Ocular antisense oligonucleotide delivery by cationic nanoemulsion for improved treatment of ocular neovascularization: an in-vivo study in rats and mice.

The efficacy of an antisense oligonucleotide (ODN17) cationic nanoemulsion directed at VEGF-R2 to reduce neovascularization was evaluated using rat corneal neovascularization and retinopathy of prematurity (ROP) mouse models. Application of saline solution or scrambled ODN17 solution on eyes of rats led to the highest extent of corneal neovascularization. The groups treated with blank nanoemulsion or scrambled ODN17 nanoemulsion showed moderate inhibition in corneal neovascularization with no significant difference with the saline and scrambled ODN17 control solution groups, while the groups treated with ODN17 solution or Avastin® (positive ODN17 control) clearly elicited marked significant inhibition in corneal neovascularization confirming the results reported in the literature. The highest significant corneal neovascularization inhibition efficiency was noted in the groups treated with ODN17 nanoemulsion (topical and subconjunctivally). However, in the ROP mouse model, the ODN17 in PBS induced a 34% inhibition of retinal neovascularization when compared to the aqueous-vehicle-injected eyes. A significantly higher inhibition of vitreal neovascularization (64%) was observed in the group of eyes treated with ODN17 nanoemulsion. No difference in extent of neovascularization was observed between blank nanoemulsion, scrambled ODN17 nanoemulsion, vehicle or non-treated eyes. The overall results indicate that cationic nanoemulsion can be considered a promising potential ocular delivery system and an effective therapeutic tool of high clinical significance in the prevention and forthcoming treatment of ocular neovascular diseases.

Ocular biocompatibility of novel Cyclosporin A formulations based on methoxy poly(ethylene glycol)-hexylsubstituted poly(lactide) micelle carriers.

Topical ocular drug delivery has always been a challenge for pharmaceutical technology scientists. In the last two decades, many nano-systems have been studied to find ways to overcome the typical problems of topical ocular therapy, such as difficult corneal penetration and poor drug availability. In this study, methoxy poly(ethylene glycol)-hexylsubstituted poly(lactides) (MPEG-hexPLA) micelle formulations, which are promising nanocarriers for poorly water soluble drugs, were investigated for the delivery of Cyclosporin A (CsA) to the eye. As a new possible pharmaceutical excipient, the ocular compatibility of MPEG-hexPLA micelle formulations was evaluated. An in vitro biocompatibility assessment on human corneal epithelial cells was carried out using different tests. Cytotoxicity was studied by using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), and clonogenic tests and revealed that the CsA formulations and copolymer solutions were not toxic. After incubation with MPEG-hexPLA micelle formulations, the activation of caspase-dependent and -independent apoptosis as well as autophagy was evaluated using immunohistochemistry by analyzing the localization of four antibodies: (1) anti-caspase 3; (2) anti-apoptotic inducing factor (AIF); (3) anti-IL-Dnase II and (4) anti-microtubule-associated protein 1 light chain 3 (LC3). No apoptosis was induced when the cells were treated with the micelle solutions that were either unloaded or loaded with CsA. The ocular tolerance was assessed in vivo on rabbit eyes by Confocal Laser Scanning Ophthalmoscopy (CLSO), and very good tolerability was seen. The observed corneal surface was comparable to a control surface that was treated with a 0.9% NaCl solution. In conclusion, these results demonstrate that MPEG-hexPLA micelles are promising drug carriers for ocular diseases involving the activation of cytokines, such as dry eye syndrome and autoimmune uveitis, or for the prevention of corneal graft rejection.

Atributos topográficos na diferenciação de Argissolos

A topografia do terreno controla muitos processos hidrológicos, geomorfológicos e pedológicos, influenciando a radiação solar, precipitação pluvial, escoamento superficial, evaporação, regime de umidade do solo e tipo de vegetação, entre outros. Desta maneira, atributos topográficos derivados de um modelo digital de elevação foram utilizados para explicar a diferenciação de solos com horizonte B textural da região de ''Mar de Morros'', no noroeste do Estado do Rio de Janeiro. Foram estudados oito perfis de solo (quatro Argissolos Vermelhos e quatro Argissolos Vermelho-Amarelos), desenvolvidos de granulitos noríticos nos municípios de São José de Ubá e Itaperuna. Os dados dos atributos topográficos em cada perfil de solo (elevação, declividade, aspecto, plano e perfil de curvatura, radiação solar e índice topográfico combinado) foram extraídos, utilizando-se uma janela de 7 x 7 pixels, com os perfis ocupando o centro dessa janela. Os Argissolos que ocorrem nas encostas noroeste e nordeste recebem maior quantidade de radiação solar (mais quentes e secas) e por isto são vermelhos, eutróficos e não apresentam horizonte B latossólico, enquanto os solos das encostas sudeste (relativamente mais frias e úmidas) são vermelho-amarelados, distróficos e com horizonte B latossólico. A radiação solar, a declividade e o aspecto são os atributos topográficos relacionados com as diferenças entre os perfis de solos estudados. Os atributos topográficos analisados pelas técnicas multivariadas apresentaram-se efetivos para a distinção entre os Argissolos Vermelho-Amarelos distróficos e os Argissolos Vermelhos eutróficos, exceto o P7 (PVe). Estudos relacionando a influência da radiação solar na pedogênese são escassos em condições tropicais e, embora menos atuante em regiões tropicais, foi a radiação solar que determinou diretamente a diferenciação dos solos da área estudada.

