158 research outputs found
The Proterozoic GuanhĂŁes banded iron formations, Southeastern border of the SĂŁo Francisco Craton, Brazil: evidence of detrital contamination
A sequĂȘncia supracrustal GuanhĂŁes, portadora de formaçÔes ferrĂferas bandadas (BIFs), ocorre como fatias tectĂŽnicas superpostas ao embasamento de terrenos granito-gnĂĄissicos do tipo TTG de idade Arqueana, desenvolvidas no limite entre o perĂodo Proterozoico e o Paleozoico, durante a colagem Brasiliana. A idade mĂĄxima de deposição da sucessĂŁo Ă© de ~2,18 Ga e foi determinada por datação de zircĂ”es detrĂticos em quartzitos. AlĂ©m de quartzitos, a sucessĂŁo Ă© composta por xistos, BIFs, gnaisses e anfibolitos, todos metamorfisados em condiçÔes de fĂĄcies anfibolito. A anĂĄlise dos Elementos Terras Raras + Y (ETR+Y), normalizados ao PASS, para as BIFs de GuanhĂŁes, mostra enriquecimento em ETR pesados e anomalia positiva de Eu. Dois tipos de contaminação foram observados nas amostras. O primeiro Ă© uma contaminação detrĂtica que resultou em baixos valores de Y/Ho (< 30) e Pr/Yb (SN). As evidĂȘncias de contaminação desse tipo, combinadas Ă anĂĄlise do empilhamento estratigrĂĄfico do pacote de rochas supracrustais, indicam que as BIFs de GuanhĂŁes foram depositadas em ambiente marinho raso. Um evento Cambriano expressivo estĂĄ presente nos dados relativos Ă datação de zircĂ”es. O segundo tipo de contaminação resultou em maiores valores de anomalia de Eu, anomalia positiva de Ce e maiores concentraçÔes de ETR, possivelmente devido Ă interação entre fluidos magmĂĄticos posteriores e as BIFs de GuanhĂŁes. As amostras sem contaminação mostram distribuição de ETR semelhante a outras BIFs PrĂ©cambrianas, particularmente Ă s BIFs da SequĂȘncia do Morro Escuro e do Grupo Serra da Serpentina, com ausĂȘncia de anomalia verdadeira de Ce e Y/Ho prĂłximo aos valores da ĂĄgua do mar (45). Os dados geocronolĂłgicos e geoquĂmicos apresentados neste artigo sugerem correlação entre a sucessĂŁo supracrustal de GuanhĂŁes (GSSu) e os Grupos Serra da Serpentina e Serra de SĂŁo JosĂ©.The GuanhĂŁes banded iron formation (BIF) bearing succession occurs as tectonic slices, juxtaposed to Archean TTG granite-gneissic basement rock, developed during the Neoproterozoic-Cambrian Brasiliano collage. The succession has a maximum depositional age of ~2.18 Ga, from detrital zircons in quartzite, and consists of quartzites, schists, BIFs, gneiss and amphibolite, all metamorphosed under amphibolite facies conditions. The GuanhĂŁes BIF shows HREE enrichment and consistent positive Eu anomaly (PAAS-normalized REE+Y). Two types of contamination were observed in the samples. The first is contamination by an exotic detrital component, which resulted in low Y/Ho (< 30) and Pr/Yb (SN) ratios. Evidence of such contamination, combined with inferred stratigraphic stacking data, indicates that the GuanhĂŁes BIFs were deposited on a shallow marine environment. The second type of contamination resulted in higher Eu-anomalies, positive Ce-anomalies, and higher REE+Y concentrations, possibly due to the interaction between later magmatic fluids and the GuanhĂŁes BIF. A strong Cambrian event is recorded in zircon age data. The uncontaminated samples display REE+Y distribution similar to other Precambrian BIFs, particularly those from the Morro-Escuro Sequence and the Serra da Serpentina Group, without true Ce-anomalies and Y/Ho close to seawater values (45). Geochronological and geochemical data presented in this paper strongly suggest a correlation between the GuanhĂŁes supracrustal succession and the Serra da Serpentina and Serra de SĂŁo JosĂ© Groups.
