Cross-protection between attenuated Plasmodium berghei and P. yoelii sporozoites

An attenuatedPlasmodium falciparum sporozoite (PfSPZ) vaccine is under development, in part, based on studies in mice withP. berghei. We usedP. berghei andP. yoelii to study vaccine-induced protection against challenge with a species of parasite different from the immunizing parasite in BALB/c mice. One-hundred percent of mice were protected against homologous challenge. Seventy-nine percent immunized with attenuatedP. berghei sporozoite (PbSPZ)(six experiments) were protected against challenge withP. yoelii sporozoite (PySPZ), and 63% immunized with attenuatedPySPZ(three experiments) were protected against challenge withPbSPZ. Antibodies in sera of immunized mice only recognized homologous sporozoites and could not have mediated protection against heterologous challenge. Immunization with attenuatedPySPZ orPbSPZ induced CD8+ T cell-dependent protection against heterologous challenge. Immunization with attenuatedPySPZ induced CD8+ T cell-dependent protection against homologous challenge. However, homologous protection induced by attenuatedPbSPZ was not dependent on CD8+ or CD4+ T cells, and depletion of both populations only reduced protection by 36%. Immunization of C57BL/10 mice withPbSPZ induced CD8+ T cell-dependent protection againstP. berghei, but no protection againstP. yoelii. The cross-protection data in BALB/c mice support testing a human vaccine based on attenuatedPfSPZ for its efficacy againstP. vivax

Weinberg like sum rules revisited

The generalized Weinberg sum rules containing the difference of isovector vector and axial-vector spectral functions saturated by both finite and infinite number of narrow resonances are considered. We summarize the status of these sum rules and analyze their overall agreement with phenomenological Lagrangians, low-energy relations, parity doubling, hadron string models, and experimental data.Comment: 31 pages, noticed misprints are corrected, references are added, and other minor corrections are mad

Protective CD8+ T lymphocytes in Primates Immunized with Malaria Sporozoites

Live attenuated malaria vaccines are more potent than the recombinant protein, bacterial or viral platform vaccines that have been tested, and an attenuated sporozoite vaccine against falciparum malaria is being developed for humans. In mice, attenuated malaria sporozoite vaccines induce CD8+ T cells that kill parasites developing in the liver. We were curious to know if CD8+ T cells were also important in protecting primates against malaria. We immunized 9 rhesus monkeys with radiation attenuated Plasmodium knowlesi sporozoites, and found that 5 did not develop blood stage infections after challenge with live sporozoites. We then injected 4 of these protected monkeys with cM-T807, a monoclonal antibody to the CD8 molecule which depletes T cells. The fifth monkey received equivalent doses of normal IgG. In 3 of the 4 monkeys receiving cM-T807 circulating CD8+ T cells were profoundly depleted. When re-challenged with live sporozoites all 3 of these depleted animals developed blood stage malaria. The fourth monkey receiving cM-T807 retained many circulating CD8+ T cells. This monkey, and the vaccinated monkey receiving normal IgG, did not develop blood stage malaria at re-challenge with live sporozoites. Animals were treated with antimalarial drugs and rested for 4 months. During this interval CD8+ T cells re-appeared in the circulation of the depleted monkeys. When all vaccinated animals received a third challenge with live sporozoites, all 5 monkeys were once again protected and did not develop blood stage malaria infections. These data indicate that CD8+ T cells are important effector cells protecting monkeys against malaria sporozoite infection. We believe that malaria vaccines which induce effector CD8+ T cells in humans will have the best chance of protecting against malaria

A proteogenomic update to Yersinia: enhancing genome annotation

<p>Abstract</p> <p>Background</p> <p>Modern biomedical research depends on a complete and accurate proteome. With the widespread adoption of new sequencing technologies, genome sequences are generated at a near exponential rate, diminishing the time and effort that can be invested in genome annotation. The resulting gene set contains numerous errors in even the most basic form of annotation: the primary structure of the proteins.</p> <p>Results</p> <p>The application of experimental proteomics data to genome annotation, called proteogenomics, can quickly and efficiently discover misannotations, yielding a more accurate and complete genome annotation. We present a comprehensive proteogenomic analysis of the plague bacterium, <it>Yersinia pestis KIM</it>. We discover non-annotated genes, correct protein boundaries, remove spuriously annotated ORFs, and make major advances towards accurate identification of signal peptides. Finally, we apply our data to 21 other <it>Yersinia </it>genomes, correcting and enhancing their annotations.</p> <p>Conclusions</p> <p>In total, 141 gene models were altered and have been updated in RefSeq and Genbank, which can be accessed seamlessly through any NCBI tool (e.g. blast) or downloaded directly. Along with the improved gene models we discover new, more accurate means of identifying signal peptides in proteomics data.</p

