Ionic Mechanisms of Spinal Neuronal Cold Hypersensitivity in Ciguatera

Cold hypersensitivity is evident in a range of neuropathies and can evoke sensations of paradoxical burning cold pain. Ciguatoxin poisoning is known to induce a pain syndrome caused by consumption of contaminated tropical fish that can persist for months and include pruritus and cold allodynia; at present no suitable treatment is available. These studies for the first time examine neural substrates and molecular components of Pacific ciguatoxin-2 induced cold hypersensitivity. Electrophysiological recordings of dorsal horn lamina V/VI wide dynamic range neurones were made in non-sentient rats. Subcutaneous injection of 10 nM ciguatoxin-2 into the receptive field increased neuronal responses to innocuous and noxious cooling. In addition, neuronal responses to low threshold but not noxious punctate mechanical stimuli were also elevated. The resultant cold hypersensitivity was not reversed by M8-An, an antagonist of TRPM8. Both mechanical and cold hypersensitivity were completely prevented by co-injection with Nav1.8 antagonist A803467, whereas TRPA1 antagonist A967079 only prevented hypersensitivity to innocuous cooling and partially prevented hypersensitivity to noxious cooling. In naïve rats, neither innocuous nor noxious cold evoked neuronal responses were inhibited by antagonists of Nav1.8, TRPA1 or TRPM8 alone. Ciguatoxins may confer cold sensitivity to a subpopulation of cold-insensitive Nav1.8/TRPA1+ primary afferents, which could underlie cold allodynia reported in ciguatera. These data expand the understanding of central spinal cold sensitivity under normal conditions and the role of these ion channels in this translational rat model of ciguatoxin induced-hypersensitivity. This article is protected by copyright. All rights reserved

Classification of river morphology and hydrology to support management and restoration

The work leading to this paper has received funding from the European Union’s FP7 programme under Grant Agreement No. 282656 (REFORM

Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

Conceptual comparison of constructs as first step in data harmonization: Parental sensitivity, child temperament, and social support as illustrations

This article presents a strategy for the initial step of data harmonization in Individual Participant Data syntheses, i.e., making decisions as to which measures operationalize the constructs of interest - and which do not. This step is vital in the process of data harmonization, because a study can only be as good as its measures. If the construct validity of the measures is in question, study results are questionable as well. Our proposed strategy for data harmonization consists of three steps. First, a unitary construct is defined based on the existing literature, preferably on the theoretical framework surrounding the construct. Second, the various instruments used to measure the construct are evaluated as operationalizations of this construct, and retained or excluded based on this evaluation. Third, the scores of the included measures are recoded on the same metric. We illustrate the use of this method with three example constructs focal to the Collaboration on Attachment Transmission Synthesis (CATS) study: parental sensitivity, child temperament, and social support. This process description may aid researchers in their data pooling studies, filling a gap in the literature on the first step of data harmonization. • Data harmonization in studies using combined datasets is of vital importance for the validity of the study results. • We have developed and illustrated a strategy on how to define a unitary construct and evaluate whether instruments are operationalizations of this construct as the initial step in the harmonization process. • This strategy is a transferable and reproducible method to apply to the data harmonization process

Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma

There is currently no standard salvage chemotherapy regimen in relapsed and refractory lymphoma. Gemcitabine is a novel nucleoside analogue, which acts synergistically with cisplatin both in vitro and in clinical studies. We evaluated the combination of gemcitabine, cisplatin and methylprednisolone (GEM-P) in 41 heavily pretreated patients with relapsed and refractory Hodgkin's and non-Hodgkin's lymphoma. The best-achieved response rate (RR) was 79% (95% CI 64–91), with a complete RR of 21%. In patients with chemo-resistant disease, the RR was 63%. Myelosuppression was the main toxicity, the incidence of Grade 3 or 4 anaemia, neutropenia and thrombocytopenia was 17.1, 61.0 and 53.7% respectively. Only one patient had neutropenic sepsis and none of the patients suffered from haemorrhage. Grade 3 or 4 nonhaematological toxicity was minimal and stem cell mobilisation was not inhibited. GEM-P is an effective salvage regimen and its use prior to autologous stem cell transplant warrants further investigation

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Acidic motif responsible for plasma membrane association of the voltage-dependent calcium channel β1b subunit

Voltage-dependent calcium channels consist of a pore-forming transmembrane α1-subunit, which is known to associate with a number of accessory subunits, including α2-δ- and β-subunits. The β-subunits, of which four have been identified (β1–4), are intracellular proteins that have marked effects on calcium channel trafficking and function. In a previous study, we observed that the β1b-subunit showed selective plasma membrane association when expressed alone in COS7 cells, whereas β3 and β4 did not. In this study, we have examined the basis for this, and have identified, by making chimeric β-subunits, that the C-terminal region, which shows most diversity between β-subunits, of β1b is responsible for its plasma membrane association. Furthermore we have identified, by deletion mutations, an 11-amino acid motif present in the C terminus of β1b but not in β3 (amino acids 547–556 of β1b, WEEEEDYEEE), which when deleted, reduces membrane association of β1b. Future research aims to identify what is binding to this sequence in β1b to promote membrane association of this calcium channel subunit. It is possible that such membrane association is important for the selective localization or clustering of particular calcium channels with which β1b is associated

Patient-reported outcomes of brentuximab vedotin in Hodgkin lymphoma and anaplastic large-cell lymphoma

Robert Chen,1 Suzanne Allibone,2 Nancy L Bartlett,3 Pauline Brice,4 Andy Chen,5 Katrina Pose,6 Lynn Rich,7 Vijay Bonthapally,8 Phillip M Garfin,9 Michelle Fanale10 1Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA; 2The Lymphoma Service of the Christie NHS Foundation Trust, Manchester, UK; 3Department of Medical Oncology, Washington University School of Medicine, St Louis, MO, USA; 4Department of Hemato-Oncology, Hôpital Saint-Louis, Paris, France; 5Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 6Lymphoma and Cancer Survivorship Stanford Comprehensive Cancer Center, Stanford, CA, 7Lymphoma Program, James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, 8Millennium Pharmaceuticals Inc., Cambridge, MA, 9Seattle Genetics, Inc., Bothell, WA, 10Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: Patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) or R/R systemic anaplastic large-cell lymphoma (sALCL) treated with brentuximab vedotin (BV) experienced high remission rates in two Phase II trials. With increased response rates and survival times, patient-reported outcomes (PROs) and health-related quality of life (HRQoL) are becoming increasingly important and can help inform treatment decisions to enhance care of cancer patients.Objective: The objective was to qualitatively assess HRQoL in long-term survivors treated with BV.Methods: An eight-question survey assessing PRO-related aspects was developed and fielded to a subset of patients with HL or sALCL who remained in long-term follow-up after completing BV treatment in the two pivotal studies.Results: The survey was completed by 25 of 38 patients (12 with HL, 13 with sALCL). The majority of patients reported that their energy level, outlook on life, difficulties with daily activities, ability to participate in physical activities, and overall HRQoL improved compared to those before BV treatment.Limitations: Small sample size and lack of a baseline questionnaire or validated assessment instrument limit broad applicability of these findings to large populations of patients with HL or sALCL.Conclusion: This is the first report of BV PRO data in R/R HL and sALCL. Given the patients’ poor prognostic outcomes before stem cell transplant, these encouraging results warrant formal evaluation of PRO end points in BV trials. Keywords: patient well-being, brentuximab vedotin, health-related quality of life, pilot study, activities of daily livin