Um novo paradigma de assistĂȘncia Ă s vĂtimas de crimes e a proteção dos direitos humanos pela Defensoria PĂșblica
The cases of violence in Brazil shows a serious threat to public security, they cause high costs to the state budget, and postpone economic and social development. At the same time, the Brazilian legal framework does not provide enough measures to restore the dignity of victims of crime. In this context, this article aims to demonstrate the essential need for the emergence of a new paradigm of public policy to assist victims of crime, based on the recognition of vulnerability. In addition, it seeks to establish possibilities of action of the Defensorship as an institution protecting human rights with a view to ensuring access to justice for this vulnerable group.Os casos de violĂȘncia no Brasil revelam grave problema de segurança pĂșblica, provocam alto custo para o orçamento estatal e atrasam o desenvolvimento econĂŽmico e social. Ao mesmo tempo, o ordenamento jurĂdico brasileiro nĂŁo prevĂȘ medidas suficientes para restabelecer a dignidade das vĂtimas de crimes. Nesse contexto, o presente artigo tem por finalidade demonstrar a imprescindibilidade do surgimento de um novo paradigma de polĂtica pĂșblica de assistĂȘncia Ă s vĂtimas de crimes e amparado no reconhecimento da vulnerabilidade. Para alĂ©m, busca demonstrar as possibilidades de atuação da Defensoria PĂșblica, como instituição protetora dos direitos humanos, com vistas a assegurar o acesso Ă justiça por esse grupo de vulnerĂĄveis
The structure of western Serra do Curral, QuadrilĂĄtero FerrĂfero, and tectonic control of the high-grade iron hard bodies
The structure of western Serra do Curral, QuadrilĂĄtero FerrĂfero, represents the partial exposure of a syncline that verges to NNW - Piedade Syncline. This regional structure has parasitic folds denominated as B1A which are refolded by folds B1B that also have vergence to NNW. Both of them have ENE-WSW direction, are non-cylindrical folds and configure an interference pattern that is similar to Type 3 from Ramsay. This refolding occur during progressive deformation. The occurrence of highgrade magnetitic-martitic accumulation (> 64% Fe) of medium size (~ 100 Mt) is controlled by the combination of these folds and high angle thrust fault, both with the same direction. Above these structures, there is a development of folds with NNWSSE direction and WSW vergence (B2 folds). These folds are restricted to the B1 limbs and they configure an interference pattern named "abbuting fold". The age obtained by U/Pb SHRIMP on monazite grains is 2034 ± 11 Ma. The monazite grains occur on textural balance with the iron oxide from high-grade accumulations. This age corresponds to the formation timing of the high-grade bodies and suggests that the mineralization process is contemporary to the regional metamorphic peak of QuadrilĂĄtero FerrĂfero
Oesophageal Perforation: A diagnostic and therapeutic challenge in a resource limited setting. A report of three cases
Oesophageal perforation is a condition associated with a high mortality. Its management is still controversial with operative treatment being favoured but a shift to conservative management is occurring. Very little exists in medical literature about its management in Sub-Saharan Africa, where the paucity of thoracic surgeons is compounded by limited diagnostic and therapeutic facilities. We report three cases of oesophageal perforation which were all treated conservatively with tube thoracostomy, nil by mouth with feeding gastrostomy, intravenous antibiotics and chest physiotherapy. Two patients achieved oesophageal healing but one died due to severe septicaemia. In a resource restricted setting, conservative management which includes enteral nutrition by feeding gastrostomy, tube thoracostomy to drain inter pleural contaminants, intravenous antibiotics and chest physiotherapy is a safe and effective treatment for oesophageal perforations
Targeted PEG-poly(glutamic acid) complexes for inhalation protein delivery to the lung
Pulmonary delivery is increasingly seen as an attractive, non-invasive route for the delivery of forthcoming protein therapeutics. In this context, here we describe protein complexes with a new âcomplexing excipientâ - vitamin B12-targeted poly(ethylene glycol)-block-poly(glutamic acid) copolymers. These form complexes in sub-200 nm size with a model protein, suitable for cellular targeting and intracellular delivery. Initially we confirmed expression of vitamin B12-internalization receptor (CD320) by Calu-3 cells of the in vitro lung epithelial model used, and demonstrated enhanced B12 receptor-mediated cellular internalization of B12-targeted complexes, relative to non-targeted counterparts or protein alone. To develop an inhalation formulation, the protein complexes were spray dried adopting a standard protocol into powders with aerodynamic diameter within the suitable range for lower airway deposition. The cellular internalization of targeted complexes from dry powders applied directly to Calu-3 model was found to be 2â3 fold higher compared to non-targeted complexes. The copolymer complexes show no complement activation, and in vivo lung tolerance studies demonstrated