NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials

BACKGROUND HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. NGX-4010 is a capsaicin 8% dermal patch with demonstrated efficacy in the treatment of HIV-DSP. Data from two phase III, double-blind studies were integrated to further analyze the efficacy and safety of NGX-4010 and explore the effect of demographic and baseline factors on NGX-4010 treatment in HIV-DSP. METHODS Data from two similarly designed studies in which patients with HIV-DSP received NGX-4010 or a low-concentration control patch (capsaicin 0.04% w/w) for 30 or 60 minutes were integrated. Efficacy assessments included the mean percent change from baseline in Numeric Pain Rating Scale (NPRS) scores to Weeks 2-12. Safety and tolerability assessments included adverse events (AEs) and pain during and after treatment. RESULTS Patients (n = 239) treated with NGX-4010 for 30 minutes demonstrated significantly (p = 0.0026) greater pain relief compared with controls (n = 100); the mean percent change in NPRS scores from baseline to Weeks 2-12 was -27.0% versus -15.7%, respectively. Patients who received a 60-minute application of NGX-4010 (n = 243) showed comparable pain reductions (-27.5%) to patients treated for 30 minutes, but this was not statistically superior to controls (n = 115). NGX-4010 was effective regardless of gender, baseline pain score, duration of HIV-DSP, or use of concomitant neuropathic pain medication, although NGX-4010 efficacy was greater in patients not receiving concomitant neuropathic pain medications. NGX-4010 was well tolerated; the most common AEs were application-site pain and erythema, and most AEs were mild to moderate. The transient increase in pain associated with NGX-4010 treatment decreased the day after treatment and returned to baseline by Day 2. CONCLUSIONS A single 30-minute application of NGX-4010 provides significant pain relief for at least 12 weeks in patients with HIV-DSP and is well tolerated. TRIAL REGISTRATION C107 = NCT00064623; C119 = NCT00321672

Legume based plant mixtures for delivery of multiple ecosystem services: An overview of benefits

As costs for mineral fertilizers rise, legume-based leys are recognised as a potential alternative nitrogen source for crops. Here we demonstrate that including species-rich legume-based leys in the rotation helps to maximize synergies between agricultural productivity and other ecosystem services. By using functionally diverse plant species mixtures these services can be optimised and fine-tuned to regional and farm-specific needs. Field experiments run over three years at multiple locations showed that the stability of ley performance was greater in multi-species mixtures than in legume monocultures. In addition, mixing different legume species in the ley helps to suppress both early and late weeds. Further, combining complementary phenologies of different legume species extended forage availability for key pollinator species. Finally, widening the range of legume species increases opportunities to build short term leys into rotations on conventional farms via cover cropping or undersowing

Effect of Vascular Cadherin Knockdown on Zebrafish Vasculature during Development

Background: Vascular endothelial cadherin (VE-cad) is essential for endothelial barrier integrity and vascular sprouting. However, the role of this important protein in cardiovascular development is only recently becoming apparent. Methodology/Principal Findings: To characterize the role of VE-cadherin in cardiovascular development, we analyzed cardiovascular development in a zebrafish VE-cad knockdown model. Embryos deficient in VE-cad show profoundly impaired cardiac development despite having apparently normal peripheral vasculature. Initial formation of the heart proceeds normally in knockdown embryos, but subsequent looping morphogenesis is impaired. Consistent with these results, VE-cad knockdown embryos demonstrate impaired cardiac function and early circulatory arrest. Histologic examination of knockdown embryos shows persistent, abnormal separation of the endocardial and myocardial layers. Using transmission electron microscopy, we demonstrate that endocardial junctions form poorly in VE-cad knockdown embryos, with resulting leak across the endothelial layer and reduction in the density of the cardiac jelly. Conclusions: Our results demonstrate a significant role for VE-cadherin in cardiac development independent of its effects on the formation of the peripheral vasculature

Causes and Consequences of Broad-Scale Changes in the Distribution of Migratory Caribou (Rangifer tarandus) of Southern Hudson Bay

