Using pH abnormalities in diseased skin to trigger and target topical therapy

Abstract Purpose: The pH discrepancy between healthy and atopic dermatitis skin was identified as a site specific trigger for delivering hydrocortisone from microcapsules. Methods: Using Eudragit L100, a pH-responsive polymer which dissolves at pH 6, hydrocortisone-loaded microparticles were produced by oil-in-oil microencapsulation or spray drying. Release and permeation of hydrocortisone from microparticles alone or in gels was assessed and preliminary stability data was determined. Results: Drug release from microparticles was pH-dependent though the particles produced by spray drying also gave significant non-pH dependent burst release, resulting from their porous nature or from drug enrichment on the surface of these particles. This pH-responsive release was maintained upon incorporation of the oil-in-oil microparticles into Carbopol- and HPMC-based gel formulations. In-vitro studies showed 4 to 5-fold higher drug permeation through porcine skin from the gels at pH 7 compared to pH 5. Conclusions: Permeation studies showed that the oil-in-oil generated particles deliver essentially no drug at normal (intact) skin pH (5.0 – 5.5) but that delivery can be triggered and targeted to atopic dermatitis skin where the pH is elevated. The incorporation of these microparticles into Carbopol- and HPMC-based aqueous gel formulations demonstrated good stability and pH-responsive permeation into porcine skin.

An integrated multi-stage model of knowledge management in international joint ventures: identifying a trigger for knowledge exploration and knowledge harvest

This paper examines the evolution of knowledge management from the initial knowledge migration stage, through adaptation and creation, to the reverse knowledge migration stage in international joint ventures (IJVs). While many studies have analyzed these stages (mostly focusing on knowledge transfer), we investigated the path-dependent nature of knowledge flow in IJVs. The results from the empirical analysis based on a survey of 136 Korean parent companies of IJVs reveal that knowledge management in IJVs follows a sequential, multi-stage process, and that the knowledge transferred from parents to IJVs must first be adapted within its new environment before it reaches the creation stage. We also found that only created knowledge is transferred back to parents.

Field line resonances as a trigger and a tracer for substorm onset

In this paper, we show that periodic auroral arc structures are seen at the location of one particular auroral substorm onset for the 15 min preceding onset, suggesting that field line resonances should be considered a strong candidate for triggering substorm onset. Irrespective of whether this field line resonance is coincidentally or causally linked to this substorm onset, the characteristics of the field line resonance can be used to remote sense the characteristics of the geomagnetic field line that supports substorm onset. In this instance, the eigenfrequency of this resonance is around 12 mHz. Interestingly, however, there is no evidence of this field line resonance in a seven satellite major Time History of Events and Macroscale Interactions during Substorms (THEMIS)-GOES conjunction, ranging from geosynchronous orbit to ~30 RE. However, using space-based cross-phase measurements of the local field line eigenfrequency at the inner THEMIS locations, we find that the local field line eigenfrequency is 6–10 mHz. Hence, we can reliably say that this 12 mHz Field Line Resonance (FLR) must lie inside of THEMIS locations. Our conclusion is that a high-m field line resonance can both represent a strong candidate for a trigger for substorm onset, as first proposed by Samson et al. (1992), and that its characteristics can provide invaluable information as to where substorm onset occurs in the magnetosphere.

Using virtual environments for trigger identification in addiction treatment

This paper presents a novel application of virtual environments to assist in encouraging behavior change in individuals who misuse drugs or alcohol. We describe the user-centered design of a series of scenes to engage users in the identification of triggers and to encourage discussions about relevant coping skills. Results from the initial testing of this application with six service users showed variation in user responses. Results also suggested that the system should encourage group discussion and that it was linked to a small improvement in users’ confidence in understanding and identifying triggers.

Single versus multiple occupancy - Effects on toxicity parameters measured on Eisenia fetida in lead nitrate-treated soil

The mortality (7 and 14 d), weight change (7 and 14 d), and metal uptake of Eisenia fetida (Savigny, 1826) kept in Pb(NO3)(2)-treated Kettering loam soil in single- and multiple-occupancy (10 earthworms) test containers were determined. The number of earthworms to dry mass (g) ratio of soil was 1:50 in both sets of test containers. Lead concentrations were in the nominal range of 0 to 10,000 mg Pb/kg soil (mg/kg hereafter). Levels of mortality at a given concentration were statistically identical between the single- and multiple-occupancy tests, except at 1,800 mg/kg, at which significantly (p less than or equal to 0.05) more mortality occurred in the multiple-occupancy tests. Death of individual earthworms in the multiple-occupancy tests did not trigger death of the other earthworms in that soil. The LC50 values (concentration statistically likely to kill 50% of the population) were identical between the multiple- and single-occupancy soils: 2,662 mg/kg (2,598-2,984, 7 d) and 2,589 mg/kg (2,251-3,013, 14 d) for the multiple-occupancy soils and 2,827 mg/kg (2,443-3,168, both 7 and 14 d) for the single-occupancy soils (values in brackets represent the 95% confidence intervals). Data were insufficient to calculate the concentration statistically likely to reduce individual earthworm mass by 50% (EC50), but after 14 d, the decrease in earthworm weight in the 1,800 and 3,000 mg/kg tests was significantly greater in the multiple- than in the single-occupancy soils. At 1,000, 1,800, and 3,000 mg/kg tests, earthworm Pb tissue concentration was significantly (p less than or equal to 0.05) greater in earthworms from the multiple-occupancy soils. The presence of earthworms increased the NH3 content of the soil; earthworm mortality increased NH3 concentrations further but not to toxic levels.

