Synthetic Geopolymers for Controlled Delivery of Oxycodone: Adjustable and Nanostructured Porosity Enables Tunable and Sustained Drug Release

In this article we for the first time present a fully synthetic mesoporous geopolymer drug carrier for controlled release of opioids. Nanoparticulate precursor powders with different Al/Si-ratios were synthesized by a sol-gel route and used in the preparation of different geopolymers, which could be structurally tailored by adjusting the Al/Si-ratio and the curing temperatures. In particular, it was shown that the pore sizes of the geopolymers decreased with increasing Al/Si ratio and that completely mesoporous geopolymers could be produced from precursor particles with the Al/Si ratio 2∶1. The mesoporosity was shown to be associated with a sustained and linear in vitro release profile of the opioid oxycodone. A clinically relevant release period of about 12 h was obtained by adjusting the size of the pellets. The easily fabricated and tunable geopolymers presented in this study constitute a novel approach in the development of controlled release formulations, not only for opioids, but whenever the clinical indication is best treated with a constant supply of drugs and when the mechanical stability of the delivery vehicle is crucial

Lessons Learnt From the 2009 Padang Indonesia, 2011 Tōhoku Japan and 2016 Muisne Ecuador Earthquakes

This paper presents the observations during the UK Earthquake Engineering Field Investigation Team (EEFIT)'s post-earthquake reconnaissance missions to the September 20, 2009 Padang (Mw7.6), March 11, 2011 Tōhoku (Mw9.0) and April 16, 2016 Muisne (Mw7.8) earthquakes. The performance of buildings and geotechnical structures within the affected regions were investigated to gain insights on their design and construction deficiencies. Findings on these damages observed are compared along with the characteristics of the earthquake and nature of building codes in these countries. They include building damages attributed to a combination of structural resonance, deficiencies in reinforcement detailing, vulnerability to soft story collapse, ground settlement, soil liquefaction, and landslides. It was demonstrated that buildings which were severely damaged had natural building frequencies coinciding with the dominant frequencies of the ground shaking. The locations of damage of several such buildings showed insufficient confining reinforcements and lapping of stirrup links. Soft story collapses were also observed in the three earthquakes, although many were attributed to old building codes that were less effective. In areas affected by the Muisne earthquake, soft story collapses were mainly found at mid height of the building rather than at the ground floor as observed in the Padang and Tōhoku earthquakes, likely due to extension of building long after the bottom floors were completed. Such extension of building can either lead to local reduction in capacity due to weaker concrete-rebar bonding, possibly insufficient lapping of reinforcement, as well as increased axial loads. In the aspect of geotechnical failure, foundations of buildings found on piles performed reasonably well, except for areas affected by soil liquefaction. Landslides occurred following these earthquakes led to large concentration of casualties and property losses, motivating the EEFIT teams to invest efforts in hazard mapping and ground-truthing exercises using satellite images at Padang and Muisne earthquakes respectively. Such geospatial tools applied in these three earthquakes were reviewed and demonstrated to be capable of identifying landslide sites and producing reliable landslide hazard map

Functional Changes in Muscle Afferent Neurones in an Osteoarthritis Model: Implications for Impaired Proprioceptive Performance

Impaired proprioceptive performance is a significant clinical issue for many who suffer osteoarthritis (OA) and is a risk factor for falls and other liabilities. This study was designed to evaluate weight-bearing distribution in a rat model of OA and to determine whether changes also occur in muscle afferent neurones.Intracellular recordings were made in functionally identified dorsal root ganglion neurones in acute electrophysiological experiments on the anaesthetized animal following measurements of hind limb weight bearing in the incapacitance test. OA rats but not naïve control rats stood with less weight on the ipsilateral hind leg (P = 0.02). In the acute electrophysiological experiments that followed weight bearing measurements, action potentials (AP) elicited by electrical stimulation of the dorsal roots differed in OA rats, including longer AP duration (P = 0.006), slower rise time (P = 0.001) and slower maximum rising rate (P = 0.03). Depolarizing intracellular current injection elicited more APs in models than in naïve muscle afferent neurones (P = 0.01) indicating greater excitability. Axonal conduction velocity in model animals was slower (P = 0.04).The present study demonstrates changes in hind limb stance accompanied by changes in the functional properties of muscle afferent neurones in this derangement model of OA. This may provide a possible avenue to explore mechanisms underlying the impaired proprioceptive performance and perhaps other sensory disorders in people with OA

