Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis.

Protease-sensitive macromolecular prodrugs have attracted interest for bio-responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site-selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation.

Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement.

With six targeted agents approved (sorafenib, sunitinib, temsirolimus, bevacizumab [+interferon], everolimus and pazopanib), many patients with metastatic renal cell carcinoma (mRCC) will receive multiple therapies. However, the optimum sequencing approach has not been defined. A group of European experts reviewed available data and shared their clinical experience to compile an expert agreement on the sequential use of targeted agents in mRCC. To date, there are few prospective studies of sequential therapy. The mammalian target of rapamycin (mTOR) inhibitor everolimus was approved for use in patients who failed treatment with inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) based on the results from a Phase III placebo-controlled study; however, until then, the only licensed agents across the spectrum of mRCC were VEGF(R) inhibitors (sorafenib, sunitinib and bevacizumab + interferon), and as such, a large body of evidence has accumulated regarding their use in sequence. Data show that sequential use of VEGF(R) inhibitors may be an effective treatment strategy to achieve prolonged clinical benefit. The optimal place of each targeted agent in the treatment sequence is still unclear, and data from large prospective studies are needed. The Phase III AXIS study of second-line sorafenib vs. axitinib (including post-VEGF(R) inhibitors) has completed, but the data are not yet published; other ongoing studies include the Phase III SWITCH study of sorafenib-sunitinib vs. sunitinib-sorafenib (NCT00732914); the Phase III 404 study of temsirolimus vs. sorafenib post-sunitinib (NCT00474786) and the Phase II RECORD 3 study of sunitinib-everolimus vs. everolimus-sunitinib (NCT00903175). Until additional data are available, consideration of patient response and tolerability to treatment may facilitate current decision-making regarding when to switch and which treatment to switch to in real-life clinical practice.

Genetic characterization and nitrogen fixation capacity of Rhizobium strains on common bean

This study aimed to genetically characterize four new Rhizobium strains, and to evaluate their nodulation and fixation capacity compared to commercial strains and to native rhizobia population of a Brazilian Rhodic Hapludox. Two experiments were carried out in randomized blocks design, under greenhouse conditions, in 2007. In the first experiment, the nodulation and nitrogen fixation capacity of new strains were evaluated, in comparison to the commercial strains CIAT-899 and PRF-81 and to native soil population. It was carried out in plastic tubes filled with vermiculite. DNA extractions and PCR sequencing of the intergenic space were made from the isolated pure colonies, in order to genetically characterize the strains and the native rhizobia population. In the second experiment, the nodulation and productivity of common beans Perola cultivar were determined, with the use of evaluated strains, alone or in mixture with PRF-81 strain. It was carried out in pots filled with soil. The native soil population was identified as Rhizobium sp. and was inefficient in nitrogen fixation. Three different Rhizobium species were found among the four new strains. The LBMP-4BR and LBMP-12BR new strains are among the ones with greatest nodulation and fixation capacity and exhibit differential responses when mixed to PRF-81.

Genetic control of grain yield and nitrogen use efficiency in tropical maize

The objectives of this work were to study the genetic control of grain yield (GY) and nitrogen (N) use efficiency (NUE, grain yield/N applied) and its primary components, N uptake efficiency (NUpE, N uptake/N applied) and N utilization efficiency (NUtE, grain yield/N uptake), in maize grown in environments with high and low N availability. Experiments with 31 maize genotypes (28 hybrid crosses and three controls) were carried out in soils with high and low N rates, in the southeast of the state of Minas Gerais, Brazil. There was a reduction of 23.2% in average GY for maize grown in soil with low N, in comparison to that obtained with high N. There were 26.5, 199 and 400% increases in NUtE, NUpE, and NUE, respectively, for maize grown with low N. The general combining ability (GCA) and specific combining ability (SCA) were significant for GY, NUE and NUpE for maize grown in high N soil. Only GCA was significant for NUpE for maize grown in low N soil. The GCA and SCA for NUtE were not significant in either environment. Additive and non-additive genetic effects are responsible for the genetic control of NUE and GY for maize grown in soils with high N availability, although additive effects are more important.

