Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in mycobacterium tuberculosis–infected individuals

Copyright © 2009 by the American Thoracic Society.Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNγ and IL-2 ELISpot assays and FACS. Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-γ and IL-2 response that was durable for 52 weeks. The magnitude of IFN-γ response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin–vaccinated individuals. Antigen 85A–specific polyfunctional CD4+ T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas.Oxford Biomedical Research Centre, Wellcome Trust, and AFTBVAC

High-frequency homogenization for periodic media

This article is available open access through the publisher’s website at the link below. Copyright @ 2010 The Royal Society.An asymptotic procedure based upon a two-scale approach is developed for wave propagation in a doubly periodic inhomogeneous medium with a characteristic length scale of microstructure far less than that of the macrostructure. In periodic media, there are frequencies for which standing waves, periodic with the period or double period of the cell, on the microscale emerge. These frequencies do not belong to the low-frequency range of validity covered by the classical homogenization theory, which motivates our use of the term ‘high-frequency homogenization’ when perturbing about these standing waves. The resulting long-wave equations are deduced only explicitly dependent upon the macroscale, with the microscale represented by integral quantities. These equations accurately reproduce the behaviour of the Bloch mode spectrum near the edges of the Brillouin zone, hence yielding an explicit way for homogenizing periodic media in the vicinity of ‘cell resonances’. The similarity of such model equations to high-frequency long wavelength asymptotics, for homogeneous acoustic and elastic waveguides, valid in the vicinities of thickness resonances is emphasized. Several illustrative examples are considered and show the efficacy of the developed techniques.NSERC (Canada) and the EPSRC

Constraints in the post-harvest processing of cassava at household level in two districts of southern Tanzania

This project, funded by the Overseas Development Administration (ODA), aims to improve rapid cassava processing methods in rural households where a need is evident. The development and adoption of appropriate processing methods will be through participatory research involving, to a high degree, those who will use the technology. The project is being undertaken in partnership with the Tanzania Food and Nutrition Centre, as lead collaborator; Regional Agriculture and Livestock Development Office, Mtwara; Agricultural Research Institute Naliendele, Mtwara; and Rural Integrated Project Support Programme, a FINNIDA funded project in Mtwara and Lindi. This participatory rural appraisal (PRA) study included eight villages in two districts of Southern Tanzania and aimed to: (1) obtain an inventory of existing traditional processing methods; (2) document information on farmers and processors preferences for processed products and situations that influence their choice of processing method, such as varietal preferences, storability, food safety, marketing and indigenous knowledge; (3) identify processing needs and constraints to develop improved processing methods; and (4) learn from the experiences of previous cassava processing technology transfer activities undertaken by the extension services

Lattice collapse and quenching of magnetism in CaFe2As2 under pressure: A single crystal neutron and x-ray diffraction investigation

Single crystal neutron and high-energy x-ray diffraction have identified the phase lines corresponding to transitions between the ambient-pressure tetragonal (T), the antiferromagnetic orthorhombic (O) and the non-magnetic collapsed tetragonal (cT) phases of CaFe2As2. We find no evidence of additional structures for pressures up to 2.5 GPa (at 300 K). Both the T-cT and O-cT transitions exhibit significant hysteresis effects and we demonstrate that coexistence of the O and cT phases can occur if a non-hydrostatic component of pressure is present. Measurements of the magnetic diffraction peaks show no change in the magnetic structure or ordered moment as a function of pressure in the O phase and we find no evidence of magnetic ordering in the cT phase. Band structure calculations show that the transition results in a strong decrease of the iron 3d density of states at the Fermi energy, consistent with a loss of the magnetic moment.Comment: List of authors in metadata and typos in labeling of inset in Fig. 1(a) corrected. One ref. added. No other change

Microfossils from the late Mesoproterozoic - early Neoproterozoic Atar/EI Mreiti Group, Taoudeni Basin, Mauritania, northwestern Africa

