Diagnostic accuracy of TB-LAMP for pulmonary tuberculosis: a systematic review and meta-analysis.

BACKGROUND:The need for a rapid, molecular test to diagnose tuberculosis (TB) has prompted exploration of TB-LAMP (Eiken; Tokyo, Japan) for use in resource-limited settings. We conducted a systematic review to assess the accuracy of TB-LAMP as a diagnostic test for pulmonary TB. METHODS:We analyzed individual-level data for eligible patients from all studies of TB-LAMP conducted between Jan 2012 and October 2015 to compare the diagnostic accuracy of TB-LAMP with that of smear microscopy and Xpert MTB/RIF® using 3 reference standards of varying stringency. Pooled sensitivity and specificity and pooled differences in sensitivity and specificity were estimated using random effects meta-analysis. Study quality was evaluated using QUADAS-2. RESULTS:Four thousand seven hundred sixty individuals across 13 studies met eligibility criteria. Methodological quality was judged to be low for all studies. TB-LAMP had higher sensitivity than sputum smear microscopy (pooled sensitivity difference + 13·2, 95% CI 4·5-21·9%) and similar sensitivity to Xpert MTB/RIF (pooled sensitivity difference - 2·5, 95% CI -8·0 to + 2·9) using the most stringent reference standard available. Specificity of TB-LAMP was similar to that of sputum smear microscopy (pooled specificity difference - 1·8, 95% CI -3·8 to + 0·2) and Xpert MTB/RIF (pooled specificity difference 0·5, 95% CI -0·9 to + 1·8). CONCLUSIONS:From the perspective of diagnostic accuracy, TB-LAMP may be considered as an alternative test for sputum smear microscopy. Additional factors such as cost, feasibility, and acceptability in settings that continue to rely on sputum smear microscopy should be considered when deciding to adopt this technology. Xpert MTB/RIF should continue to be preferred in settings where resource and infrastructure requirements are adequate and where HIV co-infection or drug-resistance is of concern

Majorana spinors and extended Lorentz symmetry in four-dimensional theory

An extended local Lorentz symmetry in four-dimensional (4D) theory is considered. A source of this symmetry is a group of general linear transformations of four-component Majorana spinors GL(4,M) which is isomorphic to GL(4,R) and is the covering of an extended Lorentz group in a 6D Minkowski space M(3,3) including superluminal and scaling transformations. Physical space-time is assumed to be a 4D pseudo-Riemannian manifold. To connect the extended Lorentz symmetry in the M(3,3) space with the physical space-time, a fiber bundle over the 4D manifold is introduced with M(3,3) as a typical fiber. The action is constructed which is invariant with respect to both general 4D coordinate and local GL(4,M) spinor transformations. The components of the metric on the 6D fiber are expressed in terms of the 4D pseudo-Riemannian metric and two extra complex fields: 4D vector and scalar ones. These extra fields describe in the general case massive particles interacting with an extra U(1) gauge field and weakly interacting with ordinary particles, i.e. possessing properties of invisible (dark) matter.Comment: 24 page

Trisubstituted pyrazolopyrimidines as novel angiogenesis inhibitors.

Current inhibitors of angiogenesis comprise either therapeutic antibodies (e.g. bevacicumab binding to VEGF-A) or small molecular inhibitors of receptor tyrosin kinases like e.g. sunitinib, which inhibits PDGFR and VEGFR. We have recently identified cyclin-dependent kinase 5 (Cdk5) as novel alternative and pharmacologically accessible target in the context of angiogenesis. In the present work we demonstrate that trisubstituted pyrazolo[4,3-d]pyrimidines constitute a novel class of compounds which potently inhibit angiogenesis. All seven tested compounds inhibited endothelial cell proliferation with IC(50) values between 1 and 18 µM. Interestingly, this seems not to be due to cytotoxicity, since none of them showed acute cytotoxic effects on endothelial cells at a concentration of 10 µM,. The three most potent compounds (LGR1404, LGR1406 and LGR1407) also inhibited cell migration (by 27, 51 and 31%, resp.), chemotaxis (by 50, 70 and 60% in accumulative distance, resp.), and tube formation (by 25, 60 and 30% of total tube length, resp.) at the non-toxic concentration of 10 µM. Furthermore, angiogenesis was reduced in vivo in the CAM assay by these three compounds. A kinase selectivity profiling revealed that the compounds prevalently inhibit Cdk2, Cdk5 and Cdk9. The phenotype of the migrating cells (reduced formation of lamellipodia, loss of Rac-1 translocation to the membrane) resembles the previously described effects of silencing of Cdk5 in endothelial cells. We conclude that especially LGR1406 and LGR1407 are highly attractive anti-angiogenic compounds, whose effects seem to largely depend on their Cdk5 inhibiting properties