that repeated administration of formulated dry powders over a 3 week period in healthy BALB/c mice induced no significant toxicity or indications of lung inflammation, as assessed by cell population count and quantification of IL-1ÎČ, IL-6, and TNF-α pro-inflammatory markers. Importantly, the in vivo data appear to suggest that B12-targeted polymer complexes administered as dry powder enhance lung retention of their protein payload, relative to protein alone and non-targeted counterparts. Taken together, our data illustrate the potential developability of novel B12-targeted poly(ethylene glycol)-poly(glutamic acid) copolymers as excipients suitable to be formulated into a dry powder product for the inhalation delivery of proteins, with no significant lung toxicity, and with enhanced protein retention at their in vivo target tissue
Evolutionary patterns of two major reproduction candidate genes (Zp2 and Zp3) reveal no contribution to reproductive isolation between bovine species
<p>Abstract</p> <p>Background</p> <p>It has been established that mammalian egg zona pellucida (ZP) glycoproteins are responsible for species-restricted binding of sperm to unfertilized eggs, inducing the sperm acrosome reaction, and preventing polyspermy. In mammals, ZP apparently represents a barrier to heterospecific fertilization and thus probably contributes to reproductive isolation between species. The evolutionary relationships between some members of the tribe Bovini are complex and highly debatable, particularly, those involving <it>Bos </it>and <it>Bison </it>species for which interspecific hybridization is extensively documented. Because reproductive isolation is known to be a major precursor of species divergence, testing evolutionary patterns of ZP glycoproteins may shed some light into the speciation process of these species. To this end, we have examined intraspecific and interspecific genetic variation of two ZP genes (<it>Zp2 </it>and <it>Zp3</it>) for seven representative species (111 individuals) from the Bovini tribe, including five species from <it>Bos </it>and <it>Bison</it>, and two species each from genera <it>Bubalus </it>and <it>Syncerus</it>.</p> <p>Results</p> <p>A pattern of low levels of intraspecific polymorphism and interspecific divergence was detected for the two sequenced fragments each for <it>Zp2 </it>and <it>Zp3</it>. At intraspecific level, none of neutrality tests detected deviations from neutral equilibrium expectations for the two genes. Several haplotypes in both genes were shared by multiple species from <it>Bos </it>and <it>Bison</it>.</p> <p>Conclusions</p> <p>Here we argue that neither ancestral polymorphism nor introgressive hybridization alone can fully account for haplotype sharing among species from <it>Bos </it>and <it>Bison</it>, and that both scenarios have contributed to such a pattern of haplotype sharing observed here. Additionally, codon-based tests revealed strong evidence for purifying selection in the <it>Zp3 </it>coding haplotype sequences and weak evidence for purifying selection in the <it>Zp2 </it>coding haplotype sequences. Contrary to a general genetic pattern that genes or genomic regions contributing to reproductive isolation between species often evolve rapidly and show little or no gene flow between species, these results demonstrate that, particularly, those sequenced exons of the <it>Zp2 </it>and the <it>Zp3 </it>did not show any contribution to reproductive isolation between the bovine species studied here.</p
Development of dry powder formulations for inhalation based on nanomedicine for targeted lung cancer therapy
Le cancer du poumon est lâun des cancers les plus frĂ©quents dans le monde et reste le plus meurtrier actuellement en terme dâincidence absolue. Les traitements employĂ©s chez les patients atteints dâun cancer du poumon consistent en une combinaison de chirurgie, de radiothĂ©rapie et de chimiothĂ©rapie. Alors quâil y a quelques annĂ©es, les guidelines de traitement Ă©taient principalement basĂ©es sur le stade clinique de la maladie, le dĂ©veloppement de nouvelles thĂ©rapies a menĂ© Ă une classification plus appropriĂ©e des cancers du poumon. Cette nouvelle classification se base, en plus du stade clinique de la maladie, sur lâexpression de diffĂ©rents biomarqueurs exprimĂ©s chez des sous-populations bien dĂ©finies de patients. Ces biomarqueurs sont par exemple la mutation dâun gĂšne ou lâexpression dâune protĂ©ine. Au cours de ces dix derniĂšres annĂ©es, la recherche a Ă©tĂ© trĂšs active dans ce domaine avec lâarrivĂ©e de nouveaux traitements plus spĂ©cifiques pour ces sous-populations de patients. Des exemples concrets de ces nouvelles thĂ©rapies sont les chimiothĂ©rapies dites ciblĂ©es et lâimmunothĂ©rapie. LâarrivĂ©e de tels traitements a parmi dâaugmenter significativement le pronostic de la maladie et Ă©galement de rĂ©duire considĂ©rablement les graves effets secondaires des chimiothĂ©rapies conventionnelles. Toutefois, le bĂ©nĂ©fice en termes de survie reste modĂ©rĂ©. Le taux de survie des patients Ă cinq ans est actuellement de 15%. Il y a donc toujours un besoin urgent de mettre au point de nouvelles stratĂ©gie de traitement.La chimiothĂ©rapie inhalĂ©e constitue une perspective de