Skin delivery potency and antitumor activities of temozolomide ester prodrugs

Clinical trials have shown temozolomide to be an effective agent for treatment of malignant melanoma. In order to investigate its suitability for delivery via the skin, a series of temozolomide esters was synthesized as prodrugs. In vitro assays demonstrated temozolomide, temozolomide acid and the hexyl ester equi-effective against selected cancer cell lines. The susceptibility of the esters to enzyme hydrolysis and their effectiveness for application to the skin were investigated. The esters effectively diffuse through rat skin and the hexyl ester demonstrated profound potency for penetrating through skin. Topical application of 5% (w/v) hexyl ester in DMSO solution on a mouse model demonstrated a significant inhibition of tumor growth. These results suggest that temozolomide esters could be an effective alternative to temozolomide in the treatment of skin cancer. © 2005 Elsevier Ireland Ltd. All rights reserved.

Drug delivery strategies for the treatment of Helicobacter pylori infections

Helicobacter pylori is one of the most common pathogenic bacterial infections, colonising an estimated half of all humans. It is associated with the development of serious gastroduodenal disease - including peptic ulcers, gastric lymphoma and acute chronic gastritis. Current recommended regimes are not wholly effective and patient compliance, side-effects and bacterial resistance can be problematic. Drug delivery to the site of residence in the gastric mucosa may improve efficacy of the current and emerging treatments. Gastric retentive delivery systems potentially allow increased penetration of the mucus layer and therefore increased drug concentration at the site of action. Proposed gastric retentive systems for the enhancement of local drug delivery include floating systems, expandable or swellable systems and bioadhesive systems. Generally, problems with these formulations are lack of specificity, limited to mucus turnover or failure to persist in the stomach. Gastric mucoadhesive systems are hailed as a promising technology to address this issue, penetrating the mucus layer and prolonging activity at the mucus-epithelial interface. This review appraises gastroretentive delivery strategies specifically with regard to their application as a delivery system to target Helicobacter. As drug-resistant strains emerge, the development of a vaccine to eradicate and prevent reinfection is an attractive proposition. Proposed prophylactic and therapeutic vaccines have been delivered using a number of mucosal routes using viral and non-viral vectors. The delivery form, inclusion of adjuvants, and delivery regime will influence the immune response generated. © 2005 Bentham Science Publishers Ltd.

Where next for PSMs - a grass-roots revolution?

Over the last 30 years, the field of problem structuring methods (PSMs) has been pioneered by a handful of 'gurus'—the most visible of whom have contributed other viewpoints to this special issue. As this generation slowly retires, it is opportune to survey the field and their legacy. We focus on the progress the community has made up to 2000, as work that started afterwards is ongoing and its impact on the field will probably only become apparent in 5–10 years time. We believe that up to 2000, research into PSMs was stagnating. We believe that this was partly due to a lack of new researchers penetrating what we call the 'grass-roots community'—the community which takes an active role in developing the theory and application of problem structuring. Evidence for this stagnation (or lack of development) is that, in 2000, many PSMs still relied heavily on the same basic methods proposed by the originators nearly 30 years earlier—perhaps only supporting those methods with computer software as a sign of development. Furthermore, no new methods had been integrated into the literature which suggests that revolutionary development, at least by academics, has stalled. We are pleased to suggest that from papers in this double special issue on PSMs this trend seems over because new authors report new PSMs and extend existing PSMs in new directions. Despite these recent developments of the methods, it is important to examine why this apparent stagnation took place. In the following sections, we identify and elaborate a number of reasons for it. We also consider the trends, challenges and opportunities that the PSM community will continue to face. Our aim is to evaluate the pre-2000 PSM community to encourage its revolutionary development post-2006 and offer directions for the long term sustainability of the field.