The well-preserved Meso-Neoproterozoic shallow marine succession of the Atar/EI Mreiti Group, in the Taoudeni Basin, Mauritania, offers a unique opportunity to investigate the mid-Proterozoic eukaryotic record in Western Africa. Previous investigations focused on stromatolites, biomarkers, chemostratigraphy and palaeoredox conditions. However, only a very modest diversity of organic-walled microfossils (acritarchs) has been documented. Here, we present a new, exquisitely well-preserved and morphologically diverse assemblage of organic-walled microfossils from three cores drilled through the Atar/El Mreiti Group. A total of 48 distinct entities including 11 unambiguous eukaryotes (ornamented and process-bearing acritarchs), and 37 taxonomically unresolved taxa (including 9 possible eukaryotes, 6 probable prokaryotes, and 22 other prokaryotic or eukaryotic taxa) were observed. Black shales preserve locally abundant fragments of organic-rich laminae interpreted as benthic microbial mats. We also document one of the oldest records of Leiosphaeridia kulgunica, a species showing a circular opening interpreted as a sophisticated circular excystment structure (a pylome), and one of the oldest records of Trachyhystrichosphaera aimika and T. botula, two distinctive process-bearing acritarchs present in well dated 1.1 Ga formations at the base of the succession. The general assemblage composition and the presence of three possible index fossils (A. tetragonala, S. segmentata and T. aimika) support a late Mesoproterozoic to early Neoproterozoic (Tonian) age for the Atar/El Mreiti Group, consistent with published lithostratigraphy, chemostratigraphy and geochronology. This study provides the first evidence for a moderately diverse eukaryotic life, at least 1.1 billion years ago in Western Africa. Comparison with coeval worldwide assemblages indicates that a broadly similar microbial biosphere inhabited (generally redox-stratified) oceans, placing better time constraints on early eukaryote palaeogeography and biostratigraphy

Late Ediacaran Redox Stability and Metazoan Evolution

The Neoproterozoic arrival of animals fundamentally changed Earth's biological and geochemical trajectory. Since the early description of Ediacaran and Cambrian animal fossils, a vigorous debate has emerged about the drivers underpinning their seemingly rapid radiation. Some argue for predation and ecology as central to diversification, whereas others point to a changing chemical environment as the trigger. In both cases, questions of timing and feedbacks remain unresolved. Through these debates, the last fifty years of work has largely converged on the concept that a change in atmospheric oxygen levels, perhaps manifested indirectly as an oxygenation of the deep ocean, was causally linked to the initial diversification of large animals. What has largely been absent, but is provided in this study, is a multi-proxy stratigraphic test of this hypothesis. Here, we describe a coupled geochemical and paleontological investigation of Neoproterozoic sedimentary rocks from northern Russia. In detail, we provide iron speciation data, carbon and sulfur isotope compositions, and major element abundances from a predominantly siliciclastic succession (spanning>1000 m) sampled by the Kel'tminskaya-1 drillcore. Our interpretation of these data is consistent with the hypothesis that the $pO_2$ threshold required for diversification of animals with high metabolic oxygen demands was crossed prior to or during the Ediacaran Period. Redox stabilization of shallow marine environments was, however, also critical and only occurred about 560 million years ago (Ma), when large motile bilaterians first enter the regional stratigraphic record. In contrast, neither fossils nor geochemistry lend support to the hypothesis that ecological interactions altered the course of evolution in the absence of environmental change. Together, the geochemical and paleontological records suggest a coordinated transition from low oxygen oceans sometime before the Marinoan (~635 Ma) ice age, through better oxygenated but still redox-unstable shelves of the early Ediacaran Period, to the fully and persistently oxygenated marine environments characteristic of later Ediacaran successions that preserve the first bilaterian macrofossils and trace fossils.Earth and Planetary SciencesOrganismic and Evolutionary Biolog