Pedogênese e classificação de latossolos desenvolvidos de itabiritos no Quadrilátero Ferrífero, MG

Localizado na porção centro-oeste do Estado de Minas Gerais, o Quadrilátero Ferrífero abrange uma área de aproximadamente 7.000 km². Desde o século XVII, a região é conhecida como uma província aurífera e ferrífera, sendo por essa razão uma das regiões mais bem estudadas do Brasil no contexto geológico. A região é de topografia muito acidentada, onde predominam solos pouco evoluídos pedogeneticamente, com destaque para Cambissolos Háplicos, Neossolos Litólicos e Neossolos Regolíticos. Em menor proporção e em rampas de colúvio (relevo suave ondulado), ocorrem Latossolos Vermelhos muito ricos em Fe, anteriormente denominados Latossolos Ferríferos. Neste trabalho, foram realizados estudos para caracterizar física, química e mineralogicamente amostras de nove perfis de Latossolos Vermelhos férricos e perférricos, desenvolvidos de itabirito e rochas afins no Quadrilátero Ferrífero, com os objetivos de melhor entender sua gênese e avaliar critérios taxonômicos que permitam sua diferenciação no SiBCS, em níveis categóricos mais baixos. Os elevados valores de densidade de partículas são peculiares nesses solos e, ao lado da estrutura forte, muito pequena e granular, são fatores que contribuem para subestimar os teores de argila e superestimar os de silte, resultando em relação silte/argila maior do que aquela proposta pelo SiBCS para os Latossolos. A variação dos teores de SiO2, Fe2O3, Al2O3, TiO2, MnO, P2O5 e de alguns elementos-traço aponta para a diversidade na composição química do itabirito ou, ainda, provável mistura com rochas filíticas da região. Os valores das relações Fe2O3/TiO2 (não molecular) e TiO2/Fe2O3 (molecular) revelaram-se diferentes daqueles sugeridos na literatura para separação de Latossolos Vermelhos desenvolvidos de itabirito daqueles de rochas máficas. As frações areia, silte e argila apresentaram grande variação na atração magnética, com as duas primeiras frações evidenciando maior magnetização, em razão da presença de magnetita. Os valores de substituição isomórfica de Fe por Al variaram 0,07 a 0,11 e 0,09 a 0,38 mol mol-1 nas estruturas da hematita e magnetita, respectivamente.

Factors affecting snow damage of trees with particular reference to European conditions

Summary

In vivo inhibition of lens regrowth by fibroblast growth factor 2-saporin.

PURPOSE: To investigate the ability of fibroblast growth factor (FGF) 2-saporin to prevent lens regrowth in the rabbit. METHODS: Chemically conjugated and genetically fused FGF2-saporin (made in Escherichia coli) were used. Extracapsular extraction of the lens was performed on the rabbit, and the cytotoxin either was injected directly into the capsule bag or was administered by FGF2-saporin-coated, heparin surface-modified (HSM) polymethylmethacrylate intraocular lenses. The potential of the conjugate was checked by slit lamp evaluation of capsular opacification and by measuring crystallin synthesis. Toxin diffusion and sites of toxin binding were assessed by immunohistochemistry. Possible toxicity was determined by histologic analysis of ocular tissues. RESULTS: FGF2-saporin effectively inhibited lens regrowth when it was injected directly into the capsular bag. However, high concentration of the toxin induced transient corneal edema and loss of pigment in the iris. Intraocular lenses coated with FGF2-saporin reduced lens regrowth and crystallin synthesis without any detectable clinical side effect. After implantation, FGF2-saporin was shown to have bound to the capsules and, to a lesser extent, to the iris; no histologic damage was found on ocular tissues as a result of implantation of drug-loaded HSM intraocular lenses. CONCLUSIONS: Chemically conjugated (FGF2-SAP) and genetically fused FGF2-saporin (rFGF2-SAP) bound to HSM intraocular lenses can prevent lens regrowth in the rabbit.

