Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model.

PURPOSE: The combination of embolic beads with a multitargeted tyrosine kinase inhibitor that inhibits tumor vessel growth is suggested as an alternative and improvement to the current standard doxorubicin-eluting beads for use in transarterial chemoembolization. This study demonstrates the in vitro loading and release kinetics of sunitinib using commercially available embolization microspheres and evaluates the in vitro biologic efficacy on cell cultures and the resulting in vivo pharmacokinetics profiles in an animal model. MATERIALS AND METHODS: DC Bead microspheres, 70-150 µm and 100-300 µm (Biocompatibles Ltd., Farnham, United Kingdom), were loaded by immersion in sunitinib solution. Drug release was measured in saline in a USP-approved flow-through apparatus and quantified by spectrophotometry. Activity after release was confirmed in cell culture. For pharmacokinetics and in vivo toxicity evaluation, New Zealand white rabbits received sunitinib either by intraarterial injection of 100-300 µm sized beads or per os. Plasma and liver tissue drug concentrations were assessed by liquid chromatography-tandem mass spectroscopy. RESULTS: Sunitinib loading on beads was close to complete and homogeneous. A total release of 80% in saline was measured, with similar fast-release profiles for both sphere sizes. After embolization, drug plasma levels remained below the therapeutic threshold (< 50 ng/mL), but high concentrations at 6 hours (14.9 µg/g) and 24 hours (3.4 µg/g) were found in the liver tissue. CONCLUSIONS: DC Bead microspheres of two sizes were efficiently loaded with sunitinib and displayed a fast and almost complete release in saline. High liver drug concentrations and low systemic levels indicated the potential of sunitinib-eluting beads for use in embolization.

Long-term treatment of aggregating brain cell cultures with low concentrations of lead acetate.

Aggregating brain cell cultures were used as a model to study the effect of chronic exposure to low levels of lead acetate. Long-term maintenance of cultures could be improved by supplementation of the medium with albumin-bound lipids. Exposure for 9 days to 10(-6)-10(-4) M lead acetate caused a decrease of GABAergic (glutamic acid decarboxylase) and astrocytic (glutamine synthetase) markers which was also found after prolonged treatment (50 days) with 10(-7) M lead acetate. Total protein content and choline acetyltransferase were not changed. The results show that prolonged exposure of aggregating brain cell cultures to a low concentration of lead acetate causes distinct changes of cell type-specific parameters.

Total fatty acid composition in the characterization and identification of orchid mycorrhizal fungi Epulorhiza spp.

Rhizoctonia-like fungi are the main mycorrhizal fungi in orchid roots. Morphological characterization and analysis of conserved sequences of genomic DNA are frequently employed in the identification and study of fungi diversity. However, phytopathogenic Rhizoctonia-like fungi have been reliably and accurately characterized and identified through the examination of the fatty acid composition. To evaluate the efficacy of fatty acid composition in characterizing and identifying Rhizoctonia-like mycorrhizal fungi in orchids, three Epulorhiza spp. mycorrhizal fungi from Epidendrum secundum, two unidentified fungi isolated from Epidendrum denticulatum, and a phytopathogenic fungus, Ceratorhiza sp. AGC, were grouped based on the profile of their fatty acids, which was assessed by the Euclidian and Mahalanobis distances and the UPGMA method. Dendrograms distinguished the phytopathogenical isolate of Ceratorhiza sp. AGC from the mycorrhizal fungi studied. The symbionts of E. secundum were grouped into two clades, one containing Epulorhiza sp.1 isolates and the other the Epulorhiza sp.2 isolate. The similarity between the symbionts of E. denticulatum and Epulorhiza spp. fungi suggests that symbionts found in E. denticulatum may be identified as Epulorhiza. These results were corroborated by the analysis of the rDNA ITS region. The dendrogram constructed based on the Mahalanobis distance differentiated the clades most clearly. Fatty acid composition analysis proved to be a useful tool for characterizing and identifying Rhizoctonia-like mycorrhizal fungi.