Classic beta-amyloid deposits cluster around large diameter blood vessels rather than capillaries in sporadic Alzheimer's disease

Various hypotheses could explain the relationship between beta-amyloid (Abeta) deposition and the vasculature in Alzheimer's disease (AD). Amyloid deposition may reduce capillary density, affect endothelial cells of blood vessels, result in diffusion from blood vessels, or interfere with the perivascular clearance mechanism. Hence, the spatial pattern of the classic ('cored') type of Abeta deposit was studied in the upper laminae (I,II/III) of the superior frontal gyrus in nine cases of sporadic AD (SAD). Sections were immunostained with antibodies against Abeta and with collagen IV to study the relationships between the spatial distribution of the classic deposits and the blood vessel profiles. Both the classic deposits and blood vessel profiles were distributed in clusters. In all cases, there was a positive spatial correlation between the clusters of the classic deposits and the larger diameter (>10 microm) blood vessel profiles and especially the vertically penetrating arterioles. In only 1 case, was there a significant spatial correlation between the clusters of the classic deposits and the smaller diameter (<10 microm) capillaries. There were no negative correlations between the density of Abeta deposits and the smaller diameter capillaries. In 9/11 cases, the clusters of the classic deposits were significantly larger than those of the clusters of the larger blood vessel profiles. In addition, the density of the classic deposits declined as a negative exponential function with distance from a vertically penetrating arteriole. These results suggest that the classic Abeta deposits cluster around the larger blood vessels in the upper laminae of the frontal cortex. This aggregation could result from diffusion of proteins from blood vessels or from overloading the system of perivascular clearance from the brain.

Spatial distribution of diffuse, primitive, and classic amyloid-beta deposits and blood vessels in the upper laminae of the frontal cortex in Alzheimer disease

The spatial distribution of the diffuse, primitive, and classic amyloid-beta deposits was studied in the upper laminae of the superior frontal gyrus in cases of sporadic Alzheimer disease (AD). Amyloid-beta-stained tissue was counterstained with collagen IV to determine whether the spatial distribution of the amyloid-beta deposits along the cortex was related to blood vessels. In all patients, amyloid-beta deposits and blood vessels were aggregated into distinct clusters and in many patients, the clusters were distributed with a regular periodicity along the cortex. The clusters of diffuse and primitive deposits did not coincide with the clusters of blood vessels in most patients. However, the clusters of classic amyloid-beta deposits coincided with those of the large diameter (>10 microm) blood vessels in all patients and with clusters of small-diameter (< 10 microm) blood vessels in four patients. The data suggest that, of the amyloid-beta subtypes, the clusters of classic amyloid-beta deposits appear to be the most closely related to blood vessels and especially to the larger-diameter, vertically penetrating arterioles in the upper cortical laminae.

Dispersion of classic beta-amyloid deposits around blood vessels in Alzheimer’s disease

The spatial pattern of the classic (‘cored’) type of beta-amyloid (Abeta) deposit was studied in the upper laminae of the superior temporal gyrus in 9 cases of sporadic Alzheimer’s disease (SAD). Abeta stained tissue was counterstained with collagen IV to study the relationships between the spatial distribution of the classic deposits and the blood vessel profiles. Both the classic deposits and blood vessel profiles were distributed in clusters. In all cases, there was a spatial correlation between the clusters of the classic deposits and the larger diameter (>10 micron) blood vessel profiles and especially the vertically penetrating arterioles. In only 1 case, was there a significant spatial correlation between the clusters of the classic deposits and the smaller diameter (<10 micron) capillaries. In 9/11 cases, the clusters of the classic deposits were significantly larger than those of the clusters of the larger blood vessels. In addition, the density of the classic deposits declined as a negative exponential function with distance from the vertically penetrating arterioles. These results suggest that the classic Abeta deposits cluster around the larger blood vessels in the frontal cortex and that diffusion of proteins from these blood vessels could be involved in the pathogenesis of the classic deposits in SAD.

