Intraperitoneal and intra-nasal vaccination of mice with three distinct recombinant Neospora caninum antigens results in differential effects with regard to protection against experimental challenge with Neospora caninum tachyzoites

Recombinant NcPDI(recNcPDI), NcROP2(recNcROP2), and NcMAG1(recNcMAG1) were expressed in Escherichia coli and purified, and evaluated as potential vaccine candidates by employing the C57Bl/6 mouse cerebral infection model. Intraperitoneal application of these proteins suspended in saponin adjuvants lead to protection against disease in 50% and 70% of mice vaccinated with recNcMAG1 and recNcROP2, respectively, while only 20% of mice vaccinated with recNcPDI remained without clinical signs. In contrast, a 90% protection rate was achieved following intra-nasal vaccination with recNcPDI emulsified in cholera toxin. Only 1 mouse vaccinated intra-nasally with recNcMAG1 survived the challenge infection, and protection achieved with intra-nasally applied recNcROP2 was at 60%. Determination of cerebral parasite burdens by real-time PCR showed that these were significantly reduced only in recNcROP2-vaccinated animals (following intraperitoneal and intra-nasal application) and in recNcPDI-vaccinated mice (intra-nasal application only). Quantification of viable tachyzoites in brain tissue of intra-nasally vaccinated mice showed that immunization with recNcPDI resulted in significantly decreased numbers of live parasites. These data show that, besides the nature of the antigen, the protective effect of vaccination also depends largely on the route of antigen delivery. In the case of recNcPDI, the intra-nasal route provides a platform to generate a highly protective immune respons

Molecular characterization of Neospora caninum MAG1, a dense granule protein secreted into the parasitophorous vacuole, and associated with the cyst wall and the cyst matrix

SUMMARY: In Neospora caninum and Toxoplasma gondii, the parasitophorous vacuole (PV) is synthesized at the time of infection. During tachyzoite-to-bradyzoite stage conversion, the PV is later transformed into a tissue cyst that allows parasites to survive in their host for extended periods of time. We report on the characterization of NcMAG1, the N. caninum orthologue of T. gondii MAG1 (matrix antigen 1; TgMAG1). The 456 amino acid predicted NcMAG1 protein is 54% identical to TgMAG1. By immunoblotting, a rabbit antiserum raised against recombinant NcMAG1 detected a major product of approximately 67 kDa in extracts of N. caninum tachyzoite-infected Vero cells, which was stained more prominently in extracts of infected Vero cells treated to induce in vitro bradyzoite conversion. Immunofluorescence and TEM localized the protein mainly within the cyst wall and the cyst matrix. In both tachyzoites and bradyzoites, NcMAG1 was associated with the parasite dense granules. Comparison between NcMAG1 and TgMAG1 amino acid sequences revealed that the C-terminal conserved regions exhibit 66% identity, while the N-terminal variable regions exhibit only 32% identity. Antibodies against NcMAG1-conserved region cross-reacted with the orthologuous protein in T. gondii but those against the variable region did not. This indicates that the variable region possesses unique antigenic characteristics

Cyclotron resonant scattering feature simulations. I. Thermally averaged cyclotron scattering cross sections, mean free photon-path tables, and electron momentum sampling

Electron cyclotron resonant scattering features (CRSFs) are observed as absorption-like lines in the spectra of X-ray pulsars. A significant fraction of the computing time for Monte Carlo simulations of these quantum mechanical features is spent on the calculation of the mean free path for each individual photon before scattering, since it involves a complex numerical integration over the scattering cross section and the (thermal) velocity distribution of the scattering electrons. We aim to numerically calculate interpolation tables which can be used in CRSF simulations to sample the mean free path of the scattering photon and the momentum of the scattering electron. The tables also contain all the information required for sampling the scattering electron's final spin. The tables were calculated using an adaptive Simpson integration scheme. The energy and angle grids were refined until a prescribed accuracy is reached. The tables are used by our simulation code to produce artificial CRSF spectra. The electron momenta sampled during these simulations were analyzed and justified using theoretically determined boundaries. We present a complete set of tables suited for mean free path calculations of Monte Carlo simulations of the cyclotron scattering process for conditions expected in typical X-ray pulsar accretion columns (0.01<B/B_{crit}<=0.12, where B_{crit}=4.413x10^{13} G and 3keV<=kT<15keV). The sampling of the tables is chosen such that the results have an estimated relative error of at most 1/15 for all points in the grid. The tables are available online at http://www.sternwarte.uni-erlangen.de/research/cyclo.Comment: A&A, in pres

