Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABA(B) receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABA(B) receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain

Toxoplasma gondii infection and liver disease: a case-control study in a Northern Mexican population

<p>Abstract</p> <p>Background</p> <p>Infection with the protozoan parasite <it>Toxoplasma gondii </it>may cause liver disease. However, the impact of the infection in patients suffering from liver disease is unknown. Therefore, through a case-control study design, 75 adult liver disease patients attending a public hospital in Durango City, Mexico, and 150 controls from the general population of the same region matched by gender, age, and residence were examined with enzyme-linked immunoassays for the presence of anti-<it>Toxoplasma </it>IgG and anti-<it>Toxoplasma </it>IgM antibodies. Socio-demographic, clinical and behavioral characteristics from the study subjects were obtained.</p> <p>Results</p> <p>Seroprevalence of anti-<it>Toxoplasma </it>IgG antibodies and IgG titers did not differ significantly in patients (10/75; 13.3%) and controls (16/150; 10.7%). Two (2.7%) patients and 5 (3.3%) controls had anti-<it>Toxoplasma </it>IgM antibodies (<it>P </it>= 0.57). Seropositivity to <it>Toxoplasma </it>did not show any association with the diagnosis of liver disease. In contrast, seropositivity to <it>Toxoplasma </it>in patients was associated with consumption of venison and quail meat. <it>Toxoplasma </it>seropositivity was more frequent in patients with reflex impairment (27.8%) than in patients without this impairment (8.8%) (<it>P </it>= 0.05). Multivariate analysis showed that <it>Toxoplasma </it>seropositivity in patients was associated with consumption of sheep meat (OR = 8.69; 95% CI: 1.02-73.71; <it>P </it>= 0.04) and rabbit meat (OR = 4.61; 95% CI: 1.06-19.98; <it>P </it>= 0.04).</p> <p>Conclusions</p> <p>Seropositivity to <it>Toxoplasma </it>was comparable among liver disease patients and controls. Further studies with larger sample sizes are needed to elucidate the association of <it>Toxoplasma </it>with liver disease. Consumption of venison, and rabbit, sheep, and quail meats may warrant further investigation.</p

Phytoplankton dynamics in relation to seasonal variability and upwelling and relaxation patterns at the mouth of Ria de Aveiro (West Iberian Margin) over a four-year period

From June 2004 to December 2007, samples were weekly collected at a fixed station located at the mouth of Ria de Aveiro (West Iberian Margin). We examined the seasonal and inter-annual fluctuations in composition and community structure of the phytoplankton in relation to the main environmental drivers and assessed the influence of the oceano-graphic regime, namely changes in frequency and intensity of upwelling events, over the dynamics of the phytoplankton assemblage. The samples were consistently handled and a final subset of 136 OTUs (taxa with relative abundance > 0.01%) was subsequently submitted to various multivariate analyses. The phytoplankton assemblage showed significant changes at all temporal scales but with an overriding importance of seasonality over longer-(inter-annual) or shorter-term fluctuations (upwelling-related). Sea-surface temperature, salinity and maximum upwelling index were retrieved as the main driver of seasonal change. Seasonal signal was most evident in the fluctuations of chlorophyll a concentration and in the high turnover from the winter to spring phytoplankton assemblage. The seasonal cycle of production and succession was disturbed by upwelling events known to disrupt thermal stratification and induce changes in the phytoplankton assemblage. Our results indicate that both the frequency and intensity of physical forcing were important drivers of such variability, but the outcome in terms of species composition was highly dependent on the available local pool of species and the timing of those events in relation to the seasonal cycle. We conclude that duration, frequency and intensity of upwelling events, which vary seasonally and inter-annually, are paramount for maintaining long-term phytoplankton diversity likely by allowing unstable coexistence and incorporating species turnover at different scales. Our results contribute to the understanding of the complex mechanisms of coastal phytoplankton dynamics in relation to changing physical forcing which is fundamental to improve predictability of future prospects under climate change.Portuguese Foundation for Science and Technology (FCT, Portugal) [SFRH/BPD/ 94562/2013]; FEDER funds; national funds; CESAM [UID/AMB/50017]; FCT/MEC through national funds; FEDERinfo:eu-repo/semantics/publishedVersio

Cost effectiveness of palivizumab in Spain: an analysis using observational data

Objectives: To assess the cost effectiveness of palivizumab for prevention of severe respiratory syncytial virus (RSV) disease in high-risk infants in Spain, incorporating country-specific observational hospitalisation data. Methods: An existing decision tree model, designed using data from a large international clinical trial of palivizumab versus no prophylaxis, was updated to include Spanish observational hospitalisation data. The analysis was performed for preterm children born at or before 32 weeks gestational age, who are at high risk of developing severe RSV disease requiring hospitalisation. Data sources included published literature, official price/tariff lists and national population statistics. The primary perspective of the study was that of the Spanish National Health Service in 2006. Results: The base-case analysis included the direct medical costs associated with palivizumab prophylaxis and hospital care for RSV infections. Use of palivizumab produces an undiscounted incremental cost-effectiveness ratio (ICER) of €6,142 per quality-adjusted life-year (QALY), and a discounted ICER of €12,814/QALY. Conclusion: Palivizumab provides a cost-effective method of prophylaxis against severe RSV disease requiring hospitalisation among preterm infants in Spain