Understanding the factors driving changes in species distributions is fundamental to conservation, but for wide-ranging species this is often complicated by the need for broad-scale observations across space and time. In the last three decades, the location of summer concentrations of migratory caribou (Rangifer tarandus) in southern Hudson Bay (SHB), Canada, has shifted south and east as much as 500 km. We used long-term data (1987 – 2011) to test two hypotheses that could explain the distribution shift: forage depletion and anthropogenic disturbance. Over time and space, we compared the body size of live-captured adult female caribou, dietary quality from fecal nitrogen in July, the location of VHF- and GPS-collared female caribou in July, distribution of all-terrain vehicle (ATV) tracks and caribou tracks in August, and the proximity of collared caribou to sections of the coast with higher ATV activity in spring and summer. The forage depletion hypothesis was supported by greater body size and dietary quality in caribou of the eastern portion of SHB than in western SHB animals in 2009 – 11. The anthropogenic disturbance hypothesis was supported by the negative correlation of the distributions of ATV tracks and caribou tracks on the coast in 2010 and the fact that caribou avoided areas with ATV activity by 10 – 14 km. In 1987, collared caribou were observed largely along the coast in western SHB in mid-July, while in 2009 – 11, they were inland in western SHB and along the coast in eastern SHB. While these locations demonstrate a substantial change in summer distri­bution over three decades, we were unable to differentiate between forage depletion and anthropogenic disturbance as a single causal factor of the distribution shift.La compréhension des facteurs qui influencent les changements caractérisant les distributions des espèces est fondamentale aux efforts de conservation, mais pour les espèces dont l’aire de distribution est étendue, ce principe est souvent compliqué par la nécessité de faire des observations à grande échelle, dans le temps et dans l’espace. Au cours des trois dernières décennies, l’emplacement des concentrations estivales du caribou migrateur (Rangifer tarandus) dans le sud de la baie d’Hudson (SBH), au Canada, s’est déplacé vers le sud et vers l’est dans une mesure de 500 km. Nous nous sommes appuyés sur des données de longue haleine (1987–2011) pour mettre à l’épreuve deux hypothèses susceptibles d’expliquer ce changement en matière de distribution, soit l’appauvrissement du fourrage et la perturbation anthropique. Au fil du temps et de l’espace, nous avons comparé la taille du corps des caribous femelles adultes capturées vivantes, la qualité de leur alimentation à partir de l’azote fécal en juillet, l’emplacement des femelles portant un collier de type VHF ou GPS en juillet, la répartition des traces de véhicules tout terrain (VTT) et des pistes de caribou en août de même que la proximité des caribous portant un collier aux tronçons de la côte où la présence de VTT est plus grande au printemps et à l’été. L’hypothèse de l’appauvrissement du fourrage a été étayée par la plus grande taille du corps et la qualité de l’alimentation du caribou de la zone est du SBH comparativement à celles du caribou de l’ouest du SBH entre 2009 et 2011. Pour sa part, l’hypothèse perturbation anthropique a été appuyée par la corrélation négative caractérisant la répartition des pistes de VTT et des traces de caribou sur la côte en 2010 et par le fait que les caribous sont restés à l’écart des zones fréquentées par les VTT dans une mesure de 10 à 14 km. En 1987, des caribous portant un collier ont été observés en grand nombre le long de la côte ouest du SBH à la mi-juillet, tandis que de 2009 à 2011, ils ont été repérés à l’intérieur des terres dans l’ouest du SBH et le long de la côte est du SBH. Bien que ces emplacements indiquent un important changement en matière de distribution estivale au cours de trois décennies, nous n’avons pas été en mesure de faire une distinction entre l’appauvrissement du fourrage et la perturbation anthropique en tant que facteur causal unique du changement de distribution

Structural relationships among dimensions of the DSM-IV anxiety and mood disorders and dimensions of negative affect, positive affect, and autonomic arousal.

Using outpatients with anxiety and mood disorders (N = 350), Ihe authors tested several models of the structural relationships of dimensions of key features of selected emotional disorders and dimensions of the tripartite model of anxiety and depression. Results supported the discriminant validity of the 5 symptom domains examined (mood disorders; generalized anxiety disorder, GAD; panic disorder; obsessive-compulsive disorder; social phobia). Of various structural models evaluated, the best fitting involved a structure consistent with the tripartite model (e.g., the higher order factors, negative affect and positive affect, influenced emotional disorder factors in the expected manner). The latent factor, GAD, influenced the latent factor, autonomic arousal, in a direction consistent with recent laboratory findings (autonomic suppression). Findings are discussed in the context of the growing literature on higher order trait dimensions (e.g., negative affect) that may be of considerable importance to the understanding of the pathogenesis, course, and co-occurrence of emotional disorders. Over the past few decades, the number of diagnostic categories has increased markedly with each edition of the major classification systems for mental disorders (e.g., the Diagnostic an