traitement adjuvant du cancer du poumon trĂšs intĂ©ressante, comparĂ©e Ă la chimiothĂ©rapie conventionnelle. En effet, elle permettrait dâadministrer des doses dâanticancĂ©reux plus importantes directement au niveau du site tumoral tout en limitant lâexposition systĂ©mique du mĂ©dicament dans lâorganisme, et donc, les toxicitĂ©s importantes sây rapportant. Toutefois, aucun mĂ©dicament suivant cette approche nâest actuellement disponible sur le marchĂ© et ce, malgrĂ© quelques Ă©tudes cliniques de Phase I/II. Cela peut principalement sâexpliquer par (i) lâincapacitĂ© dâadministrer des doses inhalĂ©es efficaces dâagent anticancĂ©reux avec les dispositifs dâinhalation utilisĂ©s (les nĂ©buliseurs), (ii) les inquiĂ©tudes quant Ă une possible augmentation des toxicitĂ©s pulmonaires des agents anticancĂ©reux administrĂ©s par inhalation, (iii) les moyens devant ĂȘtre mis en place afin dâassurer la non-contamination de lâenvironnement et du personnel soignant lors dâune sĂ©ance dâinhalation. BasĂ©e sur de nouvelles technologies pharmaceutiques (lâinhalation sous forme de poudre sĂšche, les nanomĂ©decines, les thĂ©rapies ciblĂ©es, etc.) et sur une meilleure connaissance de la biologie des cancers, la stratĂ©gie scientifique que nous proposons pourrait permettre dâapporter une solution aux problĂ©matiques prĂ©citĂ©es. Ce travail dĂ©crit le dĂ©veloppement de nouvelles formulations de poudre sĂšche pour inhalation (« dry powder for inhalation », DPI) Ă base de nanovecteurs ciblĂ©s contre le rĂ©cepteur au folate (« folate receptor », FR) pour le traitement sĂ©lectif de cancers du poumon FR-positifs. Ces formulations permettraient le ciblage (i) du site tumoral par lâutilisation de lâadministration pulmonaire et (ii) spĂ©cifique des cellules cancĂ©reuses du poumon par les nanovecteurs ciblĂ©s. Trois parties constituent ce travail.Dans la premiĂšre partie, deux nouveaux excipients folatĂ©s (c.Ă .d. sur lesquels ont Ă©tĂ© greffĂ©s des groupements folates) ont Ă©tĂ© synthĂ©tisĂ©s en trois Ă©tapes principales par une mĂ©thode de synthĂšse faisant appel Ă des dĂ©rivĂ©s de carbodiimide. Ces excipients comportent trois types de composants majeures relatifs Ă leur fonction :un ligand, le groupement folate, pour le ciblage des FRs ;un composĂ© de charge, un polysaccharide, capable dâinteragir avec lâagent anticancĂ©reux ou une structure contenant celui-ci ;et un spacer, le poly(Ă©thylĂšne glycol), afin dâassurer une bonne flexibilitĂ© du folate et ainsi permettre une bonne interaction avec le FR. Ces nouveaux excipients folatĂ©s ont Ă©tĂ© caractĂ©risĂ©s par RMN du proton, par spectromĂ©trie de masse et par analyse thermique. Lâexcipient F-PEG-HMD (« folate-poly(ethylene glycol)-hydrophobically-modified dextran ») Ă©tait capable de former des micelles caractĂ©risĂ©es par une distribution de taille particulaire bimodale dans lâeau, avec un diamĂštre moyen dâenviron 80 nm. F-PEG-HMD Ă©tait caractĂ©risĂ© par une concentration micellaire critique de 4 x 10-7 M. Lâexcipient F-PEG-HTCC (« Folate-poly(ethylene glycol)-(N-[(2-hydroxy- 3-trimethylammonium)propyl] chitosan ») prĂ©sentait des charges positives permettant de se solubiliser en milieu aqueux, indĂ©pendamment du pH.Dans la deuxiĂšme partie du travail, des formulations DPI ont Ă©tĂ© dĂ©veloppĂ©es Ă base de lâagent anticancĂ©reux tĂ©mozolomide (TMZ). Celui-ci a Ă©tĂ© choisi comme premier modĂšle de principe actif pour son mĂ©canisme dâaction particulier qui lui confĂšre une activitĂ© dans les cancers apopto-rĂ©sistants, comme câest le cas de beaucoup de cancers du poumon. De plus, lâadministration dâune formulation de TMZ sous forme de nanovecteur permettrait de considĂ©rablement augmenter son activitĂ© en augmentant, par exemple, sa stabilitĂ© in vivo, ou encore son incorporation intracellulaire spĂ©cifique dans les cellules cancĂ©reuses. Toutefois, le TMZ est caractĂ©risĂ© par des propriĂ©tĂ©s physicochimiques ne permettant que trĂšs difficilement son encapsulation dans des nanovecteurs. Le TMZ est une petite molĂ©cule, faiblement soluble dans lâeau sans toutefois ĂȘtre lipophile. Comme type de nanovecteur, les micelles polymĂ©riques pourraient prĂ©senter un bon profil pour encapsuler le TMZ. Des micelles composĂ©es de F-PEG-HMD et de TMZ ont Ă©tĂ© prĂ©parĂ©es par solubilisation de ces deux composĂ©s en prĂ©sence. La solubilitĂ© dans lâeau du TMZ a pu ainsi ĂȘtre doublĂ©e en prĂ©sence de F-PEG-HMD, ce qui pourrait mener Ă des concentrations de TMZ augmentĂ©es au sein du site tumoral. Les micelles polymĂ©riques prĂ©sentaient un diamĂštre moyen de 50-60 nm, en fonction de la concentration en F-PEG-HMD utilisĂ©e. Les formulations DPI ont Ă©tĂ© prĂ©parĂ©es par spray-drying des micelles en prĂ©sence de mannitol et de leucine. Le TMZ est restĂ© stable durant lâĂ©tape de spray-drying, ainsi confirmĂ© par des propriĂ©tĂ©s antiprolifĂ©ratives in vitro des formulations DPI semblables Ă une solution de TMZ. Deux des formulations DPI dĂ©veloppĂ©es prĂ©sentaient de bonnes propriĂ©tĂ©s aĂ©rodynamiques, avec des fractions en particule fine jusquâĂ 50%, et Ă©taient capable de libĂ©rer les micelles polymĂ©riques rapidement en milieu aqueux. Toutefois, les taux dâencapsulation obtenus Ă©taient relativement bas (infĂ©rieurs Ă 10%). Le travail sâest