Design and Development of Liquid Drug Reservoirs for Microneedle Delivery of Poorly Soluble Drug Molecules

The poor aqueous solubility of existing and emerging drugs is a major issue faced by the pharmaceutical industry. Water-miscible organic solvents, termed co-solvents, can be used to enhance the solubility of poorly soluble substances. Typically, drugs with poor aqueous solubility and Log P > 3 are not amenable to delivery across the skin. This study investigated the use of co-solvents as reservoirs to be used in combination with hydrogel-forming microneedles to enhance the transdermal delivery of hydrophobic compounds, namely Nile red, olanzapine and atorvastatin. A custom-made Franz cell apparatus was fabricated to test the suitability of a liquid drug reservoir in combination with polymeric microneedles. A co-solvency approach to reservoir formulation proved effective, with 83.30% ± 9.38% of Nile red dye, dissolved in 1 mL poly(ethylene glycol) (PEG 400), permeating neonatal porcine skin over 24 h. PEG 400 and propylene glycol were found to be suitable reservoir media for olanzapine and atorvastatin, with approximately 50% of each drug delivered after 24 h. This work provides crucial proof-of-concept evidence that the manipulation of microneedle reservoir properties is an effective method to facilitate microneedle-mediated delivery of hydrophobic compounds

Arctic Sea Ice Loss in Different Regions Leads to Contrasting Northern Hemisphere Impacts

To explore the mechanisms linking Arctic sea-ice loss to changes in mid-latitude surface temperatures, we conduct idealized modeling experiments using an intermediate general circulation model and with sea-ice loss confined to the Atlantic or Pacific sectors of the Arctic (Barents-Kara or Chukchi-Bering Seas). Extending previous findings, there are opposite effects on the winter stratospheric polar vortex for both large-magnitude (late twenty-first century) and moderate-magnitude sea-ice loss. Accordingly, there are opposite tropospheric Arctic Oscillation (AO) responses for moderate-magnitude sea-ice loss. However, there are similar strength negative AO responses for large-magnitude sea-ice loss, suggesting that tropospheric mechanisms become relatively more important than stratospheric mechanisms as the sea-ice loss magnitude increases. The mid-latitude surface temperature response for each loss region and magnitude can be understood as the combination of an ‘indirect’ part induced by the large-scale circulation (AO) response, and a residual ‘direct’ part that is local to the loss region

Animistic pragmatism and native ways of knowing: adaptive strategies for overcoming the struggle for food in the sub-Arctic

Background. Subsistence norms are part of the “ecosophy” or ecological philosophy of Alaska Native Peoples in the sub-Arctic, such as the Inupiat of Seward Peninsula. This kind of animistic pragmatism is a special source of practical wisdom that spans over thousands of years and which has been instrumental in the Iñupiat’s struggle to survive and thrive in harsh and evolving environments. Objective. I hope to show how narrative in relationship to the “ecosophy” of Alaska Native peoples can help to promote a more ecological orientation to address food insecurity in rural communities in Alaska. Alaska Native ecosophy recommends central values and virtues necessary to help address concerns in Alaska’s rural communities. Design. Here, I will tease out the nature of this “ecosophy” in terms of animistic pragmatism and then show why this form of pragmatism can be instrumental for problematizing multi-scalar, intergenerational, uncertain and complex environmental challenges like food security. Results. Native elders have been the embodiment of trans-generational distributed cognition,1 for example, collective memory, norms, information, knowledge, technical skills and experimental adaptive strategies. They are human “supercomputers,” historical epistemologists and moral philosophers of a sort who use narrative, a form of moral testimony, to help their communities face challenges and seize opportunities in the wake of an ever-changing landscape. Conclusions. The “ecosophy” of the Iñupiat of Seward Peninsula offers examples of “focal practices”, which are essential for environmental education. These focal practices instil key virtues, namely humility, gratitude, self-reliance, attentiveness, responsibility and responsiveness, that are necessary for subsistence living