Solubilização Potencial de Fosfatos Mediada pela Microbiota Rizosférica de Eucalipto Cultivado em Topossequência Típica da Zona da Mata Mineira

O uso de fosfatos naturais, aliado ao adequado manejo de microrganismos do solo solubilizadores de fosfato, é uma alternativa para reduzir os custos da adubação fosfatada. No entanto, ambas as práticas requerem a avaliação prévia do potencial da microbiota rizosférica em solubilizar fontes de P pouco reativas em condições de campo. O objetivo deste trabalho foi avaliar o potencial da microbiota do solo de solubilizar os fosfatos de Ca, Fe, Al, além dos fosfatos naturais de Araxá e Catalão em amostras de solo rizosférico e não rizosférico de plantio do hibrido Eucalyptus grandis × E. urophylla, localizados em três pontos de uma topossequência típica da Zona da Mata de Minas Gerais. Adicionalmente, avaliou-se a atividade de fosfatases ácidas e alcalinas sob as mesmas condições experimentais. A microbiota rizosférica das plantas do topo e da baixada apresentou maior potencial de solubilização de fosfato de Ca (5.745,09 e 6.452,80 μg de P, respectivamente), enquanto o solo da encosta não apresentou diferenças entre as fontes inorgânicas testadas. O fosfato de Catalão foi a fonte de fosfato natural com maior potencial de solubilização (1.209,71 μg de P) pela microbiota do solo nas condições avaliadas. O pH final do meio de cultura correlacionou-se negativamente com os valores de P solubilizado, indicando que a acidificação do ambiente foi um dos mecanismos de solubilização utilizados pela microbiota rizosférica in vitro. A atividade das fosfatases ácida e alcalina foi maior na rizosfera de plantas do topo, área com maior teor de matéria orgânica. Não foi observada correlação clara entre o potencial de solubilização de fosfato ou a atividade das fosfatases com o diâmetro médio à altura do peito das árvores do plantio. Este estudo demonstra o efeito da topografia no potencial de solubilização da microbiota do solo, que é influenciada positivamente pelo teor de matéria orgânica do solo.

Assessing the Functionality and Biocompatibility of a Wireless Contact Lens Sensor for 24 hour-intraocular Pressure Monitoring in Volunteers: Preliminary Results

Purpose: In vitro studies in porcine eyes have demonstrated a good correlation between induced intraocular pressure variations and corneal curvature changes, using a contact lens with an embedded microfabricated strain gauge. Continuous 24 hour-intraocular pressure (IOP) monitoring to detect large diurnal fluctuation is currently an unmet clinical need. The aims of this study is to evaluate precision of signal transmission and biocompatibility of 24 hour contact lens sensor wear (SENSIMED Triggerfish®) in humans. Methods: After full eye examination in 10 healthy volunteers, a 8.7 mm radius contact lens sensor and an orbital bandage containing a loop antenna were applied and connected to a portable recorder. Best corrected visual acuity and position, lubrication status and mobility of the sensor were assessed after 5 and 30 minutes, 4, 7 and 24 hours. Subjective comfort was scored and activities documented in a logbook. After sensor removal full eye examination was repeated, and the registration signal studied. Results: The comfort score was high and did not fluctuate significantly, except at the 7 hour-visit. The mobility of the contact lens was minimal but its lubrication remained good. Best corrected visual acuity was significantly reduced during the sensor wear and immediately after its removal. Three patients developed mild corneal staining. In all but one participant we obtained a registration IOP curve with visible ocular pulse amplitude. Conclusions: This 24 hour-trial confirmed the functionality and biocompatibility of SENSIMED Triggerfish® wireless contact lens sensor for IOP-fluctuation monitoring in volunteers. Further studies with a range of different contact lens sensor radii are indicated.

La Topografía médica de Vic de Antonio Millet: 1798

En primer lloc, aquest llibre conté una traducció i transcripció de la Topografia Mèdica de Vic, d'Antoni Millet, de 1798. Aquesta transcripció es completa amb una investigació analítica i detallada del context cultural en què sorgiren les primeres topografies mèdiques al nostre país.El present document suposa el redescobriment d'una figura rellevant de la medicina catalana, Antoni Millet, de qui també es recull una segona obra entorn a una epidèmia que afectà la ciutat de Ripoll l'any 1790.

Les Topografies mèdiques de la Reial Acadèmia de Medicina de Catalunya

En aquesta publicació el doctor Vallribera enumera part del fons no catalogat de la Reial Acadèmia de Medicina de Catalunya, en concret 145 memòries trameses a l¿Acadèmia per tal d¿optar als premis de Topografies Mèdiques. L¿autor n¿enumera les característiques i afegeix una valoració personal.El valor dels treballs recollits rau en la diversitat d¿enfocaments dintre de la temàtica sanitària i en el seu considerable interès sociològic i per a la petita història local, doncs força d¿aquestes memòries es refereixen a poblacions catalanes però també a algunes espanyoles i fins i tot de les filipines.

