shaffer. Cases with secondary PAS were excluded. Results: The rate of PAS was between 0.3% and 1.7% in people with wide angles (grades 3 and 4). In those with grade 2 angles, PAS were seen in between 8% of eyes. In eyes with grade 1 angles, the rate rose to 17% in Chinese Singaporeans, and 31% in Mongolians. The odds of PAS were higher in people with narrower angles. However, there was a greater absolute number of people with PAS whose drainage angles were classified as “not occludable” than those classified “occludable.” Conclusions: The traditional view that primary angle closure becomes a significant possibility in drainage angles of ⩽ grade 2 (approximately 20°) is valid in east Asians. The definition of an “occludable” angle examined here excludes many people with PAS. This probably serves to underemphasise the role of PAC in population surveys of glaucoma prevalence in Asian people.
The ion velocity distribution functions of thermonuclear plasmas generated by spherical laser direct drive implosions are studied using deuterium-tritium (DT) and deuterium-deuterium (DD) fusion ...neutron energy spectrum measurements. A hydrodynamic Maxwellian plasma model accurately describes measurements made from lower temperature (< 10 keV), hydrodynamiclike plasmas, but is insufficient to describe measurements made from higher temperature more kineticlike plasmas. The high temperature measurements are more consistent with Vlasov-Fokker-Planck (VFP) simulation results which predict the presence of a bimodal plasma ion velocity distribution near peak neutron production. Furthermore, these measurements provide direct experimental evidence of non-Maxwellian ion velocity distributions in spherical shock driven implosions and provide useful data for benchmarking kinetic VFP simulations.
Woodland caribou (Rangifer tarandus caribou) are a species of increasing conservation concern across North America. Throughout much of boreal Canada, human developments, including forestry and energy ...development, are now accepted causes of the decline in the number and distribution of caribou. One of the hypothesised mechanisms for the decline is altered predator–prey dynamics. We quantified the impacts of a variety of industrial activities on gray wolf (Canis lupus) and caribou interactions at a regional scale. We used animal locations collected with global positioning system collars and field data to examine how a range of industrial developments influenced the movements of wolves. We quantified the speed of wolf movements and the tortuosity of movement paths at two spatiotemporal scales across forested boreal and mountainous environments occupied by woodland caribou. Habitat and disturbance features better explained wolf movements during the weekly scale. In general, linear movements increased during winter, which paralleled past studies that suggested linear travel by wolves was associated with deep snow and the increased maintenance and patrol of territories. Wolves decreased movement rates but not sinuosity within close proximity to disturbance features, thus implying behaviours near such features were more closely associated with prey searching and hunting. Alternatively, wolves increased movement rates and linear travel through areas with high densities of linear and non-linear industrial features; this response suggested that wolves avoided spending time in high-risk areas associated with human activities. Results of this study further our understanding of wolf distribution and behaviour in habitats supporting populations of caribou within a matrix of industrial developments.
Matrix metalloproteinase-14 (MMP-14) promotes vulnerable plaque morphology in mice, whereas tissue inhibitor of metalloproteinases-3 (TIMP-3) overexpression is protective. MMP-14 hi TIMP-3 lo ...rabbit foam cells are more invasive and more prone to apoptosis than MMP-14 lo TIMP-3 hi cells. We investigated the implications of these findings for human atherosclerosis. In vitro generated macrophages and foam-cell macrophages, together with atherosclerotic plaques characterised as unstable or stable, were examined for expression of MMP-14, TIMP-3, and inflammatory markers. Proinflammatory stimuli increased MMP-14 and decreased TIMP-3 mRNA and protein expression in human macrophages. However, conversion to foam-cells with oxidized LDL increased MMP-14 and decreased TIMP-3 protein, independently of inflammatory mediators and partly through posttranscriptional mechanisms. Within atherosclerotic plaques, MMP-14 was prominent in foam-cells with either pro- or anti-inflammatory macrophage markers, whereas TIMP-3 was present in less foamy macrophages and colocalised with CD206. MMP-14 positive macrophages were more abundant whereas TIMP-3 positive macrophages were less abundant in plaques histologically designated as rupture prone. We conclude that foam-cells characterised by high MMP-14 and low TIMP-3 expression are prevalent in rupture-prone atherosclerotic plaques, independent of pro- or anti-inflammatory activation. Therefore reducing MMP-14 activity and increasing that of TIMP-3 could be valid therapeutic approaches to reduce plaque rupture and myocardial infarction.
To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.
Patients ...received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture.
Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses PRs; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07).
Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.
The cancer-related event that is most disruptive to the cancer patient's quality of life is pain. To begin to define the mechanisms that give rise to cancer pain, we examined the neurochemical ...changes that occur in the spinal cord and associated dorsal root ganglia in a murine model of bone cancer. Twenty-one days after intramedullary injection of osteolytic sarcoma cells into the femur, there was extensive bone destruction and invasion of the tumor into the periosteum, similar to that found in patients with osteolytic bone cancer. In the spinal cord, ipsilateral to the cancerous bone, there was a massive astrocyte hypertrophy without neuronal loss, an expression of dynorphin and c-Fos protein in neurons in the deep laminae of the dorsal horn. Additionally, normally non-noxious palpation of the bone with cancer induced behaviors indicative of pain, the internalization of the substance P receptor, and c-Fos expression in lamina I neurons. The alterations in the neurochemistry of the spinal cord and the sensitization of primary afferents were positively correlated with the extent of bone destruction and the growth of the tumor. This "neurochemical signature" of bone cancer pain appears unique when compared to changes that occur in persistent inflammatory or neuropathic pain states. Understanding the mechanisms by which the cancer cells induce this neurochemical reorganization may provide insight into peripheral factors that drive spinal cord plasticity and in the development of more effective treatments for cancer pain.
The transport of polystyrene microspheres was examined in packed glass beads under a variety of environmentally relevant ionic strength and flow conditions. The observed profiles of numbers of ...retained microspheres versus distance from the column entrance were much steeper than expected based on a constant rate coefficient of deposition across the length of the column, indicating apparent decreases in deposition rate coefficients with transport distance. Deviation in the profile from log-linear decreases with distance was greatest under highly unfavorable conditions (low ionic strength), relatively reduced under mildly unfavorable conditions (high ionic strength), and was eliminated under favorable conditions. The generality of apparent decreases in deposition rate coefficients with distance of transport among microspheres, bacteria, and viruses leads to the conclusion that such effects reflect processes that are fundamental to filtration under unfavorable conditions. Numerical simulations of experiments that were performed under unfavorable conditions utilized a log-normal distribution of deposition rate coefficients among the colloid population in order to simulate the effluent curves and retained profiles simultaneously. It is shown that while straining could be a significant contributor to the steep retained profiles at low ionic strength, where overall retention is low, distribution in interaction potentials among the population was a viable mechanism that can yield apparent decreases in deposition rate coefficients with distance of transport.
PDF