NuSTAR observation of GRO J1744-28 at low mass accretion rate

We present the spectral analysis of the LMXB GRO J1744-28 using $\sim$29 ks of NuSTAR data taken in 2017 February at a low luminosity of $3.2\times 10^{36}$ erg/s (3-50 keV). The continuum spectrum is modeled with an absorbed power-law with exponential cut-off, and an additional iron line component. We find no obvious indications for a CRSF and therefore perform a detailed cyclotron line search using statistical methods on the pulse phase-averaged as well as phase-resolved spectra. The previously detected Type II X-ray bursts are absent. Clear pulsations at a period of 2.141124(9) Hz are detected. The pulse profile shows an indication of a secondary peak, which was not seen at higher flux. The 4$\sigma$ upper limit for the strength of a CRSF in the 3-20 keV band is 0.07 keV, lower than the strength of the line found at higher luminosity. The detection of pulsations shows that the source did not enter the "propeller" regime, even though the source flux of $4.15\times 10^{-10}$ erg/cm$^{2}$/s was almost one order of magnitude below the threshold for the propeller regime claimed in previous studies on this source. The transition into the propeller regime in GRO J1744-28 must therefore be below a luminosity of $3.2\times 10^{36}$ erg/s, which implies a surface magnetic field $\lesssim 2.9\times 10^{11}$ G and mass accretion rate $\lesssim 1.7\times 10^{16}$ g/s. A change of the CRSF depth as function of luminosity is not unexpected and has been observed in other sources. This result possibly implies a change in emission geometry as function of mass accretion rate to reduce the depth of the line below our detection limit

Lung function and atherosclerosis: a cross-sectional study of multimorbidity in rural Uganda

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of global mortality. In high-income settings, the presence of cardiovascular disease among people with COPD increases mortality and complicates longitudinal disease management. An estimated 26 million people are living with COPD in sub-Saharan Africa, where risk factors for co-occurring pulmonary and cardiovascular disease may differ from high-income settings but remain uncharacterized. As non-communicable diseases have become the leading cause of death in sub-Saharan Africa, defining multimorbidity in this setting is critical to inform the required scale-up of existing healthcare infrastructure. Methods: We measured lung function and carotid intima media thickness (cIMT) among participants in the UGANDAC Study. Study participants were over 40 years old and equally divided into people living with HIV (PLWH) and an age- and sex-similar, HIV-uninfected control population. We fit multivariable linear regression models to characterize the relationship between lung function (forced expiratory volume in one second, FEV1) and pre-clinical atherosclerosis (cIMT), and evaluated for effect modification by age, sex, smoking history, HIV, and socioeconomic status. Results: Of 265 participants, median age was 52 years, 125 (47%) were women, and 140 (53%) were PLWH. Most participants who met criteria for COPD were PLWH (13/17, 76%). Median cIMT was 0.67 mm (IQR: 0.60 to 0.74), which did not differ by HIV serostatus. In models adjusted for age, sex, socioeconomic status, smoking, and HIV, lower FEV1 was associated with increased cIMT (β = 0.006 per 200 mL FEV1 decrease; 95% CI 0.002 to 0.011, p = 0.01). There was no evidence that age, sex, HIV serostatus, smoking, or socioeconomic status modified the relationship between FEV1 and cIMT. Conclusions: Impaired lung function was associated with increased cIMT, a measure of pre-clinical atherosclerosis, among adults with and without HIV in rural Uganda. Future work should explore how co-occurring lung and cardiovascular disease might share risk factors and contribute to health outcomes in sub-Saharan Africa