Sobre el grupo episcopal de Corduba

En este trabajo se revisa de manera preliminar la documentación disponible sobre el grupo episcopal de Corduba, con la intención de exponer una serie de consideraciones relativas a su inserción topográfica en la ciudad. Asimismo, se estudian las estructuras excavadas, con la idea de retomar la interpretación de aquellas construcciones que mejor permiten avanzar en el conocimiento general del conjunto arquitectónico.

Prognostication in comatose survivors of cardiac arrest: An advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine.

OBJECTIVES: To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy. METHODS: GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included. RESULTS AND CONCLUSIONS: Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at ?72h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron specific enolase at 48-72h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients.

Visualization of aqueous shunt position and patency using anterior segment optical coherence tomography.

PURPOSE: To describe the use of anterior segment optical coherence tomography (AS-OCT) to clarify the position and patency of aqueous shunt devices in the anterior chamber of eyes where corneal edema or tube position does not permit a satisfactory view. DESIGN: Noncomparative observational case series. METHODS: Four cases are reported in which aqueous shunt malposition or obstruction was suspected but the shunt could not be seen on clinical examination. The patients underwent AS-OCT to identify the position and patency of the shunt tip. RESULTS: In each case, AS-OCT provided data regarding tube position and/or patency that could not be obtained by slit-lamp examination or by gonioscopy that influenced management. CONCLUSIONS: AS-OCT can be used to visualize anterior chamber tubes in the presence of corneal edema that precludes an adequate view or in cases where the tube is retracted into the cornea. In such cases, AS-OCT is useful in identifying shunt patency and position, which helps guide clinical decision making.

In vivo distribution and ex vivo permeation of cyclosporine A prodrug aqueous formulations for ocular application.

Cyclosporine A is a poorly water-soluble, immunosuppressive drug used to treat a variety of ocular diseases. Its limited solubility makes challenging the development of a cyclosporine A-based eye drop for ocular topical application. Based on the prodrug strategy, the practically insoluble cyclosporine A was converted into a freely soluble prodrug. Such a water-soluble prodrug made it possible to develop water-based concentrated eye drops. The prodrug formulations were tested for their ex vivo permeation and in vivo distribution at three concentrations (equivalent to 0.05%, 0.50% and 2.00% w/v cyclosporine A). The ex vivo permeation experiments were performed on corneal and conjunctival epithelia. The in vivo distribution evaluated the total cyclosporine A present in the ocular structures as well as in serum, spleen and cervical lymphatic ganglions. Each prodrug formulation was compared to conventionally used cyclosporine A eye drops at an equivalent concentration. The experimental results showed that the tested eye drops behaved differently. The prodrug formulation was characterized by the following: i) preferential conjunctival penetration, ii) an interesting capacity to create large tissue deposits and iii) a lower risk of systemic complications and immunosuppression. The prodrug aqueous eye drop was demonstrated to be a patient-friendly option for the treatment of ocular diseases requiring high ocular levels of cyclosporine A, pushing the boundaries of the current therapeutic arsenal.

Inter- and intraobserver variability of measurements with Pentacam HR® in patients with mild to moderate keratoconus

Purpose: To evaluate inter- and intraobserver variability of indices crucial for detection of keratoconus progression derived from the Pentacam HR® (high-resolution) tomographer (OCULUS Optikgeräte GmbH, Wetzlar, Germany) in patients with mild to moderate keratoconus. Methods: Three repeated corneal topography measurements in the 25-picture mode by two independent observers were performed. The extent of variability across a large range of measurement parameters was analyzed including anterior and posterior corneal surface measurements, pachymetry values, corneal volume, anterior chamber volume and depth, and iridocorneal angle. The intraclass correlation coefficient (ICC) between and within each investigator was calculated to assess reproducibility and repeatability, respectively. Results: 31 eyes of 20 patients (mean age 31.6, SD ± 8.6) were included. Overall, the repeatability and reproducibility were excellent. The range of variability was reported by calculating the standard deviation of measurements. The detailed results are shown in Table 1. Conclusions: This study shows that the Pentacam HR® tomographer provides reliable measurements in patients with mild to moderate keratoconus. However, all parameters showed a certain range of variability. This should be taken into account when assessing keratoconus progression in order to distinguish true progression from variability in measurements. In addition, the excellent reproducibility suggests that the measurements can be reliably performed by different individuals from one visit to another.