Sequentially aerated membrane biofilm reactors for autotrophic nitrogen removal: microbial community composition and dynamics

Membrane-aerated biofilm reactors performing autotrophic nitrogen removal can be successfully applied to treat concentrated nitrogen streams. However, their process performance is seriously hampered by the growth of nitrite oxidizing bacteria (NOB). In this work we document how sequential aeration can bring the rapid and long-term suppression of NOB and the onset of the activity of anaerobic ammonium oxidizing bacteria (AnAOB). Real-time quantitative polymerase chain reaction analyses confirmed that such shift in performance was mirrored by a change in population densities, with a very drastic reduction of the NOB Nitrospira and Nitrobacter and a 10-fold increase in AnAOB numbers. The study of biofilm sections with relevant 16S rRNA fluorescent probes revealed strongly stratified biofilm structures fostering aerobic ammonium oxidizing bacteria (AOB) in biofilm areas close to the membrane surface (rich in oxygen) and AnAOB in regions neighbouring the liquid phase. Both communities were separated by a transition region potentially populated by denitrifying heterotrophic bacteria. AOB and AnAOB bacterial groups were more abundant and diverse than NOB, and dominated by the r-strategists Nitrosomonas europaea and Ca. Brocadia anammoxidans, respectively. Taken together, the present work presents tools to better engineer, monitor and control the microbial communities that support robust, sustainable and efficient nitrogen removal

Les réformes au prisme de l'autonomie et du contrôle des agents publics de base : le cas de la politique suisse du chômage

Cet article se propose de réfléchir aux réformes de l'administration en étudiant ce qu'elles deviennent au niveau des agents publics de base ou 'street-level bureaucrats'. Si la littérature qui leur est consacrée a jusqu'ici mis en avant à la fois l'autonomie décisionnelle de ces acteurs ainsi que les stratégies de contrôle de celle-ci, nous proposons ici de revisiter la problématique de l'autonomie et du contrôle à ce niveau en rendant compte de la manière dont elle est affectée par les réformes de « nouvelle gestion publique » d'une part, et les « nouvelles technologies de l'information et de la communication » d'autre part. Pour ce faire, la partie empirique présente les résultats préliminaires d'une recherche de l'auteur portant sur un type d'agent public aux premières lignes de la mise en oeuvre de la politique suisse du chômage, à savoir les taxateurs d'une caisse cantonale d'indemnisation, laquelle fonctionne selon une logique « néo-managériale ». Les données analysées montrent que si les éléments du dispositif NGP/TIC conduisent globalement à un renforcement considérable du contrôle hiérarchique et organisationnel d'une autonomie qui reste néanmoins importante, ceci s'accompagne également de modes d'appropriation spécifiques et intéressants dans ce qu'ils ont d'inattendu, de créatif voire de subversif au niveau des agents sur le terrain.

Polymers as carriers for rhizobial inoculant formulations

The aim of this work was to evaluate the efficiency of carboxymethyl cellulose (CMC) and starch blends as carrier materials of rhizobial inoculants regarding their capacity to maintain viable cells and promote cowpea (Vigna unguiculata) nodulation. The experimental design adopted was completely randomized, with three replicates. Forty different compositions of carboxymethyl cellulose (CMC) with starch, compatibilized or not with different proportions of MgO or ZnO, were evaluated regarding their ability of maintaining rhizobial viable cells during the storage period of one month at room temperature, in an initial screening. Thereafter, selected inoculant carrier blends were evaluated regarding their ability to maintain viable rhizobial cells for a period of 165 days, and their performance as inoculant carriers was compared to a peat-based inoculant carrier under greenhouse conditions. Rhizobial cells were better maintained in blends containing 50-60% CMC. Compatibilizing agents did not increase survival of rhizobial cells for 30 days of storage. The cowpea nodulation of polymer blends was statistically the same of peat-based inoculants. CMC/starch polymer blends are efficient carriers to rhizobial inoculants for up to 165 days of storage, when compatibilized with MgO (1%).

Boron, phosphorus and nitrogen fertilization in Norway spruce stands suffering from growth disturbances

Abstract

Fastidious intracellular bacteria as causal agents of community-acquired pneumonia.

Intracellular bacteria are common causes of community-acquired pneumonia that grow poorly or not at all on standard culture media and do not respond to beta-lactam antibiotic therapy. Apart from well-established agents of pneumonia such as Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae, Chlamydia psittaci and Coxiella burnetii, some new emerging pathogens have recently been recognized, mainly Parachlamydia acanthamoebae and Simkania negevensis, two Chlamydia-related bacteria. Most of them are causes of benign and self-limited infections. However, they may cause severe pneumonia in some cases (i.e., Legionnaires' disease) and they may cause outbreaks representing a public health problem deserving prompt recognition and appropriate therapy. Although extrapulmonary manifestations are often present, no clinical features allow them to be distinguished from classical bacterial agents of pneumonia such as Streptococcus pneumoniae. Thus, specific molecular diagnostic tools are very helpful for early recognition of the offending bacteria, whereas serology often only allows retrospective or late diagnosis. Macrolides remain the best empirical treatment of intracellular respiratory pathogens, although some observational studies suggest that quinolones may be superior for the treatment of legionellosis.

