Singularity formation in the strongly nonlinear wide-vortex/Tollmien-Schlichting-wave interaction equations

Published versio

Mechanisms of the gabapentinoids and α2δ-1 calcium channel subunit in neuropathic pain

The gabapentinoid drugs gabapentin and pregabalin are key front-line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α2δ-1 and α2δ-2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α2δ-1 as key in mediating the analgesic effects of gabapentinoids, how- ever the precise molecular mechanisms remain unclear. Here we review the cur- rent understanding of the pathophysiological role of the α2δ-1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids

Enhancement of Gap Junction Function During Acute Myocardial Infarction Modifies Healing and Reduces Late Ventricular Arrhythmia Susceptibility

Objectives: To investigate the effects of enhancing gap junction (GJ) coupling during acute myocardial infarction (MI) on the healed infarct scar morphology and late post-MI arrhythmia susceptibility. Background: Increased heterogeneity of myocardial scarring after MI is associated with greater arrhythmia susceptibility. We hypothesized that short-term enhancement of GJ coupling during acute MI can produce more homogeneous infarct scars, reducing late susceptibility to post-MI arrhythmias. Methods: Following arrhythmic characterisation of the rat 4-week post-MI model (n=24), a further 27 Sprague-Dawley rats were randomised to receive rotigaptide to enhance GJ coupling (n=13) or saline control (n=14) by osmotic minipump immediately prior to, and for the first 7 days following surgical MI. At 4 weeks post-MI, hearts were explanted for ex vivo programmed electrical stimulation (PES) and optical mapping. Heterogeneity of infarct border zone (IBZ) scarring was quantified by histomorphometry. Results: Despite no detectable difference in infarct size at 4 weeks post-MI, rotigaptide-treated hearts had reduced arrhythmia susceptibility during PES (Inducibility score: rotigaptide 2.40.8, control 5.00.6, p=0.02) and less heterogeneous IBZ scarring (standard deviation of IBZ Complexity Score: rotigaptide 1.10.1, control 1.40.1, p=0.04), associated with an improvement in IBZ conduction velocity (rotigaptide 43.13.4 cm/s, control 34.82.0 cm/s, p=0.04). Conclusions: Enhancement of GJ coupling for only 7 days at the time of acute MI produced more homogeneous IBZ scarring and reduced arrhythmia susceptibility at 4 weeks post-MI. Short-term GJ modulation at the time of MI may represent a novel treatment strategy to modify the healed infarct scar morphology and reduce late post-MI arrhythmic risk

Calcium channel modulation as a target in chronic pain control

Neuropathic pain remains poorly treated for large numbers of patients and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (PrialtTM ) was developed and approved as a first in class synthetic version of ω-conotoxin MVIIA, a Cav 2.2 peptide blocker. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide has restricted its use to exceptional circumstances. Ziconotide exhibits no state or use dependent block of Cav 2.2 channels; activation state dependent blockers were hypothesised to circumvent the side effects of state independent blockers by selectively targeting high frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state dependent calcium channel blockers, have displayed efficacy in pre-clinical models but have subsequently disappointed in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients, and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus evoked endpoints in pre-clinical studies and a failure to utilise translatable endpoints has likely contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant based assays provide insight into sensory and affective aspects of pain in animal models, and how these may relate to chronic pain patients in order to improve bench-to-bedside translation of calcium channel modulators

Calcium signals and calpain-dependent necrosis are essential for release of coxsackievirus B from polarized intestinal epithelial cells

Coxsackievirus B (CVB), a member of the enterovirus family, targets the polarized epithelial cells lining the intestinal tract early in infection. Although the polarized epithelium functions as a protective barrier, this barrier is likely exploited by CVB to promote viral entry and subsequent egress. Here we show that, in contrast to nonpolarized cells, CVB-infected polarized intestinal Caco-2 cells undergo nonapoptotic necrotic cell death triggered by inositol 1,4,5-trisphosphate receptor-dependent calcium release. We further show that CVB-induced cellular necrosis depends on the Ca 2+-activated protease calpain-2 and that this protease is involved in CVB-induced disruption of the junctional complex and rearrangements of the actin cytoskeleton. Our study illustrates the cell signaling pathways hijacked by CVB, and perhaps other viral pathogens, to promote their replication and spread in polarized cell types. © 2011 Bozym et al.published_or_final_versio

From fields to a super-cluster: the role of the environment at z=0.84 with HiZELS

At z=0, clusters are primarily populated by red, elliptical and massive galaxies, while blue, spiral and lower-mass galaxies are common in low-density environments. Understanding how and when these differences were established is of absolute importance for our understanding of galaxy formation and evolution, but results at high-z remain contradictory. By taking advantage of the widest and deepest H-alpha narrow-band survey at z=0.84 over the COSMOS and UKIDSS UDS fields, probing a wide range of densities (from poor fields to rich groups and clusters, including a confirmed super-cluster with a striking filamentary structure), we show that the fraction of star-forming galaxies falls continuously from ~40% in fields to approaching 0% in rich groups/clusters. We also find that the median SFR increases with environmental density, at least up to group densities - but only for low and medium mass galaxies, and thus such enhancement is mass-dependent at z~1. The environment also plays a role in setting the faint-end slope (alpha) of the H-alpha luminosity function. Our findings provide a sharper view on galaxy formation and evolution and reconcile previously contradictory results at z~1: stellar mass is the primary predictor of star formation activity, but the environment also plays a major role.Comment: 5 pages, 4 figures, to appear in the proceedings of JENAM 2010 S2: `Environment and the Formation of Galaxies: 30 years later', ASSP, Springe