Salmonella Pathogenicity Island 2 Is Expressed Prior to Penetrating the Intestine

Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that causes disease in mice that resembles human typhoid. Typhoid pathogenesis consists of distinct phases in the intestine and a subsequent systemic phase in which bacteria replicate in macrophages of the liver and spleen. The type III secretion system encoded by Salmonella pathogenicity island 2 (SPI-2) is a major virulence factor contributing to the systemic phase of typhoid pathogenesis. Understanding how pathogens regulate virulence mechanisms in response to the environment, including different host tissues, is key to our understanding of pathogenesis. A recombinase-based in vivo expression technology system was developed to assess SPI-2 expression during murine typhoid. SPI-2 expression was detectable at very early times in bacteria that were resident in the lumen of the ileum and was independent of active bacterial invasion of the epithelium. We also provide direct evidence for the regulation of SPI-2 by the Salmonella transcription factors ompR and ssrB in vivo. Together these results demonstrate that SPI-2 expression precedes penetration of the intestinal epithelium. This induction of expression precedes any documented SPI-2-dependent phases of typhoid and may be involved in preparing Salmonella to successfully resist the antimicrobial environment encountered within macrophages

Weakly dispersive modal pulse propagation in the North Pacific Ocean

Author Posting. © Acoustical Society of America, 2013. This article is posted here by permission of Acoustical Society of America or personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 134 (2013): 3386, doi:10.1121/1.4820882.The propagation of weakly dispersive modal pulses is investigated using data collected during the 2004 long-range ocean acoustic propagation experiment (LOAPEX). Weakly dispersive modal pulses are characterized by weak dispersion- and scattering-induced pulse broadening; such modal pulses experience minimal propagation-induced distortion and are thus well suited to communications applications. In the LOAPEX environment modes 1, 2, and 3 are approximately weakly dispersive. Using LOAPEX observations it is shown that, by extracting the energy carried by a weakly dispersive modal pulse, a transmitted communications signal can be recovered without performing channel equalization at ranges as long as 500 km; at that range a majority of mode 1 receptions have bit error rates (BERs) less than 10%, and 6.5% of mode 1 receptions have no errors. BERs are estimated for low order modes and compared with measurements of signal-to-noise ratio (SNR) and modal pulse spread. Generally, it is observed that larger modal pulse spread and lower SNR result in larger BERs.This work was supported by the Office of Naval Research, Code 322, Grant Nos. N00014-06-1-0245, N00014-08-1-0195, and N00014-11-1-0194

Tetracritical behavior in strongly interacting theories

We suggest a tetracritical fixed point to naturally occur in strongly interacting theories. As a fundamental example we analyze the temperature--quark chemical potential phase diagram of QCD with fermions in the adjoint representation of the gauge group (i.e. adjoint QCD). Here we show that such a non trivial multicritical point exists and is due to the interplay between the spontaneous breaking of a global U(1) symmetry and the center group symmetry associated to confinement. Our results demonstrate that taking confinement into account is essential for understanding the critical behavior as well as the full structure of the phase diagram of adjoint QCD. This is in contrast to ordinary QCD where the center group symmetry associated to confinement is explicitly broken when the quarks are part of the theory.Comment: RevTex, 5 figures. Final version to appear in PR

Reply to Comment on “Sloppy models, parameter uncertainty, and the role of experimental design"

available in PMC 2012 November 10.We welcome the commentary from Chachra, Transtrum, and Sethna1 regarding our paper “Sloppy models, parameter uncertainty, and the role of experimental design,”2 as their intriguing work shaped our thinking in this area.3 Sethna and colleagues introduced the notion of sloppy models, in which the uncertainty in the values of some combinations of parameters is many orders of magnitude greater than others.4 In our work we explored the extent to which large parameter uncertainties are an intrinsic characteristic of systems biology network models, or whether uncertainties are instead closely related to the collection of experiments used for model estimation. We were gratified to find the latter result –– that parameters are in principle knowable, which is important for the field of systems biology. The work also showed that small parameter uncertainties can be achieved and that the process can be greatly accelerated by using computational experimental design approaches5–9 deployed to select sets of experiments that effectively exercise the system in complementary directions