Analysing organisational culture : a critical ethnography of public relations and personnel specialists in a state bureaucracy

Following an introductory chapter, I examine (i) typologies which have differentiated the literature on organisational culture and symbolism (Chapter 2), (ii) the contribution of organisation theory to organisation culture (Chapter 3), and (iii) recent literature on organisational culture and symbolism (Chapter 4). Within these chapters, I adopt Habermas' (1972) notion of knowledge-constitutive interests, assessing the contrubutions to understanding organisational culture made by literature guided by technical, practical and emancipatory cognitive interests. In doing so, I suggest that more critical studies on organisational culture and symbolism have been comparatively neglected. Lamenting this neglect, I suggest that Giddens' theory of structuration can be employed to advance the development of a critical, emancipatory conceptualisation of organisational culture. In particular, I argue that this Giddensian analysis, by penetrating the existential, poltical and material processes of cultural reproduction (Chapter 5), is able to disclose some of the more contradictory features of organisation culture. The remainder of the thesis comprises of a critical ethnography of the work cultures of public relations and personnel specialists located in a state bureaucracy. I begin the ethnography with a dicussion of my research methods (Chapter 6) and an overview of the departments studied (Chapter 7): I then examine (i) the work cultures of the specialists (Chapter 8), (ii) the specialists' management of the relationships with the hosts bureaucracy (Chapter 9); and, (iii) opportunities the specialists had for developing an emancipatory praxis (Chapter 10). Finally, in a concluding section, I offer some critical reflections on the contributions of the thesis and suggest areas for future research.

The role of TG2 in ECV304-related vasculogenic mimicry

Tumour vasculogenesis can occur by a process referred to as vasculogenic mimicry, whereby the vascular structures are derived from the tumour itself. These tumours are highly aggressive and do not respond well to anti-angiogenic therapy. Here, we use the well characterised ECV304 cell line, now known as the bladder cancer epithelial cell line T24/83 which shows both epithelial and endothelial characteristics, as a model of in vitro vasculogenic mimicry. Using optimised ratios of co-cultures of ECV304 and C378 human fibroblasts, tubular structures were identifiable after 8 days. The tubular structures showed high levels of TG2 antigen and TG in situ activity. Tubular structures and in situ activity could be blocked either by site-directed irreversible inhibitors of TG2 or by silencing the ECV304 TG2 by antisense transfection. In situ activity for TG2 showed co-localisation with both fibronectin and collagen IV. Deposition of these proteins into the extracellular matrix could be reduced by inclusion of non-cell penetrating TG inhibitors when analysed by Western blotting suggesting that the contribution of TG2 to tube formation is extracellular. Incubation of ECV304 cells with these same irreversible inhibitors reduced cell migration which paralleled a loss in focal adhesion assembly, actin cytoskeleton formation and fibronectin deposition. TG2 appears essential for ECV304 tube formation, thus representing a potential novel therapeutic target in the inhibition of vasculogenic mimicry. © 2012 Springer-Verlag.

Keratoconus:a review

Keratoconus is the most common primary ectasia. It usually occurs in the second decade of life and affects both genders and all ethnicities. The estimated prevalence in the general population is 54 per 100,000. Ocular signs and symptoms vary depending on disease severity. Early forms normally go unnoticed unless corneal topography is performed. Disease progression is manifested with a loss of visual acuity which cannot be compensated for with spectacles. Corneal thinning frequently precedes ectasia. In moderate and advance cases, a hemosiderin arc or circle line, known as Fleischer's ring, is frequently seen around the cone base. Vogt's striaes, which are fine vertical lines produced by Descemet's membrane compression, is another characteristic sign. Most patients eventually develop corneal scarring. Munson's sign, a V-shape deformation of the lower eyelid in downward position; Rizzuti's sign, a bright reflection from the nasal area of the limbus when light is directed to the limbus temporal area; and breakages in Descemet's membrane causing acute stromal oedema, known as hydrops, are observed in advanced stages. Classifications based on morphology, disease evolution, ocular signs and index-based systems of keratoconus have been proposed. Theories into the genetic, biomechanical and biochemical causes of keratoconus have been suggested. Management varies depending on disease severity. Incipient cases are managed with spectacles, mild to moderate cases with contact lenses and severe cases can be treated with keratoplasty. This article provides a review on the definition, epidemiology, clinical features, classification, histopathology, aetiology and pathogenesis, and management and treatment strategies for keratoconus.