Black shale deposition and early diagenetic dolomite cementation during Oceanic Anoxic Event 1: The mid-Cretaceous Maracaibo Platform, northwestern South America

Thin laterally continuous organic-rich dolomitic marlstones were deposited in the extended Late Aptian - Early Albian epicontinental sea of northwestern South America. These intervals are the proximal equivalents of thick hemipelagic black shale-ammonitic floatstone couplets, deposited in the distally stepped, differentially subsiding part of the Maracaibo Platform. The marlstones reflect the dynamic conditions resulting from orbital forcing mechanisms and can be genetically related to (1) minor sea-level changes, (2) proximal turnovers in marine productivity, and (3) sudden climate shifts affecting mid-Cretaceous shoaling upward, shallow marine, carbonate cyclicity. Therefore, the marlstones may well be linked to the multiple environmental perturbations collectively referred to as Oceanic Anoxic Event 1. The interstitial euhedral dolomite has a medium crystallinity, and exhibits unusual textural relations with framboidal pyrite and gypsum. The authigenic mineral assemblage also includes quartz, Ca-F apatite, and barite, which together with the chemical signals of dolomite, point to an unsteady climate regime. Bulk-rock biomarker parameters, rare earth element geochemistry, and iron speciation data point to widespread photic zone anoxia and transient shallow marine euxinia by the time of deposition, with climatic instability driving the delivery of oxidized detritus from the hinterlands. These conditions led to a schizohaline redox stratified environment favorable to dolomite precipitation. In such a depositional setting, the bio-utilization of Fe, Mn, and sulfur for organic matter respiration sustained elevated pore-water alkalinity and pH, and allowed for the pre-compactional growth of interstitial dolomite

A global transition to ferruginous conditions in the early Neoproterozoic oceans

Eukaryotic life expanded during the Proterozoic eon1, 2.5 to 0.542 billion years ago, against a background of fluctuating ocean chemistry2, 3, 4. After about 1.8 billion years ago, the global ocean is thought to have been characterized by oxygenated surface waters, with anoxic and sulphidic waters in middle depths along productive continental margins and anoxic and iron-containing (ferruginous) deeper waters5, 6, 7. The spatial extent of sulphidic waters probably varied through time5, 6, but this surface-to-deep redox structure is suggested to have persisted until the first Neoproterozoic glaciation about 717 million years ago8, 9, 10, 11. Here we report an analysis of ocean redox conditions throughout the Proterozoic using new and existing iron speciation and sulphur isotope data from multiple cores and outcrops. We find a global transition from sulphidic to ferruginous mid-depth waters in the earliest Neoproterozoic, coincident with the amalgamation of the supercontinent Rodinia at low latitudes. We suggest that ferruginous conditions were initiated by an increase in the oceanic influx of highly reactive iron relative to sulphate, driven by a change in weathering regime and the uptake of sulphate by extensive continental evaporites on Rodinia. We propose that this transition essentially detoxified ocean margin settings, allowing for expanded opportunities for eukaryote diversification following a prolonged evolutionary stasis before one billion years ago

Tumour-associated immune responses and isolated carcinoembryonic antigen and alpha feto-protein levels related to survival in ovarian cancer patients.

The presence of a tumour-associated immune response in 37 patients with ovarian cancer as assessed by blastogenesis (lymphocyte transformation) evoked by ovarian cancer cell extracts, has been correlated with survival following the test. The difference in these responses is unlikely to be accounted for on the basis of general impairment of cell-mediated immuno-competence. Serum carcinoembryonic antigen (CEA) was also determined in 27 ovarian cancer patients to assess its prognostic significance. Raised CEA levels and absence of blastogenic response to tumour cell extract during relapse are associated with a worse prognosis but neither of these parameters are significant in remission. Possible applications of these findings to the clinical management of ovarian cancer patients are discussed. Serum alpha feto-protein levels measured by radioimmunoassay were not found to be raised in any of the 32 ovarian cancer patients in whom it was measured