Multicultural mediations, developing world realities: Indians, Koreans and Manila’s entertainment media

In this article, I examine the mediation of multiculturalism in the developing world city of Manila, the Philippines. Drawing on both a thematic analysis of the Manila-centric Philippine entertainment media and six focus group discussions with the city’s local Filipinos, I reveal that this instance of mediation is entangled with the broader discourses of the Philippine postcolonial nationalist project. For one, the mediation of multiculturalism in Manila tends to symbolically marginalize the city’s Indians and Koreans and, in so doing, reinforces existing negative discourses about them. I contend that this is linked to the locals’ preoccupation with establishing a unifying cultural identity that tends to make them elide the issue of their own internal cultural diversity, as well as of the increasing diasporic population of the city. Second, the said mediation also tends to valorize the lighter-skinned Koreans over the darker-skinned Indians. I posit that this is related to how the locals’ discourse of cultural homogeneity has resulted in their continued reluctance to publicly discuss the persistence of their unspoken skin-tone-based racial hierarchy not only of themselves, but also of their cultural others

Micromechanical study of the load transfer in a polycaprolactone-collagen hybrid scaffold when subjected to unconfined and confined compression

Scaffolds are used in diverse tissue engineering applications as hosts for cell proliferation and extracellular matrix formation. One of the most used tissue engineering materials is collagen, which is well known to be a natural biomaterial, also frequently used as cell substrate, given its natural abundance and intrinsic biocompatibility. This study aims to evaluate how the macroscopic biomechanical stimuli applied on a construct made of polycaprolactone scaffold embedded in a collagen substrate translate into microscopic stimuli at the cell level. Eight poro-hyperelastic finite element models of 3D printed hybrid scaffolds from the same batch were created, along with an equivalent model of the idealized geometry of that scaffold. When applying an 8% confined compression at the macroscopic level, local fluid flow of up to 20 [Formula: see text]m/s and octahedral strain levels mostly under 20% were calculated in the collagen substrate. Conversely unconfined compression induced fluid flow of up to 10 [Formula: see text]m/s and octahedral strain from 10 to 35%. No relevant differences were found amongst the scaffold-specific models. Following the mechanoregulation theory based on Prendergast et al. (J Biomech 30:539-548, 1997. https://doi.org/10.1016/S0021-9290(96)00140-6 ), those results suggest that mainly cartilage or fibrous tissue formation would be expected to occur under unconfined or confined compression, respectively. This in silico study helps to quantify the microscopic stimuli that are present within the collagen substrate and that will affect cell response under in vitro bioreactor mechanical stimulation or even after implantation

Variation in Vector Competence for Dengue Viruses Does Not Depend on Mosquito Midgut Binding Affinity

Several factors, such as mosquito and virus genetics and environmental variables, determine the ability of mosquitoes to transmit dengue viruses. In this report, we describe new and important information that in some ways contradicts what is in the literature. Midgut infection barriers have been described as important determinants of virus transmission in mosquitoes but we found that virus binding to these midgut cells does not vary. When we compared binding of 8 different, low passage dengue viruses to mosquito midguts that were dissected out of Aedes aegypti mosquitoes (the main vectors of dengue) from Mexico and Texas, we found that there were no differences. Previously, we (and others) had shown that these same viruses differed significantly in replication and dissemination throughout the rest of the mosquito body, including the salivary glands, and therefore they differed greatly in their potential to be transmitted to humans. Thus, the data presented here are important considerations for future studies of vector competence and in determining strategies for control of dengue viruses in the vector

Smad gene expression in pulmonary fibroblasts: indications for defective ECM repair in COPD

Background: Chronic Obstructive Pulmonary Disease ( COPD) is characterized by defective extracellular matrix (ECM) turnover as a result of prolonged cigarette smoking. Fibroblasts have a central role in ECM turnover. The TGF beta induced Smad pathway provides intracellular signals to regulate ECM production. We address the following hypothesis: fibroblasts have abnormal expression of genes in the Smad pathway in COPD, resulting in abnormal proteoglycan modulation, the ground substance of ECM. Methods: We compared gene expression of the Smad pathway at different time points after stimulation with TGF beta, TNF or cigarette smoke extract (CSE) in pulmonary fibroblasts of GOLD stage II and IV COPD patients, and controls. Results: Without stimulation, all genes were similarly expressed in control and COPD fibroblasts. TGF beta stimulation: downregulation of Smad3 and upregulation of Smad7 occurred in COPD and control fibroblasts, indicating a negative feedback loop upon TGF beta stimulation. CSE hardly influenced gene expression of the TGF beta-Smad pathway in control fibroblasts, whereas it reduced Smad3 and enhanced Smad7 gene expression in COPD fibroblasts. Furthermore, decorin gene expression decreased by all stimulations in COPD but not in control fibroblasts. Conclusion: Fibroblasts of COPD patients and controls differ in their regulation of the Smad pathway, the contrast being most pronounced under CSE exposure. This aberrant responsiveness of COPD fibroblasts to CSE might result in an impaired tissue repair capability and is likely important with regard to the question why only a subset of smokers demonstrates an excess ECM destruction under influence of cigarette smoking