Potential Application of Phage Therapy Against Pseudomonas aeruginosa Biofilm Infection in Cystic Fibrosis Patients

Majority of the microbial activity in humans is in the form of biofilms i.e. an Exopolysaccharide-enclosed bacterial mass. Unlike planktonic cells and the cells on the surface of the biofilm, the biofilm-embedded cells are more resistant to the effects of the antibiotics and the host cellular defense mechanisms. A combination of biofilm growth and inherent resistance prevents effective antibiotics treatment of Pseudomonas aeruginosa infections including those in patients with cystic fibrosis. This has lead to an increasing interest in alternative modalities of treatment. Thus, phages that multiply in situ, only in the presence of susceptible hosts can be used as natural, self-limiting, and deeply penetrating antibacterial agents. The objective of this study is to identify effective phages against a collection of P. aeruginosa isolates (PCOR strains) including the prototype PAOl and the isogenic constitutively alginate-producing PD0300 strains.These PCOR strains were tested against six phages (P105, P134, P140, P168, P175B and P182). Analysis shows 69 % of the PCOR isolates are sensitive and the rest are resistant to all six phages. These phages were then tested for their ability to inhibit biofilm formation using a modified biofilm assay. The analysis demonstrated that the sensitive strains showed increased resistance but none of the sensitive strains from the initial screening were resistant. Using the minimum biofilm eradication concentration (MBEC) assay for biofilm formation, the biofilm eradication ability of the phages was tested. The data showed that a higher volume of phage was required to eradicate preformed biofilms than the volume required to prevent colonization of planktonic cells. This data supports the idea of phage therapy more as a prophylactic treatment.

Optimum wireless power transmission for sensors embedded in concrete

Various nondestructive testing (NDT) technologies for construction and performance monitoring have been studied for decades. Recently, the rapid evolution of wireless sensor network (WSN) technologies has enabled the development of sensors that can be embedded in concrete to monitor the structural health of infrastructure. Such sensors can be buried inside concrete and they can collect and report valuable volumetric data related to the health of a structure during and/or after construction. Wireless embedded sensors monitoring system is also a promising solution for decreasing the high installation and maintenance cost of the conventional wire based monitoring systems. Wireless monitoring sensors need to operate for long time. However, sensor batteries have finite life-time. Therefore, in order to enable long operational life of wireless sensors, novel wireless powering methods, which can charge the sensors’ rechargeable batteries wirelessly, need to be developed. The optimization of RF wireless powering of sensors embedded in concrete is studied here. First, our analytical results focus on calculating the transmission loss and propagation loss of electromagnetic waves penetrating into plain concrete at different humidity conditions for various frequencies. This analysis specifically leads to the identification of an optimum frequency range within 20–80 MHz that is validated through full-wave electromagnetic simulations. Second, the effects of various reinforced bar configurations on the efficiency of wireless powering are investigated. Specifically, effects of the following factors are studied: rebar types, rebar period, rebar radius, depth inside concrete, and offset placement. This analysis leads to the identification of the 902–928 MHz ISM band as the optimum power transmission frequency range for sensors embedded in reinforced concrete, since antennas working in this band are less sensitive to the effects of varying humidity as well as rebar configurations. Finally, optimized rectennas are designed for receiving and/or harvesting power in order to charge the rechargeable batteries of the embedded sensors. Such optimized wireless powering systems exhibit significantly larger efficiencies than the efficiencies of conventional RF wireless powering systems for sensors embedded in plain or reinforced concrete.

Desenvolvimento de um painel sanduíche com carga de particulado oriundo de resíduo lignocelulósico para aplicação em produtos na área de equipamentos de proteção

