Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes

<p>Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients.</p> <p>Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers.</p> <p>Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance.</p> <p>Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies.</p&gt

An extended window of opportunity for G-CSF treatment in cerebral ischemia

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is known as a powerful regulator of white blood cell proliferation and differentiation in mammals. We, and others, have shown that G-CSF is effective in treating cerebral ischemia in rodents, both relating to infarct size as well as functional recovery. G-CSF and its receptor are expressed by neurons, and G-CSF regulates apoptosis and neurogenesis, providing a rational basis for its beneficial short- and long-term actions in ischemia. In addition, G-CSF may contribute to re-endothelialisation and arteriogenesis in the vasculature of the ischemic penumbra. In addition to these trophic effects, G-CSF is a potent neuroprotective factor reliably reducing infarct size in different stroke models. RESULTS: Here, we have further delayed treatment and studied effects of G-CSF on infarct volume in the middle cerebral artery occlusion (MCAO) model and functional outcome in the cortical photothrombotic model. In the MCAO model, we applied a single dose of 60 μg/kg bodyweight G-CSF in rats 4 h after onset of ischemia. Infarct volume was determined 24 h after onset of ischemia. In the rat photothrombotic model, we applied 10 μg/kg bodyweight G-CSF daily for a period of 10 days starting either 24 or 72 h after induction of ischemia. G-CSF both decreased acute infarct volume in the MCAO model, and improved recovery in the photothrombotic model at delayed timepoints. CONCLUSION: These data further strengthen G-CSF's profile as a unique candidate stroke drug, and provide an experimental basis for application of G-CSF in the post-stroke recovery phase

Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups

Confirmation of low genetic diversity and multiple breeding females in a social group of Eurasian badgers from microsatellite and field data

The Eurasian badger ( Meles meles ) is a facultatively social carnivore that shows only rudimentary co-operative behaviour and a poorly defined social hierarchy. Behavioural evidence and limited genetic data have suggested that more than one female may breed in a social group. We combine pregnancy detection by ultrasound and microsatellite locus scores from a well-studied badger population from Wytham Woods, Oxfordshire, UK, to demonstrate that multiple females reproduce within a social group. We found that at least three of seven potential mothers reproduced in a group that contained 11 reproductive age females and nine offspring. Twelve primers showed variability across the species range and only five of these were variable in Wytham. The microsatellites showed a reduced repeat number, a significantly higher number of nonperfect repeats, and moderate heterozygosity levels in Wytham. The high frequency of imperfect repeats and demographic phenomena might be responsible for the reduced levels of variability observed in the badger

Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC

COMPARATIVE VOLUME EQUATIONS ADJUSTED WITH DATA OF STEM MEASUREMENTS AND STEM ANALYSIS

Este trabalho teve como objetivo comparar estimativas de volume com casca, obtidas com equa\ue7\uf5es originadas partindo de dados da cubagem com casca e an\ue1lise de tronco sem casca respectivamente. A base de informa\ue7\uf5es para o desenvolvimento deste estudo foi obtida em povoamentos de Pinus taeda L. no munic\uedpio de Ponte Alta do Norte, Santa Catarina, sendo composta de duzentos e quarenta \ue1rvores cubadas com casca em diferentes idades, as quais foram selecionadas aleatoriamente e distribu\ueddas por classe de di\ue2metro. Outra fonte de dados foi obtida com a an\ue1lise de tronco sem casca de trinta \ue1rvores-amostra, distribu\ueddas entre m\ue9dias e dominantes. Foram testados modelos matem\ue1ticos para cada fonte de dados, afim de selecionar o de melhor ajuste e precis\ue3o, com base no crit\ue9rio de sele\ue7\ue3o do Valor Ponderado dos Escores dos Par\ue2metros Estat\uedsticos (VP). O resultado do VP revelou a equa\ue7\ue3o de Schumacher-Hall como mais adequada na estimativa do volume para as respectivas fontes de dados. A compara\ue7\ue3o entre as estimativas de volume dos modelos ajustados, partindo de dados da cubagem com casca e da an\ue1lise de tronco sem casca, foi realizada com o teste Qui-quadrado, que demonstrou n\ue3o haver diferen\ue7a significativa entre elas, permitindo afirmar que \ue9 poss\uedvel obter o volume com casca com base em uma equa\ue7\ue3o gerada com dados de volume sem casca, obtidos pela an\ue1lise de tronco.This work aimed at comparing volume estimates with bark, obtained with equations originated from data of the stem measurements with bark and stem analysis without bark, respectively. The base of information for the development of this study was obtained in forest of Pinus taeda L. in the municipal district of Ponte Alta do Norte, Santa Catarina, being composed by two hundred and forty trees measured with bark in different ages, which were selected aleatorily and distributed by diameter class. Another source of data was obtained with the stem analysis without bark of thirty sample trees, distributed among averages and dominant. Mathematical models were tested for each source of data, in order to select the one of better adjustment and precision, with base in the selection criterion of the Score Pondered Value of the Statistical Parameters (VP). The result of VP revealed the equation of Schumacher-Hall as the most appropriated one in the estimate of the volume for the respective sources of data. The comparison between the estimates of volume of the adjusted models starting from data of the stem measurements with bark and of the stem analysis without bark was accomplished with the test Qui-square, which demonstrated that there area no significant differences to be significant difference among the them allowing to affirm that it is possible to obtain the volume with bark starting from an equation generated with volume data without bark, obtained through the stem analysis