Effects of carbon dioxide on the searching behaviour of the root-feeding clover weevil Sitona lepidus (Coleoptera : Curculionidae)

The respiratory emission of CO2 from roots is frequently proposed as an attractant that allows soil-dwelling insects to locate host plant roots, but this role has recently become less certain. CO2 is emitted from many sources other than roots, so does not necessarily indicate the presence of host plants, and because of the high density of roots in the upper soil layers, spatial gradients may not always be perceptible by soil-dwelling insects. The role of CO2 in host location was investigated using the clover root weevil Sitona lepidus Gyllenhall and its host plant white clover (Trifolium repens L.) as a model system. Rhizochamber experiments showed that CO2 concentrations were approximately 1000 ppm around the roots of white clover, but significantly decreased with increasing distance from roots. In behavioural experiments, no evidence was found for any attraction by S. lepidus larvae to point emissions of CO2, regardless of emission rates. Fewer than 15% of larvae were attracted to point emissions of CO2, compared with a control response of 17%. However, fractal analysis of movement paths in constant CO2 concentrations demonstrated that searching by S. lepidus larvae significantly intensified when they experienced CO2 concentrations similar to those found around the roots of white clover (i.e. 1000 ppm). It is suggested that respiratory emissions of CO2 may act as a 'search trigger' for S. lepidus, whereby it induces larvae to search a smaller area more intensively, in order to detect location cues that are more specific to their host plant.

Evolution of late glacial ice-marginal lakes on the northwestern Canadian Shield and their influence on the location of the Dubawnt Lake palaeo-ice stream

During deglaciation of the North American Laurentide Ice Sheet large proglacial lakes developed in positions where proglacial drainage was impeded by the ice margin. For some of these lakes, it is known that subsequent drainage had an abrupt and widespread impact on North Atlantic Ocean circulation and climate, but less is known about the impact that the lakes exerted on ice sheet dynamics. This paper reports palaeogeographic reconstructions of the evolution of proglacial lakes during deglaciation across the northwestern Canadian Shield, covering an area in excess of 1,000,000 km(2) as the ice sheet retreated some 600 km. The interactions between proglacial lakes and ice sheet flow are explored, with a particular emphasis on whether the disposition of lakes may have influenced the location of the Dubawnt Lake ice stream. This ice stream falls outside the existing paradigm for ice streams in the Laurentide Ice Sheet because it did not operate over fined-grained till or lie in a topographic trough. Ice margin positions and a digital elevation model are utilised to predict the geometry and depth of proglacial takes impounded at the margin at 30-km increments during deglaciation. Palaeogeographic reconstructions match well with previous independent estimates of lake coverage inferred from field evidence, and results suggest that the development of a deep lake in the Thelon drainage basin may have been influential in initiating the ice stream by inducing calving, drawing down ice and triggering fast ice flow. This is the only location alongside this sector of the ice sheet where large (>3000 km(2)), deep lakes (similar to120 m) are impounded for a significant length of time and exactly matches the location of the ice stream. It is speculated that the commencement of calving at the ice sheet margin may have taken the system beyond a threshold and was sufficient to trigger rapid motion but that once initiated, calving processes and losses were insignificant to the functioning of the ice stream. It is thus concluded that proglacial lakes are likely to have been an important control on ice sheet dynamics during deglaciation of the Laurentide Ice Sheet. (C) 2004 Elsevier B.V. All rights reserved.

The triggering of orographic rainbands by small-scale topography

The triggering of convective orographic rainbands by small-scale topographic features is investigated through observations of a banded precipitation event over the Oregon Coastal Range and simulations using a cloud-resolving numerical model. A quasi-idealized simulation of the observed event reproduces the bands in the radar observations, indicating the model’s ability to capture the physics of the band-formation process. Additional idealized simulations reinforce that the bands are triggered by lee waves past small-scale topographic obstacles just upstream of the nominal leading edge of the orographic cloud. Whether a topographic obstacle in this region is able to trigger a strong rainband depends on the phase of its lee wave at cloud entry. Convective growth only occurs downstream of obstacles that give rise to lee-wave-induced displacements that create positive vertical velocity anomalies w_c and nearly zero buoyancy anomalies b_c as air parcels undergo saturation. This relationship is quantified through a simple analytic condition involving w_c, b_c, and the static stability N_m^2 of the cloud mass. Once convection is triggered, horizontal buoyancy gradients in the cross-flow direction generate circulations that align the bands parallel to the flow direction.

