An improved elastic-viscoplastic soil model

This paper develops an improved and accessible framework for modelling time-dependent behaviour of soils using the concepts of elasticity and viscoplasticity. The mathematical description of viscoplastic straining is formulated based on a purely viscoplastic and measurable phenomenon, namely creep. The resulting expression for the viscoplastic strain rates includes a measure of both effective stress and the corresponding volumetric packing of the soil particles. In this way, the model differs from some earlier viscoplastic models and arguably provides a better conceptual description of time-dependent behaviour. Analytical solutions are developed for the simulation of drained and undrained strain-controlled triaxial compression tests. The model is then used to back-analyze the measured response of normally consolidated to moderately overconsolidated specimens of a soft estuarine soil in undrained triaxial compression. The model captures aspects of soil behaviour that cannot be simulated using time-independent elastic–plastic models. Specifically, it can capture the dependence of stress–strain relationships and undrained shear strength on strain rate, the development of irrecoverable plastic strains at constant stress (creep), and the relaxation of stresses at constant strain

Finite element analysis of an embankment on a soft estuarine deposit using an elastic–viscoplastic soil model

A new elastic–viscoplastic (EVP) soil model has been used to simulate the measured deformation response of a soft estuarine soil loaded by a stage-constructed embankment. The simulation incorporates prefabricated vertical drains installed in the foundation soils and reinforcement installed at the base of the embankment. The numerical simulations closely matched the temporal changes in surface settlement beneath the centerline and shoulder of the embankment. More importantly, the elastic–viscoplastic model simulated the pattern and magnitudes of the lateral deformations beneath the toe of the embankment — a notoriously difficult aspect of modelling the deformation response of soft soils. Simulation of the excess pore-water pressure proved more difficult because of the heterogeneous nature of the estuarine deposit. Excess pore-water pressures were, however, mapped reasonably well at three of the six monitoring locations. The simulations were achieved using a small set of material constants that can easily be obtained from standard laboratory tests. This study validates the use of the EVP model for problems involving soft soil deposits beneath loading from a geotechnical structure.

A Diagnostic System Using Broad Categories With Clinicaly Relevant Specifiers: Lessons for ICD-10

A diagnostic system for ICD-11 is proposed which commences with broad reorganization and simplification of the current categories and the use of clinically relevant specifiers. Such changes have implications for the positioning of diagnostic groups and lead to a range of possibilities for improving terminology and the juxtaposition of individual conditions. The development of ICD-11 provides the first opportunity in almost two decades to improve the validity and reliability of the international classification system. Widespread change in broad categories and criteria cannot be justified by research that has emerged since the last revision. It would also be disruptive to clinical practice and might devalue past research work. However, the case for reorganization of the categories is stronger and has recently been made by an eminent international group of researchers (Andrews et al., 2009). A simpler, interlinked diagnostic system is proposed here which is likely to have fewer categories than its predecessor. There are major advantages of such a system for clinical practice and research and it could also produce much needed simplification for primary care (Gask et al., 2008) and the developing world (Wig, 1990; Kohn et al., 2004).

Sustained release of proteins from a modified vaginal ring device

A new vaginal ring technology, the insert vaginal ring (InVR), is presented. The InVR overcomes the current shortfall of conventional vaginal rings (VRs) that are generally ineffectual for the delivery of hydrophilic and/or macromolecular actives, including peptides, proteins and antibodies, due to their poor permeation characteristics in the hydrophobic polymeric elastomers from which VRs are usually fabricated. Release of the model protein BSA from a variety of insert matrices for the InVR is demonstrated, including modified silicone rods, directly compressed tablets and lyophilised gels, which collectively provided controlled release profiles from several hours to beyond 4 weeks. Furthermore, the InVR was shown to deliver over 1 mg of the monoclonal antibody 2F5 from a single device, offering a potential means of protecting women against the transmission of HIV.

Hyperglycaemia-induced pro-inflammatory responses by retinal Müller glia are regulated by the receptor for advanced glycation end-products (RAGE)

Aims/hypothesis: Up-regulation of the receptor for AGEs (RAGE) and its ligands in diabetes has been observed in various tissues. Here, we sought to determine levels of RAGE and one of its most important ligands, S100B, in diabetic retina, and to investigate the regulatory role of S100B and RAGE in Müller glia.

Methods: Streptozotocin-diabetes was induced in Sprague-Dawley rats. RAGE, S100B and glial fibrillary acidic protein (GFAP) were detected in retinal cryosections. In parallel, the human retinal Müller cell line, MIO-M1, was maintained in normal glucose (5.5 mmol/l) or high glucose (25 mmol/l). RAGE knockdown was achieved using small interfering RNA (siRNA), while soluble RAGE was used as a competitive inhibitor of RAGE ligand binding. RAGE, S100B and cytokines were detected using quantitative RT-PCR, western blotting, cytokine protein arrays or ELISA. Activation of mitogen-activated protein kinase (MAPK) by RAGE was determined by western blotting.

Results: Compared with non-diabetic controls, RAGE and S100B were significantly elevated in the diabetic retina with apparent localisation in the Müller glia, occurring concomitantly with upregulation of GFAP. Exposure of MIO-M1 cells to high glucose induced increased production of RAGE and S100B. RAGE signalling via MAPK pathway was linked to cytokine production. Blockade of RAGE prevented cytokine responses induced by high glucose and S100B in Müller glia.