Saliva Proteins of Vector Culicoides Modify Structure and Infectivity of Bluetongue Virus Particles

Bluetongue virus (BTV) and epizootic haemorrhagic disease virus (EHDV) are related orbiviruses, transmitted between their ruminant hosts primarily by certain haematophagous midge vectors (Culicoides spp.). The larger of the BTV outer-capsid proteins, ‘VP2’, can be cleaved by proteases (including trypsin or chymotrypsin), forming infectious subviral particles (ISVP) which have enhanced infectivity for adult Culicoides, or KC cells (a cell-line derived from C. sonorensis). We demonstrate that VP2 present on purified virus particles from 3 different BTV strains can also be cleaved by treatment with saliva from adult Culicoides. The saliva proteins from C. sonorensis (a competent BTV vector), cleaved BTV-VP2 more efficiently than those from C. nubeculosus (a less competent / non-vector species). Electrophoresis and mass spectrometry identified a trypsin-like protease in C. sonorensis saliva, which was significantly reduced or absent from C. nubeculosus saliva. Incubating purified BTV-1 with C. sonorensis saliva proteins also increased their infectivity for KC cells ∼10 fold, while infectivity for BHK cells was reduced by 2–6 fold. Treatment of an ‘eastern’ strain of EHDV-2 with saliva proteins of either C. sonorensis or C. nubeculosus cleaved VP2, but a ‘western’ strain of EHDV-2 remained unmodified. These results indicate that temperature, strain of virus and protein composition of Culicoides saliva (particularly its protease content which is dependent upon vector species), can all play a significant role in the efficiency of VP2 cleavage, influencing virus infectivity. Saliva of several other arthropod species has previously been shown to increase transmission, infectivity and virulence of certain arboviruses, by modulating and/or suppressing the mammalian immune response. The findings presented here, however, demonstrate a novel mechanism by which proteases in Culicoides saliva can also directly modify the orbivirus particle structure, leading to increased infectivity specifically for Culicoides cells and, in turn, efficiency of transmission to the insect vector

ANNUAL INCREMENT VARIATION ALONG STEM OF Pinus taeda L. IN DIFFERENT AGES AND POPULATION DENSITIES

A varia\ue7\ue3o do crescimento anual em diferentes alturas do fuste de Pinus taeda L. foi estudada por meio da an\ue1lise de tronco em \ue1rvores do estrato dominante e m\ue9dio. Foram coletadas sec\ue7\uf5es transversais ao longo do fuste de 9 \ue1rvores-amostra, tomadas na base, \ue0 altura do peito (DAP), e ap\uf3s, a cada metro. A amostragem foi constitu\uedda de 4 \ue1rvores provenientes de Canela, Rio Grande do Sul, em floresta com 17 anos de idade, submetida a um desbaste, e 5 \ue1rvores de Ponte Alta do Norte, Santa Catarina, em floresta com 34 anos, submetida a cinco desbastes. Os resultados, expressos na forma percentual do incremento em \ue1rea basal na posi\ue7\ue3o \u201ci\u201d, sobre o incremento em \ue1rea basal ao n\uedvel do DAP, mostraram a forte varia\ue7\ue3o na deposi\ue7\ue3o anual de lenho ao longo do fuste em fun\ue7\ue3o da densidade populacional, caracterizando os efeitos da competi\ue7\ue3o e da libera\ue7\ue3o pela execu\ue7\ue3o do desbaste. \uc1rvores sujeitas \ue0 competi\ue7\ue3o mostraram maior crescimento nas partes superiores do fuste, enquanto que \ue1rvores sob menor concorr\ueancia apresentaram maior crescimento em posi\ue7\uf5es inferiores, facilmente identificadas pela forma e inclina\ue7\ue3o das curvas de incremento.The variation of the annual growth in different heights of the stem of Pinus taeda L. was studied through the stem analysis, accomplished in dominant and medium stratum trees. Cross sections were collected along the stem from 9 sample trees on the base, breast height diameter (BHD) and after these positions, at every meter. The sampling was constituted of 4 trees coming from Canela, Rio Grande do Sul, in a 17-years-old stand, submitted to one thinning, and 6 trees from Ponte Alta do Norte, Santa Catarina, in a 34-years-old stand, submitted to five thinnings. The results, expressed in percentage of the basal area increment in several positions of the tree height, showed strong variation in the annual deposition of wood along the stem in function of the populational density, characterizing the effects of the competition and of the thinning liberation. Trees subjected to the competition showed larger growth on top parts of the stem, while trees under smaller competition presented larger growth on lower positions, easily identified by the form and inclination of the increment curves