donc poursuivi avec un autre agent anticancĂ©reux, le paclitaxel.Dans la troisiĂšme partie du travail, des formulations DPI Ă base de nanovecteurs chargĂ©s en paclitaxel (PTX). Le PTX a Ă©tĂ© choisi comme deuxiĂšme modĂšle dâagent anticancĂ©reux car il sâagit dâune des molĂ©cules les plus couramment utilisĂ©es dans le traitement du cancer du poumon, et ce malgrĂ© les graves effets secondaires systĂ©miques engendrĂ©s par lâadministration intraveineuse de ce mĂ©dicament. Lâutilisation de la voie pulmonaire pourrait permettre dâoptimiser les traitements Ă base de PTX, et ainsi, la qualitĂ© de vie des patients (rĂ©ductions consĂ©quentes des graves effets secondaires systĂ©miques et meilleure rĂ©ponse thĂ©rapeutique). Deux types de nanovecteurs ont Ă©tĂ© prĂ©parĂ©s avec des taux dâencapsulation en PTX dâapproximativement 100%. Des micelles polymĂ©riques Ă base de F-PEG-HMD et de PTX ont Ă©tĂ© prĂ©parĂ©es par une mĂ©thode de dialyse avec un diamĂštre moyen de 50 nm et un potentiel zĂȘta dâenviron -4 mV dans le PBS. Des nanoparticules lipidiques solides (« solid lipid nanoparticle », SLN) chargĂ©es en PTX ont Ă©tĂ© prĂ©parĂ©es par une mĂ©thode de nanoprĂ©cipitation et les SLNs ont ensuite Ă©tĂ© enrobĂ©es par F-PEG-HTCC. La prĂ©sence de lâenrobage a Ă©tĂ© confirmĂ©e par la taille et la charge des particules (diamĂštre moyen de 160 nm Ă 230 nm et potentiel zĂȘta de -20 mV Ă + 30 mV, avant et aprĂšs enrobage, respectivement). Les nanovecteurs Ă©taient capables dâĂȘtre incorporĂ©s, in vitro, dans les cellules HeLa et M109-HiFR, deux lignĂ©es de cellules cancĂ©reuses exprimant le FR, et in vivo, aprĂšs administration par inhalation sur un modĂšle orthotopique de cancer pulmonaire murin Ce modĂšle, le modĂšle M109, a Ă©tĂ© dĂ©veloppĂ© dans le cadre de ce travail Ă partir de la lignĂ©e M109-HiFR. AprĂšs administration par inhalation, les SLNs restaient enrobĂ©es dans les tissus pulmonaires et tumoraux. Les nanovecteurs ont montrĂ© une activitĂ© antiprolifĂ©rative in vitro sur les deux lignĂ©es prĂ©citĂ©es. De plus, cette activitĂ© Ă©tait significativement plus grande avec les SLNs enrobĂ©es chargĂ©es en PTX quâavec la formulation commerciale contenant le paclitaxel, le TaxolÂź, avec des concentrations inhibitrices mĂ©dianes de 60 et 340 nM, respectivement. LâactivitĂ© anti-cancĂ©reuse in vivo des SLNs enrobĂ©es, qui prĂ©sentaient un meilleur profil que les micelles polymĂ©riques pour ĂȘtre Ă©tudiĂ©es in vivo (plus haute teneur en PTX, plus grande activitĂ© antiprolifĂ©rative, et meilleure profil de libĂ©ration du PTX in vitro), a Ă©tĂ© Ă©valuĂ©e sur le modĂšle M109. Les SLNs enrobĂ©es, administrĂ©es par inhalation, seules ou en association avec le Taxol par intraveineuse, ont Ă©tĂ© comparĂ©es au TaxolÂź, administrĂ© par inhalation, par intraveineuse ou les deux, Ă la mĂȘme dose de PTX totale. Les traitements Ă base des SLNs enrobĂ©es, en particulier en association avec le TaxolÂź en intraveineuse, ont menĂ©s un allongement significatif de la survie des souris M109, par rapport au Taxol en intraveineuse seul (survie mĂ©diane de 38 et 27 jours, respectivement). De plus, la mort de la derniĂšre souris M109 a Ă©tĂ© observĂ© au jour 61 pour le traitement SLN/Taxol en association, comparĂ© au jour 33 pour le Taxol en intraveineuse, seul, Ă la mĂȘme dose totale en PTX (10-8-8-8 mg/kg), et au jour 29 pour le contrĂŽle nĂ©gatif (c.Ă .d. les souris nâayant pas reçu de traitement). Des Ă©tudes supplĂ©mentaires sont toutefois requises pour conclure une potentielle augmentation de lâactivitĂ© anticancĂ©reuse des SLNs inhalĂ©es par rapport au TaxolÂź. En effet, les doses de PTX en inhalation Ă©taient trop grandes pour le modĂšle M109 menant Ă la mort dâune partie non nĂ©gligeable des souris M109. Nous pouvons toutefois conclure que le traitement Ă base des SLNs inhalĂ©es en association avec le TaxolÂź en intraveineuse semble prometteur pour la suite du projet. Des formulations DPI ont ensuite Ă©tĂ© produites Ă partir des nanovecteurs chargĂ©s en PTX par spray-drying. Les formulations obtenues prĂ©sentaient une large dĂ©position in vitro dans les poumons, avec des fractions en particule fine allant jusquâĂ 50% et de bonnes propriĂ©tĂ©s de libĂ©ration des nanovecteurs en milieu aqueux. Quel que soit le principe actif ou le nanovecteur utilisĂ©, les formulations DPI dĂ©veloppĂ©es ont montrĂ© une large dĂ©position pulmonaire in vitro dans les voies aĂ©riennes infĂ©rieures, oĂč les adĂ©nocarcinomes pulmonaires sont le plus souvent trouvĂ©s. De plus, les formulations ne contenant que les excipients Ă©taient bien tolĂ©rĂ©es in vivo aprĂšs inhalation chez la souris saine. Cela a Ă©tĂ© vĂ©rifiĂ© par analyse des fluides bronchoalvĂ©olaires en termes de concentration totale en protĂ©ine, de population de cellules, et de concentration en cytokines IL-1ÎČ, IL-6, and TNF-α. Ce travail montre dĂšs lors Ă©galement que les formulations DPI pourraient constituer un systĂšme de dĂ©livrance de mĂ©dicament intĂ©ressant pour amener des nanovecteurs dans le tractus respiratoire oĂč la tumeur rĂ©side. Toutefois, alors que de nombreuses caractĂ©ristiques intĂ©ressantes des formulations ont Ă©tĂ© dĂ©montrĂ©es (la tolĂ©rance des excipients, les profils de libĂ©ration du PTX obtenus, lâincorporation intracellulaire