Modelling state-dependent interference in common cranes

1. Interference is a key component of food competition, but is difficult to measure in natural animal populations. Using data from a long-term study, we show that interference between common cranes Grus grus L., feeding on patches of cereal seeds, reduces intake rates at high competitor densities, and that the strength of interference is unrelated to food abundance. 2. An alternative to measuring interference directly is to predict its strength using behaviour-based models. We test an interference model, originally developed for shorebirds feeding on invertebrate prey, for cranes. We compare the predictions of a rate-maximizing model, in which animals steal food if this increases intake rate, and a state-dependent model, in which they only rate-maximize if their intake rate is below a target value, otherwise they minimize injury risk by not stealing food. State-dependent aggression occurs in cranes. 3. The state-dependent model predicts more accurately the relative aggression rates of cranes of different dominance. However, both models predict accurately the observed strength of interference, that the strength of interference is unrelated to food abundance, at least within the observed range of crane and seed densities, and that cranes of a higher dominance have a higher intake rate than those of lower dominance. 4. This paper shows how state-dependent behaviour can be incorporated into an interference model, and that the model can produce accurate predictions for a system quite different to that for which it was developed.RAS was funded by the Natural Environment Research Council. LMB was partially funded by Ministerio de Ciencia y Tecnología (MCyT) and research grant PB97-1252 of MCyT. Field work was funded by DGICYT project PB87-0389 of the MCyT.Peer reviewe

Application of mineralogical, petrological and geochemical tools for evaluating the palaeohdrogeological evolution of the PADAMOT study sites

The role of Work Package (WP) 2 of the PADAMOT project – ‘Palaeohydrogeological Data Measurements’ - has been to study late-stage fracture mineral and water samples from groundwater systems in Spain, Sweden, United Kingdom and the Czech Republic, with the aim of understanding the recent palaeohydrogeological evolution of these groundwater systems. In particular, the project sought to develop and evaluate methods for obtaining information about past groundwater evolution during the Quaternary (about the last 2 million years) by examining how the late-stage mineralization might record mineralogical, petrographical and geochemical evidence of how the groundwater system may have responded to past geological and climatological changes. Fracture-flow groundwater systems at six European sites were studied: • Melechov Hill, in the Bohemian Massif of the Czech Republic: a shallow (0-100 m) dilute groundwater flow system within the near-surface weathering zone in fractured granitic rocks; • Cloud Hill, in the English Midlands: a (~100 m) shallow dilute groundwater flow system in fractured and dolomitized Carboniferous limestone; • Los Ratones, in southwest Spain: an intermediate depth (0-500 m) dilute groundwater flow system in fractured granitic rocks; • Laxemar, in southeast Sweden: a deep (0-1000 m) groundwater flow system in fractured granitic rocks. This is a complex groundwater system with potential recharge and flushing by glacial, marine, lacustrine and freshwater during the Quaternary; • Sellafield, northwest England: a deep (0-2000 m) groundwater flow system in fractured Ordovician low-grade metamorphosed volcaniclastic rocks and discontinuous Carboniferous Limestone, overlain by a Permo-Triassic sedimentary sequence with fracture and matrix porosity. This is a complex coastal groundwater system with deep hypersaline sedimentary basinal brines, and deep saline groundwaters in crystalline basement rocks, overlain by a shallow freshwater aquifer system. The site was glaciated several times during the Quaternary and may have been affected by recharge from glacial meltwater; • Dounreay, northeast Scotland: a deep (0-1400 m) groundwater flow system in fractured Precambrian crystalline basement overlain by fractured Devonian sedimentary rocks. This is within the coastal discharge area of a complex groundwater system, comprising deep saline groundwater hosted in crystalline basement, overlain by a fracture-controlled freshwater sedimentary aquifer system. Like Sellafield, this area experienced glaciation and may potentially record the impact of glacial meltwater recharge. In addition, a study has been made of two Quaternary sedimentary sequences in Andalusia in southeastern Spain to provide a basis of estimating the palaeoclimatic history of the region that could be used in any reconstruction of the palaeoclimatic history at the Los Ratones site: • The Cúllar-Baza lacustrine sequence records information about precipitation and palaeotemperature regimes, derived largely from the analysis of the stable isotope (δ18O and δ13C) signatures from biogenic calcite (ostracod shells). • The Padul Peat Bog sequence provided information on past vegetation cover and palaeogroundwater inputs based on the study of fossil pollen and biomarkers as proxies for past climate change. Following on from the earlier EC 4th Framework EQUIP project, the focus of the PADAMOT studies has been on calcite mineralization. Calcite has been identified as a late stage mineral, closely associated with hydraulically-conductive fractures in the present-day groundwater systems at the Äspö-Laxemar, Sellafield, Dounreay and Cloud Hill sites. At Los Ratones and Melechov sites late-stage mineralization is either absent or extremely scarce, and both the quantity and fine crystal size of any late-stage fracture mineralization relevant to Quaternary palaeohydrogeological investigations is difficult to work with. The results from the material investigated during the PADAMOT studies indicate that the fracture fillings at these sites are related to hydrothermal activity, and so do not have direct relevance as Quaternary indicators. Neoformed calcite has not been found at these two sites at the present depth of the investigations. Furthermore, the HCO3 - concentration in all the Los Ratones groundwaters is mainly controlled by complex carbonate dissolution. The carbonate mineral saturation indices do not indicate precipitation conditions, and this is consistent with the fact that neoformed calcite, ankerite or dolomite have not been observed petrographically

Non-Coding Keratin Variants Associate with Liver Fibrosis Progression in Patients with Hemochromatosis

Background: Keratins 8 and 18 (K8/K18) are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with endstage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. Methods: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene) mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCRamplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previouslygenerated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. Results: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2%) and non-coding heterozygous variants in 6 additional patients (3.7%). Two novel K8 variants (Q169E/R275W) were found. K8 R341H was the most common amino-acid altering variant (4 patients), and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. I