Conclusions/interpretation: Hyperglycaemia in vivo and in vitro exposure to high glucose induce upregulation of RAGE and its ligands, leading to RAGE signalling, which links to pro-inflammatory responses by retinal Müller glia. These data shed light on the potential clinical application of RAGE blockade to inhibit the progression of diabetic retinopathy.

Arteriolar involvement in the microvascular lesions of diabetic retinopathy: Implications for pathogenesis

Diabetic retinopathy (DR) is the most widespread complication of diabetes mellitus and a major cause of blindness in the working population of developed countries. The clinicopathology of the diabetic retina has been extensively studied, although the relative contribution of the various biochemical and molecular sequelae of hyperglycemia remains ill defined. Many neural and microvascular abnormalities occur in the retina of short-term diabetic animals but it remains uncertain how closely these acute changes relate to chronic human disease. It is important to determine the relationship between alterations observed within the first weeks or months in short-term aminal models, and human disease, where clinically manifest retinopathy occurs only after durations of diabetes measured in years. This review is focused on the retinal microvasculature, although it should be appreciated that pathological changes in this system often occur in parallel with abnormalities in the neural parenchyma that may be derivative or even causal. Nevertheless, it is useful to reevaluate the microvascular lesions that are manifest in the retina during diabetes in humans and long-term animal models, since in addition to providing useful clues to the pathogenic basis of DR as a disease entity, it is in the deterrence of such changes that the efficacy of any novel treatment regimes will be measured. In particular, an emphasis will be placed on the relatively unappreciated role of arteriolar dysfunction in the clinical manifestations and pathology of this disease.

Human odontoblasts express functional thermo-sensitive TRP channels: implications for dentin sensitivity

Odontoblasts form the outermost cellular layer of the dental pulp where they have been proposed to act as sensory receptor cells. Despite this suggestion, evidence supporting their direct role in mediating thermo-sensation and nociception is lacking. Transient receptor potential (TRP) ion channels directly mediate nociceptive functions, but their functional expression in human odontoblasts has yet to be elucidated. In the present study, we have examined the molecular and functional expression of thermo-sensitive TRP channels in cultured odontoblast-like cells and in native human odontoblasts obtained from healthy wisdom teeth. PCR and western blotting confirmed gene and protein expression of TRPV1, TRPA1 and TRPM8 channels. Immunohistochemistry revealed that these channels were localised to odontoblast-like cells as determined by double staining with dentin sialoprotein (DSP) antibody. In functional assays, agonists of TRPV1, TRPA1 and TRPM8 channels elicited [Ca2+]i transients that could be blocked by relevant antagonists. Application of hot and cold stimuli to the cells also evoked rises in [Ca2+]i which could be blocked by TRP-channel antagonists. Using a gene silencing approached we further confirmed a role for TRPA1 in mediating noxious cold responses in odontoblasts. We conclude that human odontoblasts express functional TRP channels that may play a crucial role in mediating thermal sensation in teeth. Cultured and native human odontoblasts express functional TRP channels that may play a crucial role in mediating thermal sensation in teeth.

Drivers of sales performance: a contemporary meta-analysis. Have salespeople become knowledge brokers?

It has been 25 years since the publication of a comprehensive review of the full spectrum of salesperformance drivers. This study takes stock of the contemporary field and synthesizes empirical evidence from the period 1982–2008. The authors revise the classification scheme for sales performance determinants devised by Walker et al. (1977) and estimate both the predictive validity of its sub-categories and the impact of a range of moderators on determinant-sales performance relationships. Based on multivariate causal model analysis, the results make two major observations: (1) Five sub-categories demonstrate significant relationships with sales performance: selling-related knowledge (ß=.28), degree of adaptiveness (ß=.27), role ambiguity (ß=-.25), cognitive aptitude (ß=.23) and work engagement (ß=.23). (2) These sub-categories are moderated by measurement method, research context, and salestype variables. The authors identify managerial implications of the results and offer suggestions for further research, including the conjecture that as the world is moving toward a knowledge-intensive economy, salespeople could be functioning as knowledge-brokers. The results seem to back this supposition and indicate how it might inspire future research in the field of personal selling.

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products.

Aims/hypothesis: The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it.

Methods: Sprague-Dawley rats were divided into three groups: (1) non-diabetic; (2) untreated streptozotocin-induced diabetic; and (3) diabetic treated with the AGE/ALE inhibitor pyridoxamine for the duration of diabetes. Rats were killed and their retinas were evaluated for neuroglial pathology. Results: AGEs and ALEs accumulated at higher levels in diabetic retinas than in controls (p<0.001). AGE/ALE immunoreactivity was significantly diminished by pyridoxamine treatment of diabetic rats. Diabetes was also associated with the up-regulation of the oxidative stress marker haemoxygenase-1 and the induction of glial fibrillary acidic protein production in Müller glia (p<0.001). Pyridoxamine treatment of diabetic rats had a significant beneficial effect on both variables (p<0.001). Diabetes also significantly altered the normal localisation of the potassium inwardly rectifying channel Kir4.1 and the water channel aquaporin 4 to the Müller glia end-feet interacting with retinal capillaries. These abnormalities were prevented by pyridoxamine treatment.

Conclusions/interpretation: While it is established that AGE/ALE formation in the retina during diabetes is linked to microvascular dysfunction, this study suggests that these pathogenic adducts also play a role in Müller glial dysfunction.