Characterisation of a Peripheral Neuropathic Component of the Rat Monoiodoacetate Model of Osteoarthritis

Joint degeneration observed in the rat monoiodoacetate (MIA) model of osteoarthritis shares many histological features with the clinical condition. The accompanying pain phenotype has seen the model widely used to investigate the pathophysiology of osteoarthritis pain, and for preclinical screening of analgesic compounds. We have investigated the pathophysiological sequellae of MIA used at low (1 mg) or high (2 mg) dose. Intra-articular 2 mg MIA induced expression of ATF-3, a sensitive marker for peripheral neuron stress/injury, in small and large diameter DRG cell profiles principally at levels L4 and 5 (levels predominated by neurones innervating the hindpaw) rather than L3. At the 7 day timepoint, ATF-3 signal was significantly smaller in 1 mg MIA treated animals than in the 2 mg treated group. 2 mg, but not 1 mg, intra-articular MIA was also associated with a significant reduction in intra-epidermal nerve fibre density in plantar hindpaw skin, and produced spinal cord dorsal and ventral horn microgliosis. The 2 mg treatment evoked mechanical pain-related hypersensitivity of the hindpaw that was significantly greater than the 1 mg treatment. MIA treatment produced weight bearing asymmetry and cold hypersensitivity which was similar at both doses. Additionally, while pregabalin significantly reduced deep dorsal horn evoked neuronal responses in animals treated with 2 mg MIA, this effect was much reduced or absent in the 1 mg or sham treated groups. These data demonstrate that intra-articular 2 mg MIA not only produces joint degeneration, but also evokes significant axonal injury to DRG cells including those innervating targets outside of the knee joint such as hindpaw skin. This significant neuropathic component needs to be taken into account when interpreting studies using this model, particularly at doses greater than 1 mg MIA

Endothelin-1 as a neuropeptide: neurotransmitter or neurovascular effects?

Endothelin-1 (ET-1) is an endothelium-derived peptide that also possesses potent mitogenic activity. There is also a suggestion the ET-1 is a neuropeptide, based mainly on its histological identification in both the central and peripheral nervous system in a number of species, including man. A neuropeptide role for ET-1 is supported by studies showing a variety of effects caused following its administration into different regions of the brain and by application to peripheral nerves. In addition there are studies proposing that ET-1 is implicated in a number of neural circuits where its transmitter affects range from a role in pain and temperature control to its action on the hypothalamo-neurosecretory system. While the effect of ET-1 on nerve tissue is beyond doubt, its action on nerve blood flow is often ignored. Here, we review data generated in a number of species and using a variety of experimental models. Studies range from those showing the distribution of ET-1 and its receptors in nerve tissue to those describing numerous neurally-mediated effects of ET-1

Petrogenetic implications for ophiolite ultramafic bodies from lokris and beotia (central greece) based on chemistry of their Cr-spinels

Cr-spinels from ultramafic rocks from Lokris (Megaplatanos and Tragana), and Beotia (Ypato and Alyki) ophiolitic occurrences were studied. These rocks comprise principally harzburgite with minor dunite. Small amounts of clinopyroxene-rich harzburgite and lherzolite have been observed along with the harzburgite in Alyki. The Cr# in the studied spinels displays a wide variability. The spinels hosted in harzburgite and cpx-rich harzburgite display low Cr# (<0.6), typical for oceanic (including back-arc basins) ophiolites, whereas the spinels hosted in dunite with Cr# (>0.6) characterize arc-related ophiolitic sequences. Cr-spinels from Alyki indicate a moderate fertile character and are analogous to those from abyssal peridotites. The dunitic and harzburgitic spinel-olivine pairs are consistent with a Supra-Subduction Zone origin. The relatively large range in spinel Cr# and Mg# may have been resulted from a wide range of degrees of mantle melting during the evolution of the host peridotites. © 2017 by the authors. Licensee MDPI, Basel, Switzerland