Modeling the user knowledge by belief networks

This paper describes the user modeling component of EPIAIM, a consultation system for data analysis in epidemiology. The component is aimed at representing knowledge of concepts in the domain, so that their explanations can be adapted to user needs. The first part of the paper describes two studies aimed at analysing user requirements. The first one is a questionnaire study which examines the respondents' familiarity with concepts. The second one is an analysis of concept descriptions in textbooks and from expert epidemiologists, which examines how discourse strategies are tailored to the level of experience of the expected audience. The second part of the paper describes how the results of these studies have been used to design the user modeling component of EPIAIM. This module works in a two-step approach. In the first step, a few trigger questions allow the activation of a stereotype that includes a "body" and an "inference component". The body is the representation of the body of knowledge that a class of users is expected to know, along with the probability that the knowledge is known. In the inference component, the learning process of concepts is represented as a belief network. Hence, in the second step the belief network is used to refine the initial default information in the stereotype's body. This is done by asking a few questions on those concepts where it is uncertain whether or not they are known to the user, and propagating this new evidence to revise the whole situation. The system has been implemented on a workstation under UNIX. An example of functioning is presented, and advantages and limitations of the approach are discussed.

Two Independent Triggers for the Indian Ocean Dipole/Zonal Mode in a Coupled GCM

The question of whether and how tropical Indian Ocean dipole or zonal mode (IOZM) interannual variability is independent of El Nino-Southern Oscillation (ENSO) variability in the Pacific is addressed in a comparison of twin 200-yr runs of a coupled climate model. The first is a reference simulation, and the second has ENSO-scale variability suppressed with a constraint on the tropical Pacific wind stress. The IOZM can exist in the model without ENSO, and the composite evolution of the main anomalies in the Indian Ocean in the two simulations is virtually identical. Its growth depends on a positive feedback between anomalous equatorial easterly winds, upwelling equatorial and coastal Kelvin waves reducing the thermocline depth and sea surface temperature off the coast of Sumatra, and the atmospheric dynamical response to the subsequently reduced convection. Two IOZM triggers in the boreal spring are found. The first is an anomalous Hadley circulation over the eastern tropical Indian Ocean and Maritime Continent, with an early northward penetration of the Southern Hemisphere southeasterly trades. This situation grows out of cooler sea surface temperatures in the southeastern tropical Indian Ocean left behind by a reinforcement of the late austral summer winds. The second trigger is a consequence of a zonal shift in the center of convection associated with a developing El Nino, a Walker cell anomaly. The first trigger is the only one present in the constrained simulation and is similar to the evolution of anomalies in 1994, when the IOZM occurred in the absence of a Pacific El Nino state. The presence of these two triggers-the first independent of ENSO and the second phase locking the IOZM to El Nino-allows an understanding of both the existence of IOZM events when Pacific conditions are neutral and the significant correlation between the IOZM and El Nino.

Self-defence: A state of mind for states?

This paper focuses upon a comparatively overlooked issue with regard to the scope of self-defence in international law: whether the subjective ‘psychological’ positions of the states concerned in a dispute involving the use force have any impact upon the lawfulness of an action avowedly taken in self-defence. There exists a long standing conception that the motives of a state responding in self-defence are relevant to the lawfulness of that response. The purity (or impurity) of a state's motive forms the basis of a distinction for many writers between a lawful self-defence action and an unlawful armed reprisal. Similarly, in recent decisions of the ICJ, the implication has been that the subjective intention of the attacking state may be relevant to the question of whether the attack perpetrated by that state can trigger the right of self-defence. The conclusion is reached here that the lawfulness of an avowed self-defence action should be premised upon objective criteria alone. Moreover, this reflects the law as it is in fact applied in practice. It is argued that the subjective ‘psychological’ position of either the responding or attacking state has no place in the final analysis of whether an action in self-defence was lawful or unlawful.

Are Cape floral clades the same age? Contemporaneous origins of two lineages in the genistoids s.l. (Fabaceae)

The hypothesis that the elements of the modern species-rich flora of the Cape Floristic Region (CFR), South Africa, originated more or less simultaneously at the Miocene/Pliocene boundary, in response to the development of a mediterranean climate, has been challenged by numerous molecular dating estimates of Cape floral clades. These studies reveal a more gradual emergence, with the oldest clades originating in the Eocene, but others appearing later, some as recently as the Pliocene. That there are factors which might affect the dates recovered, such as choice of calibration point, analysis method, sampling density and the delimitation of Cape floral clades, suggests a need for further critical evaluation of the age estimates presented to date. In this study, the dates of origin of two Cape floral clades (the legume Crotalarieae p.p. and Podalyrieae) are estimated, constrained by a shared calibration point in a single analysis using an rDNA ITS phylogeny in which 633 taxa are sampled. The results indicate that these two clades arose contemporaneously 44-46 mya, not at the Miocene/Pliocene boundary as had been previously supposed. The contemporaneous origin of these Cape floral clades suggests that additional more inclusive analyses are needed before rejecting the hypothesis that a. single environmental trigger explains the establishment of Cape floral clades. (c) 2007 Elsevier Inc. All rights reserved.