Intercomparison of stratospheric chemistry models under polar vortex conditions

Several stratospheric chemistry modules from box, 2-D or 3-D models, have been intercompared. The intercomparison was focused on the ozone loss and associated reactive species under the conditions found in the cold, wintertime Arctic and Antarctic vortices. Comparisons of both gas phase and heterogeneous chemistry modules show excellent agreement between the models under constrained conditions for photolysis and the microphysics of polar stratospheric clouds. While the mean integral ozone loss ranges from 4-80% for different 30-50 days long air parcel trajectories, the mean scatter of model results around these values is only about +/-1.5%. In a case study, where the models employed their standard photolysis and microphysical schemes, the variation around the mean percentage ozone loss increases to about +/-7%. This increased scatter of model results is mainly due to the different treatment of the PSC microphysics and heterogeneous chemistry in the models, whereby the most unrealistic assumptions about PSC processes consequently lead to the least representative ozone chemistry. Furthermore, for this case study the model results for the ozone mixing ratios at different altitudes were compared with a measured ozone profile to investigate the extent to which models reproduce the stratospheric ozone losses. It was found that mainly in the height range of strong ozone depletion all models underestimate the ozone loss by about a factor of two. This finding corroborates earlier studies and implies a general deficiency in our understanding of the stratospheric ozone loss chemistry rather than a specific problem related to a particular model simulation

Surface engineering of poly(methylmethacrylate): Effects on fluorescence immunoassay

The authors present surface engineering modifications through chemistry of poly(methylmethacrylate) (PMMA) that have dramatic effects on the result of surface-bound fluorescence immunoassays, both for specific and nonspecific signals. The authors deduce the most important effect to be clustering of antibodies on the surface leading to significant self-quenching. Secondary effects are attributable to the formation of sparse multilayers of antibody. The authors compare PMMA as an antibody support surface with ultraviolet-ozone oxidized PMMA and also to substrates that were, after the oxidation, surface modified by a four-unit poly(ethyleneglycol) carboxylic acid (PEG4), a branched tricarboxylic acid, and a series of carboxylic acid-terminated dendrimers, from generation 1.5 to 5.5. Fluorescence immunoassay and neutron reflectometry were used to compare the apparent antibody surface loading, antigen binding and nonspecific binding on these various surfaces using anti-human IgG as a model antibody, chemically coupled to the surface by amide formation. Simple physical adsorption of the antibody on PMMA resulted in a thick antibody multilayer with small antigen binding capacity. On the carboxylated surfaces, with chemical coupling, a simple monolayer was formed. The authors deduce that antibody clustering was driven by conformational inflexibility and high carboxylate density. The PEG4-modified surface was the most conformationally flexible. The dendrimer-modified interfaces showed a collapse and densification. In fluorescence immunoassay, the optimal combination of high specific and low nonspecific fluorescence signal was found for the G3.5 dendrimer

Surface engineering of poly(methylmethacrylate): Effects on fluorescence immunoassay

The authors present surface engineering modifications through chemistry of poly(methylmethacrylate) (PMMA) that have dramatic effects on the result of surface-bound fluorescence immunoassays, both for specific and nonspecific signals. The authors deduce the most important effect to be clustering of antibodies on the surface leading to significant self-quenching. Secondary effects are attributable to the formation of sparse multilayers of antibody. The authors compare PMMA as an antibody support surface with ultraviolet-ozone oxidized PMMA and also to substrates that were, after the oxidation, surface modified by a four-unit poly(ethyleneglycol) carboxylic acid (PEG4), a branched tricarboxylic acid, and a series of carboxylic acid-terminated dendrimers, from generation 1.5 to 5.5. Fluorescence immunoassay and neutron reflectometry were used to compare the apparent antibody surface loading, antigen binding and nonspecific binding on these various surfaces using anti-human IgG as a model antibody, chemically coupled to the surface by amide formation. Simple physical adsorption of the antibody on PMMA resulted in a thick antibody multilayer with small antigen binding capacity. On the carboxylated surfaces, with chemical coupling, a simple monolayer was formed. The authors deduce that antibody clustering was driven by conformational inflexibility and high carboxylate density. The PEG4-modified surface was the most conformationally flexible. The dendrimer-modified interfaces showed a collapse and densification. In fluorescence immunoassay, the optimal combination of high specific and low nonspecific fluorescence signal was found for the G3.5 dendrimer

