The Sepoy Rebellion

No abstract provided by author

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

Evolution of the expression and regulation of the nuclear hormone receptor ERR gene family in the chordate lineage

The Estrogen Related Receptor (ERR) nuclear hormone receptor genes have a wide diversity of roles in vertebrate development. In embryos, ERR genes are expressed in several tissues, including the central and peripheral nervous systems. Here we seek to establish the evolutionary history of chordate ERR genes, their expression and their regulation. We examine ERR expression in mollusc, amphioxus and sea squirt embryos, finding the single ERR orthologue is expressed in the nervous system in all three, with muscle expression also found in the two chordates. We show that most jawed vertebrates and lampreys have four ERR paralogues, and that vertebrate ERR genes were ancestrally linked to Estrogen Receptor genes. One of the lamprey paralogues shares conserved expression domains with jawed vertebrate ERRγ in the embryonic vestibuloacoustic ganglion, eye, brain and spinal cord. Hypothesising that conserved expression derives from conserved regulation, we identify a suite of pan-vertebrate conserved non-coding sequences in ERR introns. We use transgenesis in lamprey and chicken embryos to show that these sequences are regulatory and drive reporter gene expression in the nervous system. Our data suggest an ancient association between ERR and the nervous system, including expression in cells associated with photosensation and mechanosensation. This includes the origin in the vertebrate common ancestor of a suite of regulatory elements in the 3' introns that drove nervous system expression and have been conserved from this point onwards

A pre-vertebrate endodermal origin of calcitonin-producing neuroendocrine cells

Peer reviewe

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

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

No Evidence for XMRV Nucleic Acids, Infectious Virus or Anti-XMRV Antibodies in Canadian Patients with Chronic Fatigue Syndrome

The gammaretroviruses xenotropic murine leukemia virus (MLV)-related virus (XMRV) and MLV have been reported to be more prevalent in plasma and peripheral blood mononuclear cells of chronic fatigue syndrome (CFS) patients than in healthy controls. Here, we report the complex analysis of whole blood and plasma samples from 58 CFS patients and 57 controls from Canada for the presence of XMRV/MLV nucleic acids, infectious virus, and XMRV/MLV-specific antibodies. Multiple techniques were employed, including nested and qRT-PCR, cell culture, and immunoblotting. We found no evidence of XMRV or MLV in humans and conclude that CFS is not associated with these gammaretroviruses

The Scrounge-atron: a phased approach to the Advanced Hydrotest Facility utilizing proton radiography

The Department of Energy has initiated its Stockpile Stewardship and Management Program (SSMP) to provide a single, integrated technical program for maintaining the continued safety and reliability of the nation's nuclear weapons stockpile in the absence of nuclear testing. Consistent with the SSMP, the Advanced Hydrotest Facility (AHF) has been conceived to provide improved radiographic imaging with multiple axes and multiple time frames. The AHF would be used to better understand the evolution of nuclear weapon primary implosion shape under normal and accident scenarios. There are three fundamental technologies currently under consideration for use on the AHF. These include linear induction acceleration, inductive-adder pulsed-power technology (both technologies using high current electron beams to produce an intense X-ray beam) and high-energy proton accelerators to produce a proton beam. The Scrounge-atron (a proton synchrotron) was conceived to be a relatively low cost demonstration of the viability of the third technology using bursts of energetic protons, magnetic lenses, and particle detectors to produce the radiographic image. In order for the Scrounge-atron to provide information useful for the AHF technology decision, the accelerator would have to be built as quickly and as economically as possible. These conditions can be met by "scrounging" parts from decommissioned accelerators across the country, especially the Main Ring at Fermilab. The Scrounge-atron is designed to meet the baseline parameters for single axis proton radiography: a 20 GeV proton beam of ten pulses, 10 degrees protons each, spaced 250 ns apart. (2 refs)

Developmental variations in plasma leptin, leptin soluble receptor and their molar ratio in healthy infants

<p>Abstract</p> <p>Background</p> <p>Leptin and its soluble receptor (sOB-R) are important to regulation of body composition but there are no data on the developmental variations in these plasma variables and their relationship with body composition measurements,</p> <p>Methods</p> <p>Weight, length, and body composition (bone, fat and lean mass) by dual energy absorptiometry, and plasma variables were measured in healthy infants at 2, 4, 8 and 12 months.</p> <p>Results</p> <p>15 whites and 29 African Americans (21 males and 23 females) with mean birth weight 3357 +/- 45 (SEM) g and gestation of 39.3 +/- 0.17 weeks were studied. The overall Z score for weight, length and weight for length during the study were 0.00 +/- 0.15, -0.08 +/- 0.11 and 0.12 +/- 0.14 respectively. With increasing age, plasma leptin (1.0 to 18.2, median 5.5 ng/mL) and sOB-R:leptin molar ratio (10.1 to 247.4, median 59.9) were lowered (r = -0.47, p < 0.01; and r = -0.37, p < 0.05 respectively), best predicted by weight Z score and percentage of fat mass, and higher in African American and female. Presence of body composition measurements eliminated the race and gender effect on the plasma variables. Plasma sOB-R (49.5 to 173.9, median 81.3 ng/mL) did not change significantly with age and was correlated and predicted only by body composition measurements.</p> <p>Conclusion</p> <p>In healthy growing infants, plasma leptin but not sOB-R decreases with age. Gender, race and anthropometric measurements are additional physiological determinants predictive of plasma leptin and the receptor:ligand ratio. However, body composition is the only variable that can predict plasma leptin and its soluble receptor and the receptor: ligand ratio; and body composition measurements eliminated the race and gender effect on these plasma variables.</p