This work aims to study and investigate the use of a hybrid composite polymer formed with blanket aramid (Kevlar 29) fiber blanket flax fiber and particulate dry endocarp of coconut (Cocos nucifera Linn), using as matrix an epoxy resin based thermoset for use in areas of protective equipment. Besides such material is used an aluminum plate, joined to the composite by means of glue based on epoxy and araldite commercial. The manufacturing process adopted was manual lamination (Hand Lay Up) to manufacture the hybrid composite. After the composite is prepared, an aluminum plate is subjected to pressure and glued to cure the adhesive. Layers of veil will also be used to separate the particulate from the linen blanket layer without disturbing the alignment of the fibers of the blankets. To characterize the mechanical and physical behavior was manufactured a plate of 800 x 600 mm of the hybrid composite, which were removed specimens for tests of water absorption to saturation; density; impact test (Charpy) and two test specimens for ballistic testing 220 mm x 200 mm to make a comparative study between the dry state and saturated water absorption and thus see the ballistic performance of these two conditions. The test was applied to make a comparative study of fracture in these two conditions, caused by penetrating ballistic missile (38 and 380). To test the impact (Charpy) will analyze the absorbed energy, fracture appearance and lateral contraction, also in dry condition and saturation of absorbed water, thereby analyzing situations where the impact load is relevant, such as bumps and shocks produced by stone, metal or wooden bars among others. The proposed configuration, along with the tests, has the purpose, application in the fields of equipment against ballistic impact, such as helmets; bullet proof vests; shields; protective packaging and other items to be identified in this research.

Physical properties and age determination of sediment cores from the Hinlopen/Yermak Megaslide north of Spitsbergen, Arctic Ocean

Integrated interpretation of multi-beam bathymetric, sediment-penetrating acoustic (PARASOUND) and seismic data show a multiple slope failure on the northern European continental margin, north of Spitsbergen. The first slide event occurred during MIS 3 around 30 cal. ka BP and was characterised by highly dynamic and rapid evacuation of ca. 1250 km**3 of sediment from the lower to the upper part of the continental slope. During this event, headwalls up to 1600 m high were created and ca. 1150 km**3 material from hemi-pelagic sediments and from the lower pre-existing trough mouth fan has been entrained and transported into the semi-enclosed Sophia Basin. This megaslide event was followed by a secondary evacuation of material to the Nansen Basin by funnelling of the debris through the channel between Polarstern Seamount and the adjacent continental slope. The main slide debris is overlain by a set of fining-upward sequences as evidence for the associated suspension cloud and following minor failure events. Subsequent adjustment of the eastern headwalls led to failure of rather soft sediments and creation of smaller debris flows that followed the main slide surficial topography. Discharge of the Hinlopen ice stream during the Last Glacial Maximum and the following deglaciation draped the central headwalls and created a fan deposit of glacigenic debris flows.

Bulk components and ice rafted debris of five sediment cores of the Sophia Basin, Arctic Ocean

Periods of enhanced terrigenous input to the ocean's basins of the North Atlantic have been reported for the last glacial period. We present a set of new sediment cores recovered from the Sophia Basin north of Svalbard which exhibit wide spread IRD layers reflecting enhanced terrigenous input throughout the last ~200 kyr. BP. Their consistent stratigraphic position, sedimentological character, high sedimentation rate and geochemical characteristic point to synchronously deposited layers which we name terrigenous input events (TIEs). Due to their higher densities, they generate excellent reflectors for sediment penetrating acoustic devices and prominent acoustic layers in the imagery of sedimentary structures. Therefore TIEs can be used for regional acoustic stratigraphy. Each of the events can be linked to major glacial activity on Svalbard. However, the Early Weichselian glaciation is not recorded as a TIE and, in agreement with other work, might not have occurred on Svalbard as a major glacial advance to the shelf break. Non-synchronous timing of western and northern sources on Svalbard points against sea-level induced iceberg discharge events.

Glare, a GIS tool to reconstruct the 3D surface of palaeoglaciers

Acknowledgements This research has been supported by the Leverhulme Trust International Network Grant IN-2012-140. Processing and collecting of ground penetrating data in Forgefonna was part of Elend Førre's master's project that was completed in 2009 at the Department of Geography, University of Bergen. We also acknowledge Dr Andreas Bauder for providing the subglacial topography data for Griessgletscher and Simone Tarquini for granting access to the high resolution TIN of Italy, a cut of which is provided to the reader to practice the tools (see Appendix). Referees Dr. Iestyn Barr, Dr. Jeremy Ely and Dr. Marc Oliva are thanked for their constructive comments and tool testing, which significantly improved the final output.