Current and Future Issues in the Development of Spinal Agents for the Management of Pain.

Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety

Games without frontiers: Audio games for music production and performance

The production of electronic dance music most often takes the form of sound-events arranged on a timeline, rendered as a stereo recording and mixed with other recordings in the context of mixes. Live electronic dance music on the other hand involves interaction with the sound-events in real time, but nonetheless subject to a master timekeeper. A similar comparison exists between sound for film and sound for (video) games, however in the case of games there is no assumption of a master timekeeper, and the timing of events is relative to the actions of the player and the state of the game environment. The authors explain a method by which electronic dance music can be produced in a similar manner to producing game audio, and in fact that an interactive or live piece can be considered an audio game. Musical structure is composed conceptually as scenes in a film, where interacting sound-machines generate rhythmic patterns of sound-events that place the performer/player in a virtual space. The performer/player pursues musical goals in nonlinear time while maintaining the ability to sequentially arrange pieces in a coherent mix

Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins

Lipoprotein lipase (LPL) is crucial in the hydrolysis of triglycerides (TG) in TG-rich lipoproteins in the formation of HDL particles. As both these lipoproteins play an important role in the pathogenesis of atherosclerotic vascular disease, we sought to assess the relationship between post-heparin LPL (PH-LPL) activity and lipids and lipoproteins in a large, well-defined cohort of Dutch males with coronary artery disease (CAD). These subjects were drawn from the REGRESS study, totaled 730 in number and were evaluated against 75 healthy, normolipidemic male controls. Fasting mean PH-LPL activity in the CAD subjects was 108 46 mU/ml, compared to 138 44 mU/ml in controls (P < 0.0001). When these patients were divided into activity quartiles, those in the lowest versus the highest quartile had higher levels of TG (P < 0.001), VLDLc and VLDL-TG (P = 0.001). Conversely, levels of TC, LDL, and HDLc were lower in these patients (P = 0.001, P = 0.02, and P = 0.001, respectively). Also, in this cohort PH-LPL relationships with lipids and lipoproteins were not altered by apoE genotypes. The frequency of common mutations in the LPL gene associated with partial LPL deficiency (N291S and D9N carriers) in the lowest quartile for LPL activity was more than double the frequency in the highest quartile (12.0% vs. 5.0%; P = 0.006). By contrast, the frequency of the S447X LPL variant rose from 11.5% in the lowest to 18.3% (P = 0.006) in the highest quartile. This study, in a large cohort of CAD patients, has shown that PH-LPL activity is decreased (22%; P = 0.001) when compared to controls; that the D9N and N291S, and S447X LPL variants are genetic determinants, respectively, in CAD patients of low and high LPL PH-LPL activities; and that PH-LPL activity is strongly associated with changes in lipids and lipoproteins

Thermal modeling of nuclear waste package designs for disposal in tuff

Lawrence Livermore National Laboratory is involved in the design and testing of high-level nuclear waste packages. Many of the aspects of waste package design and testing (e.g., corrosion and leaching) depend in part on the temperature history of the emplaced packages. This paper discusses thermal modeling and analysis of various emplaced waste package conceptual designs including the models used, the assumptions and approximations made, and the results obtained. 6 references, 6 figures, 3 tables

Retinoic acid-independent expression of Meis2 during autopod patterning in the developing bat and mouse limb

BackgroundThe bat has strikingly divergent forelimbs (long digits supporting wing membranes) and hindlimbs (short, typically free digits) due to the distinct requirements of both aerial and terrestrial locomotion. During embryonic development, the morphology of the bat forelimb deviates dramatically from the mouse and chick, offering an alternative paradigm for identifying genes that play an important role in limb patterning.ResultsUsing transcriptome analysis of developing Natal long-fingered bat (Miniopterus natalensis) fore- and hindlimbs, we demonstrate that the transcription factor Meis2 has a significantly higher expression in bat forelimb autopods compared to hindlimbs. Validation by reverse transcriptase and quantitative polymerase chain reaction (RT-qPCR) and whole mount in situ hybridisation shows that Meis2, conventionally known as a marker of the early proximal limb bud, is upregulated in the bat forelimb autopod from CS16. Meis2 expression is localised to the expanding interdigital webbing and the membranes linking the wing to the hindlimb and tail. In mice, Meis2 is also expressed in the interdigital region prior to tissue regression. This interdigital Meis2 expression is not activated by retinoic acid (RA) signalling as it is present in the retained interdigital tissue of Rdh10trex/trex mice, which lack RA. Additionally, genes encoding RA-synthesising enzymes, Rdh10 and Aldh1a2, and the RA nuclear receptor Rarβ are robustly expressed in bat fore- and hindlimb interdigital tissues indicating that the mechanism that retains interdigital tissue in bats also occurs independently of RA signalling.ConclusionsMammalian interdigital Meis2 expression, and upregulation in the interdigital webbing of bat wings, suggests an important role for Meis2 in autopod development. Interdigital Meis2 expression is RA-independent, and retention of interdigital webbing in bat wings is not due to the suppression of RA-induced cell death. Rather, RA signalling may play a role in the thinning (rather than complete loss) of the interdigital tissue in the bat forelimb, while Meis2 may interact with other factors during both bat and mouse autopod development to maintain a pool of interdigital cells that contribute to digit patterning and growth.Electronic supplementary materialThe online version of this article (doi:10.1186/s13227-015-0001-y) contains supplementary material, which is available to authorized users