des nanovecteur ainsi que leur bonne distribution dans du tissu tumoral in vivo et leur activitĂ© anticancĂ©reuse, etc.), lâimplication des FRs pour expliquer ces caractĂ©ristiques nâa pas pu ĂȘtre Ă©tablie clairement.Lung cancer is one of the most frequent cancers in the world, and remains the most deadly. Lung cancer therapy involves the combination of surgery, radiotherapy and chemotherapy. Whereas the treatment guidelines used to be related mainly to the stage of the disease, more recent treatments have introduced the concept of treating lung cancers according not only to the stage, but also to the specific characteristics of the tumors, i.e. a gene mutation, expression of a protein, etc. In the last decade, scientific and clinical research has been very active in this field, with recurrent introduction of new treatments, including new chemotherapies (e.g. targeted chemotherapies and immunotherapies). Many of these new treatments certainly induce better therapeutic responses and a sharp reduction in the adverse effects of conventional chemotherapies for well-defined subpopulations of patients. However, the benefit in terms of survival rates is only moderate. The five-year survival rate is currently ~15%. There is therefore no doubt that new treatment approaches and strategies are needed. One interesting approach is aerosolized chemotherapy. The pulmonary delivery of anti-cancer drugs could potentially be an interesting alternative to conventional adjuvant chemotherapy in lung cancer treatment, for many reasons. Among them, it could enhance the therapeutic ratio significantly by decreasing systemic severe toxicities and increasing anti-tumour efficacy. However, despite interesting clinical trial reports, all the strategies describing an aerosolized anti-cancer treatment have failed to bring new medicine on the market so far. The failures have been related mainly to (i) the inability to deliver proper and efficient drug doses in the lungs with the inhalation devices used in clinical trials (i.e. nebulizers), (ii) concerns about potential increase in lung toxicities engendered by these anti-cancer drug-based aerosols, and (iii) the requirement for adapted facilities to perform the inhalation procedure safely. Based on new pharmaceutical technologies (i.e. dry powder for inhalation (DPI) technology, nanomedicine, drug targeting, etc.) and on a better knowledge of cancer biology, a plausible and feasible answer to the aforementioned causes of failure was proposed. In this work, new nanomedicine-based DPI formulations were designed and developed for proposal as adjuvant chemotherapy for lung cancer treatment, especially for folate receptor (FR)-positive adenocarcinomas. These formulations would potentiate chemotherapy by means of a dual-targeting approach, i.e. the targeting of (i) lung tumor site(s) with pulmonary delivery and (ii) lung cancer cells with FR-targeted nanocarriers. To set up this approach, the work included three parts.In the first part, two new folate-grafted excipients were synthesized using carbodiimide-mediated chemistry in three main steps. These excipients consisted of three main components with a defined function: a ligand bringing selectivity, i.e. folate groups; a loading compound able to interact non-covalently with the anti-cancer drug or a drug delivery system, i.e. polysaccharides; and a spacer ensuring good flexibility of the ligand to allow its binding to the target, i.e. poly(ethylene glycol). The excipients were characterized by 1H-NMR, mass spectrometry and thermal analysis. Folate-polyethylene glycol-hydrophobically-modified dextran (F-PEG-HMD), a new folate-grafted self-assembling copolymer, presented a critical micellar concentration in water of 4 x 10-7 M. F-PEG-HMD micelles were characterized by a trimodal particle size distribution with a Z-average diameter of about 80 nm in water. Folate-polyethylene glycol-(N-[(2-hydroxy- 3-trimethylammonium)propyl] chitosan) (F-PEG-HTCC) presented positive charges and was easily dissolved in water, regardless of the pH.In the second part, dry powders were developed with the anti-cancer drug temozolomide (TMZ). TMZ was chosen as the first anti-cancer drug model due to its interesting anti-cancer activity in poor prognosis, apopto-resistant cancers, as is the case for many lung cancers. In addition, TMZ delivery via a nanocarrier might present many advantages such as prolonged lifetime and specific improved intracellular delivery into cancer cells. However, TMZ is characterized by poor properties for encapsulation into nanocarriers. It presents poor water solubility and low lipophilicity. Because of these properties, polymeric micelles presented the best profile for entrapping TMZ. TMZ-loaded F-PEG-HMD micelles were prepared by co-dissolution of TMZ and F-PEG-HMD. TMZ solubility in water was increased in the presence of F-PEG-HMD (a two-fold increase in molar solubility) which could potentially lead to increased local concentrations in the tumor site. The TMZ-loaded F-PEG-HMD micelles were characterized by Z-average diameters in the range of 50-60 nm, depending on the F-PEG-HMD concentration used. The micelles were spray dried to produce dry powders. TMZ remained stable during