Soil carbon and nitrogen mineralization caused by pig slurry application under different soil tillage systems

The objective of this work was to evaluate the change in soil C and N mineralization due to successive pig slurry application under conventional tillage (CT) and no tillage (NT) systems. The experiment was carried out in a clayey Latossolo Vermelho eutrófico (Rhodic Eutrudox) in Palotina, PR, Brazil. Increasing doses of pig slurry (0, 30, 60 and 120 m³ ha-1 per year) were applied in both tillage systems, with three replicates. Half of the pig slurry was applied before summer soil preparation, and the other half before the winter crop season. The areas were cultivated with soybean (Glycine max L.) and maize (Zea mays L.) in the summers of 1998 and 1999, respectively, and with wheat (Triticum sativum Lam.) in the winters of both years. Soil samples were collected at 0-5, 5-10, and 10-20 cm depths. Under both CT and NT systems, pig slurry application increased C and N mineralization. However, increasing pig slurry additions decreased the C to N mineralization ratio. Under the NT system, C and N mineralization was greater than in CT system.

Nitrogen metabolism in Zucker rats is affected by moderate reduction, but not by moderate incerase in dietary protein

Marked changes in the content of protein in the diet affects the rat"s pattern of growth, but there is not any data on the effects to moderate changes. Here we used a genetically obese rat strain (Zucker) to examine the metabolic modifications induced to moderate changes in the content of protein of diets, doubling (high-protein (HP): 30%) or halving (low-protein (LP): 8%) the content of protein of reference diet (RD: 16%). Nitrogen, energy balances, and amino acid levels were determined in lean (L) and obese (O) animals after 30 days on each diet. Lean HP (LHP) animals showed higher energy efficiency and amino acid catabolism but maintained similar amino acid accrual rates to the lean RD (LRD) group. Conversely, the lean LP (LLP) group showed a lower growth rate, which was compensated by a relative increase in fat mass. Furthermore, these animals showed greater efficiency accruing amino acids. Obesity increased amino acid catabolism as a result of massive amino acid intake; however, obese rats maintained protein accretion rates, which, in the OHP group, implied a normalization of energy efficiency. Nonetheless, the obese OLP group showed the same protein accretion pattern as in lean animals (LLP). In the base of our data, concluded that the Zucker rats accommodate their metabolism to support moderates increases in the content of protein in the diet, but do not adjust in the same way to a 50% decrease in content of protein, as shown by an index of growth reduced, both in lean and obese rats.

Production of annual winter forage sown before and after soybean harvest under different nitrogen fertilization levels

The objective of this work was to evaluate the effect on forage yield of sowing winter forage species before and after soybean harvest, at different nitrogen application levels. The experiment was set out in a randomized block design with a strip-split plot arrangement, and three replicates. Sowing methods (18 days before soybean harvest and six days after soybean harvest) were allocated in the main plots, and the combination among forage species (Avena strigosa cv. IAPAR 61 + Lolium multiflorum; A. strigosa cv. Comum + L. multiflorum; A. strigosa cv. Comum + L. multiflorum + Vicia villosa; A. strigosa cv. Comum + L. multiflorum + Raphanus sativus; and L. multiflorum) and nitrogen levels (0, 140, 280 and 420 kg ha-1) in the plots and subplots, respectively. Forage sowing before the soybean harvest made it possible to anticipate first grazing by 14 days, with satisfactory establishment of forage species without affecting forage production. This method permitted a longer grazing period, preventing the need for soil disking, besides allowing the use of no-tillage system. The mixture of forage species enables higher forage yield for pasture in relation to single species pastures, with response to nitrogen fertilization up to 360 kg ha-1.

Carbohydrate and nitrogen stores in Festuca paniculata under mowing explain dominance in subalpine grasslands

Cessation of traditional management threatens semi-natural grassland diversity through the colonisation or increase of competitive species adapted to nutrient-poor conditions. Regular mowing is one practice that controls their abundance. This study evaluated the ecophysiological mechanisms limiting short- and long-term recovery after mowing for Festuca paniculata, a competitive grass that takes over subalpine grasslands in the Alps following cessation of mowing. We quantified temporal variations in carbon (C) and nitrogen (N) content, starch, fructan and total soluble sugars in leaves, stem bases and roots of F. paniculata during one growth cycle in mown and unmown fields and related them to the dynamics of soil mineral N concentration and soil moisture. Short-term results suggest that the regrowth of F. paniculata following mowing might be N-limited, first because of N dilution by C increments in the plant tissue, and second, due to low soil mineral N and soil moisture at this time of year. However, despite short-term effects of mowing on plant growth, C and N content and concentration at the beginning of the following growing season were not affected. Nevertheless, total biomass accumulation at peak standing biomass was largely reduced compared to unmown fields. Moreover, lower C storage capacity at the end of the growing season impacted C allocation to vegetative reproduction during winter, thereby dramatically limiting the horizontal growth of F. paniculata tussocks in the long term. We conclude that mowing reduces the growth of F. paniculata tussocks through both C and N limitation. Such results will help understanding how plant responses to defoliation regulate competitive interactions within plant communities.