Distinct Roles for Neuropilin1 and Neuropilin2 during Mouse Corneal Innervation

Trigeminal sensory innervation of the cornea is critical for protection and synthesis of neuropeptides required for normal vision. Little is known about axon guidance during mammalian corneal innervation. In contrast to the chick where a pericorneal nerve ring forms via Npn/Sema signaling, mouse corneal axons project directly into the presumptive cornea without initial formation of an analogous nerve ring. Here we show that during development of the mouse cornea, Npn1 is strongly expressed by the trigeminal ganglion whereas Npn2 is expressed at low levels. At the same time Sema3A and Sema3F are expressed in distinct patterns in the ocular tissues. Npn1sema−/− mutant corneas become precociously and aberrantly innervated by nerve bundles that project further into the corneal stroma. In contrast, stromal innervation was not affected in Npn2−/− mutants. The corneal epithelium was prematurely innervated in both Npn1sema−/− and Npn2−/− mutants. These defects were exacerbated in Npn1sema−/−;Npn2−/− double mutants, which in addition showed ectopic innervation of the region between the optic cup and lens vesicle. Collectively, our data show that Sema3A/Npn1 and Sema3F/Npn2 signaling play distinct roles and both are required for proper innervation of the mouse cornea

Investigating the generalisation of an atlas-based synthetic-CT algorithm to another centre and MR scanner for prostate MR-only radiotherapy

There is increasing interest in MR-only radiotherapy planning since it provides superb soft-tissue contrast without the registration uncertainties inherent in a CT–MR registration. However, MR images cannot readily provide the electron density information necessary for radiotherapy dose calculation. An algorithm which generates synthetic CTs for dose calculations from MR images of the prostate using an atlas of 3 T MR images has been previously reported by two of the authors. This paper aimed to evaluate this algorithm using MR data acquired at a different field strength and a different centre to the algorithm atlas. Twenty-one prostate patients received planning 1.5 T MR and CT scans with routine immobilisation devices on a flat-top couch set-up using external lasers. The MR receive coils were supported by a coil bridge. Synthetic CTs were generated from the planning MR images with (sCT₁v) and without (sCT) a one voxel body contour expansion included in the algorithm. This was to test whether this expansion was required for 1.5 T images. Both synthetic CTs were rigidly registered to the planning CT (pCT). A 6 MV volumetric modulated arc therapy plan was created on the pCT and recalculated on the sCT and sCT₁v. The synthetic CTs' dose distributions were compared to the dose distribution calculated on the pCT. The percentage dose difference at isocentre without the body contour expansion (sCT–pCT) was ΔDsCT = (0.9 \pm 0.8)% and with sCT₁v–pCT was ΔDsCT₁v = (-0.7 \pm 0.7)% (mean  ±  one standard deviation). The sCT₁v result was within one standard deviation of zero and agreed with the result reported previously using 3 T MR data. The sCT dose difference only agreed within two standard deviations. The mean  ±  one standard deviation gamma pass rate was ΓsCT = 96.1 \pm 2.9% for the sCT and ΓsCT₁v = 98.8 \pm 0.5% for the sCT₁v (with 2% global dose difference and 2mm distance to agreement gamma criteria). The one voxel body contour expansion improves the synthetic CT accuracy for MR images acquired at 1.5 T but requires the MR voxel size to be similar to the atlas MR voxel size. This study suggests that the atlas-based algorithm can be generalised to MR data acquired using a different field strength at a different centre

Colour reconnection in e+e- -> W+W- at sqrt(s) = 189 - 209 GeV

The effects of the final state interaction phenomenon known as colour reconnection are investigated at centre-of-mass energies in the range sqrt(s) ~ 189-209 GeV using the OPAL detector at LEP. Colour reconnection is expected to affect observables based on charged particles in hadronic decays of W+W-. Measurements of inclusive charged particle multiplicities, and of their angular distribution with respect to the four jet axes of the events, are used to test models of colour reconnection. The data are found to exclude extreme scenarios of the Sjostrand-Khoze Type I (SK-I) model and are compatible with other models, both with and without colour reconnection effects. In the context of the SK-I model, the best agreement with data is obtained for a reconnection probability of 37%. Assuming no colour reconnection, the charged particle multiplicity in hadronically decaying W bosons is measured to be (nqqch) = 19.38+-0.05(stat.)+-0.08 (syst.).Comment: 30 pages, 9 figures, Submitted to Euro. Phys. J.