all the formulation steps, confirmed by similar in vitro anti-proliferative properties for the DPI formulations and a TMZ solution. Two of the developed DPI formulations were characterized by good aerodynamic properties (with a fine particle fraction of up to 50%) and were able to release the F-PEG-HMD micelles quickly in aqueous media. However, as presumed, poor entrapment efficiency values were obtained (less than 10%). A second anti-cancer compound was therefore chosen to pursue in the study, the lipophilic paclitaxel.In the third part, nanocarrier-loaded dry powders were developed with the poorly water-soluble anti-cancer drug paclitaxel (PTX) and the new folate-grafted excipients. PTX was chosen as a model drug because it is an effective anti-cancer drug currently used in lung cancer therapy and it causes severe systemic toxicities when delivered by the conventional intravenous route. Pulmonary delivery of PTX might therefore optimize treatment efficacy and/or quality of life in lung cancer patients. Two types of PTX-loaded nanocarrier were prepared with an encapsulation efficiency of approximatively 100%. PTX-loaded F-PEG-HMD micelles were prepared by a dialysis method. These had a Z-average diameter of about 50 nm and a zeta potential of about -4 mV in PBS. F-PEG-HTCC-coated solid lipid nanoparticles (SLNs) loaded with PTX were prepared in two main steps. PTX-loaded SLNs were first prepared using a nanoprecipitation method and the SLNs were then coated with F-PEG-HTCC. Efficient coating was confirmed by particle size and zeta potential (Z-average diameter of 160 nm to 230 nm and zeta potential of -20 mV to +30 mV before and after F-PEG-HTCC coating, respectively). The nanocarriers were able to enter HeLa and M109-HiFR, two FR-expressing cancer cell lines, in vitro, and in vivo after administration by inhalation to orthotopic M109-HiFR lung tumor grafted mice. This orthotopic model, i.e. the M109 model, was developed in the study. The SLNs remained coated with F-PEG-HTCC in lung tissues and tumors after inhalation. The PTX contained in the nanocarriers remained active against HeLa and M109-HiFR in vitro, as observed by means of the colorimetric MTT assays. Moreover, PTX-loaded SLNs were characterized by significantly higher anti-proliferative properties than TaxolÂź, with half-maximal inhibitory concentrations of 60 and 340 nM, respectively. Afterwards, the in vivo anti-cancer activity of the coated SLNs, which led to better profile than the polymeric micelles to be studied in vivo (i.e. higher PTX loading, higher anti-proliferative properties, and better release profile of PTX in vitro), was evaluated using the M109 model. The coated SLNs, administered by inhalation, alone or combined with intravenous TaxolÂź, were compared with TaxolÂź, administered by inhalation, IV or both, at the same PTX-relative doses. Interestingly, we observed much longer survivals for the SLN inhaled treatments, especially when combined with intravenous TaxolÂź, than for intravenous Taxol alone (median survivals of 38 and 27 days, respectively). Moreover, the last tumor-bearing mouse death occurred at day 61 for the SLN combined therapy, compared with day 33 for the intravenous therapy alone, at the same total PTX-relative dose (i.e. 10-8-8-8 mg/kg), and with day 29 for negative control (i.e. non-treated mice). However, further evaluations are needed to conclude that there is any improvement in terms of therapeutic response compared with intravenous TaxolÂź. Indeed, bias related to the fact that the aerosolized PTX doses were too high was included in the survival rate analysis and was revealed by unacceptable treatment-related deaths. Nevertheless, the combination of aerosolized, loaded SLNs and intravenous Taxol seemed to be an interesting strategy of treatment to follow. Dry powders embedding the PTX-loaded nanocarriers were developed by spray-drying. In vitro, good deposition profiles were obtained, with a fine particle fraction of up to 50% and good ability to re-disperse the nanocarriers in aqueous media.Whatever the drug or the nanocarrier adopted, the developed DPI formulations showed wide in vitro pulmonary deposition in the lower respiratory tract, where adenocarcinomas are more often found. Moreover, nanocarrier-based dry powders without drugs were well-tolerated in vivo, as assessed in healthy mice by determination of total protein content, cell count, and cytokine IL-1ÎČ, IL-6, and TNF-α concentration in bronchoalveolar lavage fluids. The present work therefore also shows that dry powders for inhalation could constitute an interesting drug delivery system able to release nanocarriers in the respiratory tract where the tumor is growing and spreading. However, in contrast to the undeniable improvements in terms of drug delivery system (e.g. safet
Evaluation des risques de compaction des sols en RĂ©gion wallonne