Endometrial stromal sarcoma: a population-based analysis

To determine independent prognostic factors for the survival of patients with endometrial stromal sarcoma (ESS), data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute from 1988 to 2003. Kaplan–Meier and Cox proportional hazards models were used for analyses. Of 831 women diagnosed with ESS, the median age was 52 years (range: 17–96 years). In total, 59.9% had stage I, 5.1% stage II, 14.9% stage III, and 20.1% had stage IV disease. Overall, 13.0, 36.1, and 34.7% presented with grades 1, 2, and 3, respectively. Patients with stage I–II vs III–IV disease had 5 years DSS of 89.3% vs 50.3% (P<0.001) and those with grades 1, 2, and 3 cancers had survivals of 91.4, 95.4, and 42.1% (P<0.001). In multivariate analysis, older patients, black race, advanced stage, higher grade, lack of primary surgery, and nodal metastasis were independent prognostic factors for poorer survival. In younger women (<50 years) with stage I–II disease, ovarian-sparing procedures did not adversely impact survival (91.9 vs 96.2%; P=0.1). Age, race, primary surgery, stage, and grade are important prognostic factors for ESS. Excellent survival in patients with grade 1 and 2 disease of all stages supports the concept that these tumors are significantly different from grade 3 tumors. Ovarian-sparing surgeries may be considered in younger patients with early-stage disease

Decadal-timescale estuarine geomorphic change under future scenarios of climate and sediment supply

© The Authors, 2009. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License. The definitive version was published in Estuaries and Coasts 33 (2010): 15-29, doi:10.1007/s12237-009-9244-y.Future estuarine geomorphic change, in response to climate change, sea-level rise, and watershed sediment supply, may govern ecological function, navigation, and water quality. We estimated geomorphic changes in Suisun Bay, CA, under four scenarios using a tidal-timescale hydrodynamic/sediment transport model. Computational expense and data needs were reduced using the morphological hydrograph concept and the morphological acceleration factor. The four scenarios included (1) present-day conditions; (2) sea-level rise and freshwater flow changes of 2030; (3) sea-level rise and decreased watershed sediment supply of 2030; and (4) sea-level rise, freshwater flow changes, and decreased watershed sediment supply of 2030. Sea-level rise increased water levels thereby reducing wave-induced bottom shear stress and sediment redistribution during the wind-wave season. Decreased watershed sediment supply reduced net deposition within the estuary, while minor changes in freshwater flow timing and magnitude induced the smallest overall effect. In all future scenarios, net deposition in the entire estuary and in the shallowest areas did not keep pace with sea-level rise, suggesting that intertidal and wetland areas may struggle to maintain elevation. Tidal-timescale simulations using future conditions were also used to infer changes in optical depth: though sea-level rise acts to decrease mean light irradiance, decreased suspended-sediment concentrations increase irradiance, yielding small changes in optical depth. The modeling results also assisted with the development of a dimensionless estuarine geomorphic number representing the ratio of potential sediment import forces to sediment export forces; we found the number to be linearly related to relative geomorphic change in Suisun Bay. The methods implemented here are widely applicable to evaluating future scenarios of estuarine change over decadal timescales.This study was supported by the US Geological Survey’s Priority Ecosystems Science program, CALFED Bay/ Delta Program, and the University of California Center for Water Resources