TRIPS implementation and secondary pharmaceutical patenting in Brazil and India

This article compares national approaches toward secondary pharmaceutical patents. Because secondary patents can extend periods of exclusivity and delay generic competition, they can raise prices and reduce access to medicines. Little is known about what measures countries have enacted policies to address applications for secondary pharmaceutical patents, how they function, and whether, in practice, these measures limit secondary patents. We analyze the cases of India and Brazil. We assemble data on pharmaceutical patent applications filed in the two countries, code each application to identify which constitute secondary applications, and examine outcomes for each application in both countries. The data indicate that Brazil is less likely to grant applications than India, but in both countries the measures designed to limit secondary patents are having little direct effect. This suggests, on the one hand, that critics of these policies, such as the transnational pharmaceutical sector and foreign governments, may be more worried than they should be. On the other hand, champions of the policies, such as NGOs and international organizations, may have cause for concern that laws on the books are not having the expected impact on patent outcomes in practice. Our findings also suggest that, at the drug level, the effects of countries’ approaches toward secondary patents need to be understood in the context of their broader approaches toward TRIPS implementation, including when and how they introduced pharmaceutical patents in the 1990s and 2000s

A study of patent thickets

Report analysing whether entry of UK enterprises into patenting in a technology area is affected by patent thickets in the technology area

A constant Cyclotron Line Energy in 4U 0115+634

We present a study of RXTE and INTEGRAL spectra of the transient 3.6 s X-ray pulsar 4U 0115+634 taken during a giant outburst in 2008 March/April. The spectra can be almost equally well modeled by two different semi-empirical continuum models, modified by an Fe Kα fluorescence line, interstellar absorption, and cyclotron resonance scattering features (CRSFs) located at ∼10.7, 21.8, 35.5, 46.7, and 59.7 keV. One of these two models, the so called NPEX model, leads to an anticorrelation between the centroid energy of the fundamental CRSF E_0 and the X-ray flux F_X, in agreement with previous works. The other model, consisting of a simple exponentially cutoff power law modified by a Gaussian emission feature around 10 keV, however, leads to a constant value for E_0 for the observed fluxes and a comparatively narrow line shape. We show that the cyclotron line model component resulting from the NPEX fits rather contribute to the broadband continuum model. We conclude that the previously reported anticorrelation is probably due to an artifact of the particular modeling of the continuum

Early intervention to promote oral feeding in patients with intracerebral hemorrhage: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Stroke is a major cause of dysphagia, but little is known about when and how dysphagic patients should be fed and treated after an acute stroke. The purpose of this study is to establish the feasibility, risks and clinical outcomes of early intensive oral care and a new speech and language therapist/nurse led structured policy for oral feeding in patients with an acute intracerebral hemorrhage (ICH).</p> <p>Methods</p> <p>A total of 219 patients with spontaneous ICH who were admitted to our institution from 2004 to 2007 were retrospectively analyzed. An early intervention program for oral feeding, which consisted of intensive oral care and early behavioral interventions, was introduced from April 2005 and fully operational by January 2006. Outcomes were compared between an early intervention group of 129 patients recruited after January 2006 and a historical control group of 90 patients recruited between January 2004 and March 2005. A logistic regression technique was used to adjust for baseline differences between the groups. To analyze time to attain oral feeding, the Kaplan-Meier method and Cox proportional hazard model were used.</p> <p>Results</p> <p>The proportion of patients who could tolerate oral feeding was significantly higher in the early intervention group compared with the control group (112/129 (86.8%) vs. 61/90 (67.8%); odds ratio 3.13, 95% CI, 1.59-6.15; P < 0.001). After adjusting for baseline imbalances, the odds ratio was 4.42 (95% CI, 1.81-10.8; P = 0.001). The incidence of chest infection was lower in the early intervention group compared with the control group (27/129 (20.9%) vs. 32/90 (35.6%); odds ratio 0.48, 95% CI, 0.26-0.88; P = 0.016). A log-rank test found a significant difference in nutritional supplementation-free survival between the two groups (hazard ratio 1.94, 95% CI, 1.46-2.71; P < 0.001).</p> <p>Conclusions</p> <p>Our data suggest that the techniques can be used safely and possibly with enough benefit to justify a randomized controlled trial. Further investigation is needed to solve the eating problems that are associated with patients recovering from a severe stroke.</p