Le projet de directive europĂ©enne COM(2006)232 Ă©tablit un cadre gĂ©nĂ©ral pour la protection des sols. Le projet prĂ©voit que les Ă©tats membres identifient les zones susceptibles dâĂȘtre touchĂ©es par des processus de dĂ©gradation (Ă©rosion, compaction, salinisation, âŠ) et quâils proposent des mesures afin de rĂ©duire les risques. La compaction peut affecter la macroporositĂ©, les mouvements de lâeau et de lâair dans le sol, les mĂ©canismes de croissance racinaire, le dĂ©veloppement de la faune du sol. De ce fait, elle est donc souvent Ă lâorigine dâune diminution du rendement des cultures. En RĂ©gion wallonne, les machines destinĂ©es Ă la rĂ©colte de betteraves risquent dâengendrer une compaction du sol car elles sont souvent utilisĂ©es alors que le sol est humide et que les charges Ă lâessieu sont importantes. Les machines dâexploitation forestiĂšre prĂ©sentent Ă©galement des risques pour la compaction du sol. La contrainte de prĂ©consolidation (Pc) est considĂ©rĂ©e comme la valeur Ă ne pas dĂ©passer pour Ă©viter que le sol subisse des dĂ©gĂąts difficilement rĂ©versibles. Si les contraintes appliquĂ©es sont supĂ©rieures Ă Pc, le sol garde un comportement Ă©lastique (Ă©tat rĂ©versible) et il nây a pas de modification dans lâorganisation de la porositĂ© du sol. Par contre, si les contraintes appliquĂ©es sont supĂ©rieures Ă Pc, le sol entre en plasticitĂ© et ses fonctions naturelles sont perturbĂ©es. Dans un premier temps, des cartes de sensibilitĂ© du sol Ă la compaction sont Ă©laborĂ©es. Elles Ă©valuent la contrainte de prĂ©consolidation des sols de la RĂ©gion wallonne, au moyen des fonctions de pĂ©dotransfert (FPT) de Lebert et Fleige (2003). Lâimpact des engins sur le sol est Ă©tudiĂ© au niveau du âsubsoilâ, sous la couche de labour, lĂ oĂč le sol ne peut pas ĂȘtre rĂ©gĂ©nĂ©rĂ© par des outils classiques de travail du sol. Les paramĂštres des FPT sont accessibles au sein de Aardewerk ou sont trouvĂ©s dans la littĂ©rature. Les valeurs de Pc sont classĂ©es selon 6 niveaux de sensibilitĂ©, Ă deux Ă©tats hydriques diffĂ©rents. Dans un deuxiĂšme temps, la distribution des contraintes verticales gĂ©nĂ©rĂ©es par le passage dâengins âtypesâ, caractĂ©risĂ©s par les dimensions des pneus, la charge Ă lâessieu et la pression de gonflage, est calculĂ©e Ă lâaide du logiciel Soilflex. Les Pc du sol sont alors comparĂ©es aux contraintes verticales induites par les engins, pour aboutir Ă des cartes de risque de compaction. Celles-ci simulent 4 scĂ©narios : deux teneurs en eau et deux types dâengins. Afin de valider ces deux types de cartes, des tests oedomĂ©triques destinĂ©s Ă mesurer Pc sont rĂ©alisĂ©s sur des sols agricoles et forestiers. Pour faciliter la dĂ©marche et calculer les FPT de Lebert et Fleige avec une plus faible incertitude, il serait utile que la CNSW comporte des donnĂ©es relatives aux fractions granulomĂ©triques, Ă la matiĂšre organique des sols, la cohĂ©sion, lâangle de frottement interne, la masse volumique apparente sĂšche de sol, âŠConvention " Evaluation des risques de compaction des sols en RĂ©gion wallonne
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An Evaluation of Grazing Intensity Influences on California Annual Range
Influences of grazing intensity on species composition and herbage production of grass-woodland and improved grassland subtypes of annual range were evaluated over a 5-year period in coastal northern California using 3 grazing treatments (100, 150, and 200% of moderate stocking). Herbage utilization did not differ significantly between the 2 subtypes but averaged 42, 52, and 69% for the respective treatments. Plant species and production responses differed significantly between woodland and grassland subtypes. On woodland, ripgut brome (Bromus rigidus Roth.) and wild oats (Avena barbata Brot. and A. fatua L.) were most sensitive to grazing intensity while wild barley (Hordeum leporinum Link. and H. hystrix Roth.) and annual fescue (Festuca dertonensis (all.) Asch. and Graebn. and F. megalura Nutt.) were least sensitive. On improved grassland, subterranean clover (Trifolium subterraneum L.) increased and soft chess (Bromus mollis L.) decreased with increasing grazing intensity. Soft chess remained most plentiful on woodland range under heaviest grazing and it continued to be a major species under heavy grazing of grassland, demonstrating tolerance to grazing intensity. Filaree (Erodium cicutarium (L.) L'Her. and E. botrys (Cav.) Bertol.) declined on woodland but increased on grassland as grazing intensified. Peak standing crop was not significantly affected by grazing intensity on woodland range but was greatest at 150% of moderate stocking and lowest at 200% of moderate stocking on grassland range. Decline in grassland herbage yield under heaviest grazing was due to reduction of soft chess which was displaced by subterranean clover. Effects of grazing intensity on range composition and productivity were confounded by innate differences in ranges and yearly weather patterns. Herbage production was impacted more by annual growing conditions than by grazing regimens, but there was no correlation between total annual precipitation and peak standing crop.This material was digitized as part of a cooperative project between the Society for Range Management and the University of Arizona Libraries.The Journal of Range Management archives are made available by the Society for Range Management and the University of Arizona Libraries. Contact [email protected] for further information.Migrated from OJS platform August 202
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