Microtuberization, minitubers formation and in vitro shoot regeneration from bud sprout of potato (Solanum tuberosum L.) cultivar K. badshah

Kufri badshah is one of the important medium maturing, blight resistant potato varieties with round to oblong tubers; it has yellowish skin, shallow eye and white pulp. This variety is popular among farmers. The study on development of tissue culture protocol was carried out using sprout as an explant for initiation of culture in MS media supplemented with eleven different combinations of growth hormones: indole butyric acid (IBA), kinetin, naphthalene acetic acid (NAA) and 2,4-dichlorophenoxy acetic acid (2,4-D). The response for growth proliferation was observed. The treatment involving a combination of IBA, kinetin, NAA and 2,4-D gave good response for growth of shoot. The resultant shoots were subcultured further using nodal cutting as explants in same media for further multiplication. The developed plantlets were hardened in green house. Hardened plants were transplanted in the soil for further growth and development. The plants yielded 3-17 healthy minitubers. For microtuber production, high level of sucrose (8%) gave promising results than low level of sucrose (3%).Keywords: Kufri badshah, explants, indole butyric acid (IBA), kinetin, naphthalene acetic acid (NAA), 2,4-dichlorophenoxy acetic acid (2,4-D) and microtuber.African Journal of Biotechnology Vol. 12(38), pp. 5640-564

A randomized comparison of retrograde left-sided versus anterograde right-sided ablation of the atrioventricular junction

Background: Catheter ablation of the atrioventricular node (AVN) is an effective treatment for patients with symptomatic atrial fibrillation. This study compares the success rate, procedure time, radiation time, and complication rates of retrograde left-sided (LSA) and anterograde right-sided (RSA) AVN ablation in a randomised controlled trial. / Methods: Thirty-one patients undergoing AVN ablation were randomized to either LSA (15 patients) or RSA (16 patients). Crossover occurred after six unsuccessful radiofrequency (RF) applications. / Results: The LSA cohort had a mean age of 77.00 ± 5.17 and the RSA cohort was 79.44 ± 6.08 (p =.0240). There were five crossovers from LSA to RSA and there was one crossover from RSA to LSA. There was no significant difference in ablation time between LSA and RSA (210.40 ± 179.77 vs. 192.19 ± 130.29 seconds, p =.748). There was no significant difference in procedure time, fluoroscopy time, radiation dose, or number of RF applications between the two groups. There was 1 (6.67%) serious adverse event in the LSA group and 1 (6.25%) in the RSA group due to femoral hematomas requiring blood transfusion or intervention. There was no significant difference in patient-reported discomfort between LSA and RSA (16.43 ± 20.67 vs. 17.87 ± 28.08, p =.877). The study was stopped before full recruitment due to futility. / Conclusions: Retrograde LSA of the AVN does not reduce RF applications, procedure time, or radiation exposure compared with conventional RSA and cannot be recommended as a first-line clinical approach

A trial of three non-invasive blood pressure monitors compared with invasive blood pressure assessment in atrial fibrillation and sinus rhythm

OBJECTIVE: To investigate the accuracy of three non‐invasive blood pressure (BP) devices in atrial fibrillation (AF) compared with invasive arterial BP. METHODS: One hundred patients aged 45‐90 years, 63% male (50 in AF and 50 age matched controls in sinus rhythm [SR]) were identified with arterial lines measuring beat‐to‐beat BP fluctuation. Non‐invasive BP measurements utilising the manual sphygmomanometer (MS), PulseCor R6.5 (PC) and automated sphygmomanometer (AS) were taken simultaneously with invasive BP in a randomised sequence. This was repeated three times in each patient. RESULTS: In SR differences in systolic BP (SBP) for MS, AS and PC were −0.34 mm Hg (95% CI −2.31 to 1.63; P = .733), −3.80 mm Hg (95% CI −5.73 to −1.87; P = .0001) and −3.90 mm Hg (95% CI −5.90 to −1.90; P = .0001) and for diastolic BP (DBP) were 6.02 mm Hg (95% CI 4.39‐7.64; P < .0001), 8.95 mm Hg (95% CI 7.36‐10.55; P < .0001) and 7.54 mm Hg (95% CI 5.89‐9.18; P < .0001), respectively. In AF mean differences in SBP for MS, AS and PC were −7.33 mm Hg (95% CI −9.11 to −5.55; P < .0001), −5.29 mm Hg (95% CI −7.08 to −3.50; P < .0001) and −5.75 mm Hg (95% CI −7.54 to −3.96; P < .0001) respectively and for DBP were 5.28 mm Hg (95% CI 4.03‐6.54; P < .0001), 6.26 mm Hg (95% CI 5.00‐7.52; P < .0001) and 6.89 mm Hg (95% CI 5.64‐8.15; P < .0001) respectively. CONCLUSIONS: The MS is accurate in SR because of direct assessment of Korotkoff sounds. Non‐invasive BP assessment in AF is significantly less accurate. These findings have important prognostic and therapeutic implications