Carbono total e δ13C em agregados do solo sob vegetação nativa e pastagem no bioma cerrado

Diferentes sistemas de uso e manejo alteram o teor de carbono no solo (C), porém diminuições no C do solo têm sido reportadas quando áreas de Cerrado nativo são convertidas em pastagem. Disso resulta a necessidade da realização de pesquisas em diferentes sistemas e condições edafoclimáticas, a fim de elucidar as tendências encontradas. O objetivo deste trabalho foi avaliar a agregação, os teores de C e a abundância natural de δ13C do solo em uma área cultivada há nove anos sob lavoura seguida de 20 anos sob pastagem, a qual atualmente apresenta sinais de degradação (PA), comparando-a a uma vegetação nativa no bioma Cerrado (CE) que ocorre em área adjacente. As áreas de estudo estão localizadas no município de Rio Verde (GO), em solo classificado como Latossolo Vermelho distrófico, de textura argilosa. Em amostras de solo coletadas nas camadas de 0-5, 5-10 e 10-20 cm de profundidade, foram determinados a distribuição de agregados estáveis em água (micro, meso e macroagregados), o diâmetro médio aritmético (DMA) e geométrico (DMG), os teores de C total e de δ13C, o tempo de residência média do C (TRM) e a fração da matéria orgânica leve livre (FLL). Os resultados indicaram que o uso sob lavoura seguido de pastagem reduziu em 21 % o estoque de C original, possivelmente devido ao menor aporte de material na FLL. O solo apresentou elevada agregação e não houve diferenças significativas entre as áreas avaliadas. No entanto, os teores de C nos macroagregados foram menores na PA em relação ao CE, enquanto nos microagregados não houve diferença entre os sistemas de uso, sugerindo, respectivamente, maior e menor sensibilidade ao manejo e menor e maior proteção do C por essas classes de agregados. Os valores de TRM e as análises isotópicas reforçaram esses resultados, mostrando, ainda, substituição de 83 % do C original durante os 29 anos de cultivo. O constante aporte de resíduos vegetais, assim como a manutenção do C no interior dos macro e mesoagregados, são importantes fatores para que ocorra o acúmulo de C nesse tipo de solo.

Equivalence of reduced, Polyakov, Faddeev-Popov, and Faddeev path-integral quantization of gauge theories

A geometrical treatment of the path integral for gauge theories with first-class constraints linear in the momenta is performed. The equivalence of reduced, Polyakov, Faddeev-Popov, and Faddeev path-integral quantization of gauge theories is established. In the process of carrying this out we find a modified version of the original Faddeev-Popov formula which is derived under much more general conditions than the usual one. Throughout this paper we emphasize the fact that we only make use of the information contained in the action for the system, and of the natural geometrical structures derived from it.

Failure of surgical treatment in 115 infected total hip arthroplasties - analysis of a 12-year prosthetic joint cohort study (1999-2010)

Infection of total hip arthroplasties (THA) leads to significant long-termmorbidity and high healthcare costs. We evaluated the differentreasons for treatment failure using different surgical modalities in a12-year prosthetic joint infection cohort study.Method: All patients hospitalized at our institution with infected THAwere included either retrospectively (1999-2007) or prospectively(2008-2010). THA infection was defined as growth of the same microorganismin ≥2 tissue or synovial fluid culture, visible purulence, sinustract or acute inflammation on tissue histopathology. Outcome analysiswas performed at outpatient visits, followed by contacting patients,their relatives and/or treating physicians afterwards.Results: During the study period, 117 patients with THA were identified.We exclude 2 patients due to missing data. The median age was69 years (range, 33-102 years); 42% were women. THA was mainlyperformed for osteoarthritis (n = 84), followed by trauma (n = 22),necrosis (n = 4), dysplasia (n = 2), rheumatoid arthritis (n = 1), osteosarcoma(n = 1) and tuberculosis (n = 1). 28 infections occurred early(≤3 months), 25 delayed (3-24 months) and 63 late (≥24 months aftersurgery). Infected THA were treated with (i) two-stage exchange in59 patients (51%, cure rate: 93%), (ii) one-stage exchange in 5 (4.3%,cure rate: 100%), (iii) debridement with change of mobile parts in18 (17%, cure rate: 83%), (iv) debridement without change of mobileparts in 17 (14%, cure rate: 53% ), (v) Girdlestone in 13 (11%, curerate: 100%), and (vi) two-stage exchange followed by removal in 3(2.6%). Patients were followed for a mean of 3.9 years (range, 0.1 to 9years), 7 patients died unrelated to the infected THA. 15 patients (13%)needed additional operations, 1 for mechanical reasons (dislocationof spacer) and 14 for persistent infection: 11 treated with debridementand retention (8 without change and 3 with change of mobile parts)and 3 with two-stage exchange. The mean number of surgery was 2.2(range, 1 to 5). The infection was finally eradicated in all patients, butthe functional outcome remained unsatisfactory in 20% (persistentpain or impaired mobility due to spacer or Girdlestone situation).Conclusions: Non-respect of current treatment concept leads totreatment failure with subsequent operations. Precise analysis of eachtreatment failures can be used for improving the treatment algorithmleading to better results.