Allergic rhinitis in South Africa: 2012 guidelines

Background. Allergic rhinitis (AR) is an important disease in South Africa. The South African Allergic Rhinitis Working Group (SAARWG) has published previous guidelines for AR diagnosis and management. Areas of concern have arisen that require additional information, including the management of AR in infancy, appropriate and inappropriate allergy testing, cost of AR management, diagnosis and distinguishing the condition from sinusitis, use of over-the-counter medications, and the concept of the ‘united airway’. Recommendations. Clinicians should consider the possibility of AR in infants with recurrent nasal symptoms. Allergy testing should be used wisely and based on local allergens. Total IgE testing is not routinely required to prove allergy. Acute and chronic sinusitis should be considered in conjunction with AR; treatment of rhinitis will improve these conditions. Over-the-counter medications should be used sparingly and with caution. Concern for long-term use of topical decongestants must be noted. Asthma should always be considered in AR diagnosis. Immunotherapy is available in SA and may be extremely useful in selected AR patients. Conclusion. The SAARWG proposed an algorithm for the diagnosis and management of rhinitis in South Africa. AR is common, important and troubling to patients; therefore, every effort should be made to target therapy correctly. Patient education is important in the management of AR

Allergic rhinitis in South Africa : 2012 guidelines

BACKGROUND: Allergic rhinitis (AR) is an important disease in South Africa. The South African Allergic Rhinitis Working Group (SAARWG) has published previous guidelines for AR diagnosis and management. Areas of concern have arisen that require additional information, including the management of AR in infancy, appropriate and inappropriate allergy testing, cost of AR management, diagnosis and distinguishing the condition from sinusitis, use of over-the-counter medications, and the concept of the ‘united airway’. RECOMMENDATIONS: Clinicians should consider the possibility of AR in infants with recurrent nasal symptoms. Allergy testing should be used wisely and based on local allergens. Total IgE testing is not routinely required to prove allergy. Acute and chronic sinusitis should be considered in conjunction with AR; treatment of rhinitis will improve these conditions. Over-the-counter medications should be used sparingly and with caution. Concern for long-term use of topical decongestants must be noted. Asthma should always be considered in AR diagnosis. Immunotherapy is available in SA and may be extremely useful in selected AR patients. CONCLUSION: The SAARWG proposed an algorithm for the diagnosis and management of rhinitis in South Africa. AR is common, important and troubling to patients; therefore, every effort should be made to target therapy correctly. Patient education is important in the management of AR.An unrestricted grant from Aspen/GSK Pharmaceuticals for sponsorship of the working group meeting on 10 - 12 February 2012.http://www.samj.org.z

PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells

Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3−/− mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease

A Genome-Wide Assessment of the Ancestral Neural Crest Gene Regulatory Network

The neural crest (NC) is an embryonic cell population that contributes to key vertebrate-specific features including the craniofacial skeleton and peripheral nervous system. Here we examine the transcriptional and epigenomic profiles of NC cells in the sea lamprey, in order to gain insight into the ancestral state of the NC gene regulatory network (GRN). Transcriptome analyses identify clusters of co-regulated genes during NC specification and migration that show high conservation across vertebrates but also identify transcription factors (TFs) and cell-adhesion molecules not previously implicated in NC migration. ATAC-seq analysis uncovers an ensemble of cis-regulatory elements, including enhancers of Tfap2B, SoxE1 and Hox-α2 validated in the embryo. Cross-species deployment of lamprey elements identifies the deep conservation of lamprey SoxE1 enhancer activity, mediating homologous expression in jawed vertebrates. Our data provide insight into the core GRN elements conserved to the base of the vertebrates and expose others that are unique to lampreys