Structural equation modeling in medical research: a primer

<p>Abstract</p> <p>Background</p> <p>Structural equation modeling (SEM) is a set of statistical techniques used to measure and analyze the relationships of observed and latent variables. Similar but more powerful than regression analyses, it examines linear causal relationships among variables, while simultaneously accounting for measurement error. The purpose of the present paper is to explicate SEM to medical and health sciences researchers and exemplify their application.</p> <p>Findings</p> <p>To facilitate its use we provide a series of steps for applying SEM to research problems. We then present three examples of how SEM has been utilized in medical and health sciences research.</p> <p>Conclusion</p> <p>When many considerations are given to research planning, SEM can provide a new perspective on analyzing data and potential for advancing research in medical and health sciences.</p

Statistical mechanics of violent relaxation in stellar systems

We discuss the statistical mechanics of violent relaxation in stellar systems following the pioneering work of Lynden-Bell (1967). The solutions of the gravitational Vlasov-Poisson system develop finer and finer filaments so that a statistical description is appropriate to smooth out the small-scales and describe the ``coarse-grained'' dynamics. In a coarse-grained sense, the system is expected to reach an equilibrium state of a Fermi-Dirac type within a few dynamical times. We describe in detail the equilibrium phase diagram and the nature of phase transitions which occur in self-gravitating systems. Then, we introduce a small-scale parametrization of the Vlasov equation and propose a set of relaxation equations for the coarse-grained dynamics. These relaxation equations, of a generalized Fokker-Planck type, are derived from a Maximum Entropy Production Principle (MEPP). We make a link with the quasilinear theory of the Vlasov-Poisson system and derive a truncated model appropriate to collisionless systems subject to tidal forces. With the aid of this kinetic theory, we qualitatively discuss the concept of ``incomplete relaxation'' and the limitations of Lynden-Bell's theory

Immunomodulation with Recombinant Interferon-γ1b in Pulmonary Tuberculosis

BACKGROUND:Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-gamma1b (rIFN-gammab) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance. METHODOLOGY/PRINCIPAL FINDINGS:We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-gamma1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1beta, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-gamma1b group from baseline to week 16. Both rIFN-gamma1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-gamma1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-gamma1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-gamma1b versus DOTS alone. CONCLUSION:Recombinant interferon-gamma1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms. TRIAL REGISTRATION:ClinicalTrials.gov NCT00201123

Effectiveness of second generation antipsychotics: A systematic review of randomized trials

<p>Abstract</p> <p>Background</p> <p>Systematic reviews based on efficacy trials are inconclusive about which second generation antipsychotic drug (SGA) should be preferred in normal clinical practice, and studies with longer duration and more pragmatic designs are called for. Effectiveness studies, also known as naturalistic, pragmatic, practical or real life studies, adhere to these principles as they aim to mimic daily clinical practice and have longer follow-up.</p> <p>Objective</p> <p>To review the head-to-head effectiveness of SGAs in the domains of global outcomes, symptoms of disease, and tolerability.</p> <p>Methods</p> <p>Searches were made in Embase, PubMED, and the Cochrane central register of controlled trials for effectiveness studies published from 1980 to 2008, week 1. Different combinations of the keywords <it>antipsychotic*, neuroleptic* AND open, pragmatic, practical, naturalistic, real life, effectiveness, side effect*, unwanted effect*, tolera* AND compar* AND random* </it>were used.</p> <p>Results</p> <p>Sixteen different reports of randomized head-to-head comparisons of SGA effectiveness were located. There were differences regarding sample sizes, inclusion criteria and follow-up periods, as well as sources of financial sponsorship. In acute-phase and first-episode patients no differences between the SGAs were disclosed regarding alleviating symptoms of disease. Olanzapine was associated with more weight gain and adverse effects on serum lipids. In the chronic phase patients olanzapine groups had longer time to discontinuation of treatment and better treatment adherence compared to other SGAs. The majority of studies found no differences between the SGAs in alleviating symptoms of psychosis in chronically ill patients. Olanzapine was associated with more metabolic adverse effects compared to the others SGAs. There were surprisingly few between-drug differences regarding side effects. First generation antipsychotics were associated with lower total mental health care costs in 2 of 3 studies on chronically ill patients, but were also associated with more extrapyramidal side effects compared to the SGAs in several studies.</p> <p>Conclusion</p> <p>In chronically ill patients olanzapine may have an advantage over other SGAs regarding longer time to treatment discontinuation and better drug adherence, but the drug is also associated with more metabolic side effects. More effectiveness studies on first-episode psychosis are needed.</p