Equivalence Between the Lagrangian and Hamiltonian Formalisms for Constrained Systems

The equivalence between the Lagrangian and Hamiltonian formalism is studied for constraint systems. A procedure to construct the Lagrangian constraints from the Hamiltonian constraints is given. Those Hamiltonian constraints that are first class with respect to the Hamiltonian constraints produce Lagrangian constraints that are FL-projectable.

Carbono orgânico total, biomassa microbiana e atividade enzimática do solo de áreas agrícolas, florestais e pastagem no médio Vale do Paraíba do Sul (RJ)

Características do solo, como o carbono orgânico total (COT), a biomassa microbiana e a atividade enzimática, são influenciadas por diversos fatores e têm sido apontadas como indicadores adequados de alterações provocadas por diferentes sistemas de uso e manejo do solo. O objetivo deste trabalho foi avaliar o COT, a biomassa microbiana e a atividade enzimática de um Cambissolo Háplico Tb distrófico típico de áreas agrícolas, florestais e de pastagem, no Médio Vale do Paraíba do Sul (RJ). Os sistemas avaliados foram: agricultura anual (AgAn); agricultura perene (AgP); pasto; floresta secundária em estádio inicial de sucessão (FSEI); floresta secundária em estádio médio de sucessão (FSEM); e floresta secundária em estádio avançado de sucessão (FSEA). Foram coletadas amostras de terra na camada de 0-5 cm, em duas épocas distintas (úmida e seca), e analisados o COT e as propriedades biológicas: C da biomassa microbiana - CBM; N da biomassa microbiana - NBM; respiração basal - RB; quociente metabólico - qCO2; quociente microbiano - qMIC; e atividade das enzimas arilsulfatase, β-glicosidase e fosfatase ácida. As áreas agrícolas apresentaram redução no COT e nas propriedades biológicas (atividade enzimática e carbono e nitrogênio da biomassa microbiana) do solo quando comparadas ao pasto e às áreas florestais. Com as análises de componentes principais, foi possível separar os sistemas agrícolas e os sistemas florestais e de pasto. Observou-se que, em ambas as épocas, a FSEM e o pasto estiveram associados ao COT e à maioria das variáveis biológicas, ao contrário dos sistemas agrícolas.

Equivalence of paper and pencil vs internet forms of the ZKPQ-50-CC in Spanish and French samples

This study was designed to check for the equivalence of the ZKPQ-50-CC (Spanish and French versions) through Internet on-line (OL) and paper and pencil (PP) answer format. Differences in means and devia- tions were significant in some scales, but effect sizes are minimal except for Sociability in the Spanish sample. Alpha reliabilities are also very similar in both versions with no significant differences between formats. A robust factorial structure was found for the two formats and the average congruency coefficients were 0.98. The goodness-of-fit indexes obtained by confirmatory factorial analysis are very similar to those obtained in the ZKPQ-50-CC validation study and they do not differ between the two formats. The multi-group analysis confirms the equivalence among the OL-PP formats in both countries. These results in general support the validity and reliability of the Internet as a method in investigations using the ZKPQ-50-CC.

Cost-effective experimental design to support modeling of concentration-response functions

Modeling concentration-response function became extremely popular in ecotoxicology during the last decade. Indeed, modeling allows determining the total response pattern of a given substance. However, reliable modeling is consuming in term of data, which is in contradiction with the current trend in ecotoxicology, which aims to reduce, for cost and ethical reasons, the number of data produced during an experiment. It is therefore crucial to determine experimental design in a cost-effective manner. In this paper, we propose to use the theory of locally D-optimal designs to determine the set of concentrations to be tested so that the parameters of the concentration-response function can be estimated with high precision. We illustrated this approach by determining the locally D-optimal designs to estimate the toxicity of the herbicide dinoseb on daphnids and algae. The results show that the number of concentrations to be tested is often equal to the number of parameters and often related to the their meaning, i.e. they are located close to the parameters. Furthermore, the results show that the locally D-optimal design often has the minimal number of support points and is not much sensitive to small changes in nominal values of the parameters. In order to reduce the experimental cost and the use of test organisms, especially in case of long-term studies, reliable nominal values may therefore be fixed based on prior knowledge and literature research instead of on preliminary experiments