Calculating WCET Estimates from Timed Traces

© The Author(s) 2015. This article is published with open access at Springerlink.comReal-time systems engineers face a daunting duty: They must ensure that each task in their system can always meet its deadline. To analyse schedulability they must know the worst-case execution time (WCET) of each task. However, determining exact WCETs is practically infeasible in cost-constrained industrial settings involving real-life code and COTS hardware. Static analysis tools that could yield sufficiently tight WCET bounds are often unavailable. As a result, interest in portable analysis approaches like measurement-based timing analysis (MBTA) is growing. We present an approach based on integer linear programming (ILP) for calculating a WCET estimate from a given database of timed execution traces. Unlike previous work, our method specifically aims at reducing overestimation, by means of an automatic classification of code executions into scenarios with differing worst-case behaviour. To ease the integration into existing analysis tool chains, our method is based on the implicit path enumeration technique (IPET). It can thus reuse flow facts from other analysis tools and produces ILP problems that can be solved by off-the-shelf solvers.Peer reviewe

DIAMETER BY BASAL AREA RATIO AND COMPETITION ZONES IN Eucalyptus saligna MONOCLONAL STAND

O presente trabalho foi desenvolvido com o objetivo de estudar a rela\ue7\ue3o do di\ue2metro e \ue1rea basal, as zonas de competi\ue7\ue3o, a densidade relativa e o autodesbaste em popula\ue7\uf5es monoclonais de Eucalyptus saligna Smith, com base em 238 parcelas permanentes distribu\ueddas em povoamentos com densidade completa, medidas dos 3 aos 18 anos de idade. Os resultados obtidos permitiram concluir que o modelo de densidade de Tang apresentou uma boa precis\ue3o e efici\ueancia. O autodesbaste tem in\uedcio quando a popula\ue7\ue3o atinge um di\ue2metro m\ue9dio de 8 cm, quando a densidade foi igual a 0,3446 (34,46 %), com linha do gradiente de 1,5818 (b). O m\ue1ximo incremento corrente anual em di\ue2metro ocorreu entre as idades de 14 e 15 anos quando as densidades eram de 12,5 e 25 % caracterizando a zona de crescimento livre de competi\ue7\ue3o entre os indiv\uedduos. A zona de aumento da competi\ue7\ue3o entre as densidades relativas de 25 e 50 % e a zona de iminente mortalidade ocorreu entre as densidades relativas de 50 e 100 %. O modelo permitiu estabelecer em rela\ue7\ue3o \ue0 densidade relativa, cinco zonas de concorr\ueancia no desenvolvimento da popula\ue7\ue3o, definidas por zonas de espa\ue7o excessivo, crescimento livre, aumento de competi\ue7\ue3o, estoque completo e iminente mortalidade.The present work was developed in order to study the relation among the diameter and the basal area, the competition zones, the relative density, and the self-tinning in Eucalyptus saligna Smith monoclonal stand, with 238 pair's data basis of permanent sampling by full density stand distribution, observed from 3 to 18 years old. The results obtained allowed to conclude that Tang's density model was very precise and efficient. The self-thinning begins when the population reaches an average diameter of 8 cm. The relative density was equal 34.46%, with line gradient of 1.5818 (b). The maximum current annual increment in diameter and between the relative densities was observed between the ages of 14 and 15 years when the relative densities were 12.5% and 25%, characterizing a free growth competition zone among the individuals of the population. The zone of increasing competition between the relative densities of 25 and 50% and the imminent mortality zone occurred between the relative densities of 50 and 100%. The density model allowed detecting five competition zones, in the development of the stands, defined by zones of: excessive space, free growth, increase of competition, complete stock and imminent mortality, in relation to the relative density of the population