Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1)

Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration inf

Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs.

2.5 weeks) resumption of SSZ resistance and ABCG2 expression as in the original CEM/SSZ cells. CEM/SSZ cells displayed diminished sensitivity to the DMARDs leflunomide (5.1-fold) and methotrexate (1.8-fold), were moderately more sensitive (1.6-2.0 fold) to cyclosporin A and chloroquine, and markedly more sensitive (13-fold) to the glucocorticoid dexamethasone as compared with parental CEM cells. CONCLUSION: The drug efflux pump ABCG2 has a major role in conferring resistance to SSZ. The collateral sensitivity of SSZ resistant cells for some other (non-related) DMARDs may provide a further rationale for sequential mono- or combination therapies with distinct DMARDs upon decreased efficacy of SSZ

International Veterinary Epilepsy Task Force consensus report on epilepsy definition, classification and terminology in companion animals

Dogs with epilepsy are among the commonest neurological patients in veterinary practice and therefore have historically attracted much attention with regard to definitions, clinical approach and management. A number of classification proposals for canine epilepsy have been published during the years reflecting always in parts the current proposals coming from the human epilepsy organisation the International League Against Epilepsy (ILAE). It has however not been possible to gain agreed consensus, “a common language”, for the classification and terminology used between veterinary and human neurologists and neuroscientists, practitioners, neuropharmacologists and neuropathologists. This has led to an unfortunate situation where different veterinary publications and textbook chapters on epilepsy merely reflect individual author preferences with respect to terminology, which can be confusing to the readers and influence the definition and diagnosis of epilepsy in first line practice and research studies. In this document the International Veterinary Epilepsy Task Force (IVETF) discusses current understanding of canine epilepsy and presents our 2015 proposal for terminology and classification of epilepsy and epileptic seizures. We propose a classification system which reflects new thoughts from the human ILAE but also roots in former well accepted terminology. We think that this classification system can be used by all stakeholders

Implementation of Dynamical Nucleation Theory Effective Fragment Potentials Method for Modeling Aerosol Chemistry

In this work, the dynamical nucleation theory (DNT) model using the ab initio based effective fragment potential (EFP) is implemented for evaluating the evaporation rate constant and molecular properties of molecular clusters. Predicting the nucleation rates of aerosol particles in different chemical environments is a key step toward understanding the dynamics of complex aerosol chemistry. Therefore, molecular scale models of nanoclusters are required to understand the macroscopic nucleation process. On the basis of variational transition state theory, DNT provides an efficient approach to predict nucleation kinetics. While most DNT Monte Carlo simulations use analytic potentials to model critical sized clusters, or use ab initio potentials to model very small clusters, the DNTEFP Monte Carlo method presented here can treat up to critical sized clusters using the effective fragment potential (EFP), a rigorous nonempirical intermolecular model potential based on ab initio electronic structure theory calculations, improvable in a systematic manner. The DNTEFP method is applied to study the evaporation rates, energetics, and structure factors of multicomponent clusters containing water and isoprene. The most probable topology of the transition state characterizing the evaporation of one water molecule from a water hexamer at 243 K is predicted to be a conformer that contains six hydrogen bonds, with a topology that corresponds to two water molecules stacked on top of a quadrangular (H2O)4 cluster. For the water hexamer in the presence of isoprene, an increase in the cluster size and a 3-fold increase in the evaporation rate are predicted relative to the reaction in which one water molecule evaporates from a water hexamer cluster

Abnormal motor activity during anaesthesia in a dog: a case report

Seizures or convulsions that occur during anaesthesia in veterinary patients are infrequently reported in the literature. Consequently, the incidence of such events is unknown. Several drugs commonly used in clinical veterinary anaesthesia have been shown to induce epileptiform activity in both human clinical patients and experimental candidates. The present case report describes convulsions in a four-year old male Bernese mountain dog during maintenance of anaesthesia with isoflurane after premedication with acepromazine and methadone followed by co-induction with propofol and ketamine. The dog had no history of previous convulsions. The use of several sedative and anaesthetic drugs makes it difficult to find one single causative pharmaceutical

Structural neuroimaging biomarkers for obsessive-compulsive disorder in the ENIGMA-OCD consortium: medication matters

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker

Hydrophobically Modified Sulfobetaine Copolymers with Tunable Aqueous UCST through Postpolymerization Modification of Poly(pentafluorophenyl acrylate)

Polysulfobetaines, polymers carrying highly polar zwitterionic side chains, present a promising research field by virtue of their antifouling properties, hemocompatibility, and stimulus-responsive behavior. However, limited synthetic approaches exist to produce sulfobetaine copolymers comprising hydrophobic components. Postpolymerization modification of an activated ester precursor, poly(pentafluorophenyl acrylate), employing a zwitterionic amine, 3-((3-aminopropyl)dimethylammonio)propane-1-sulfonate, ADPS, is presented as a novel, one-step synthetic concept toward sulfobetaine (co)polymers. Modifications were performed in homogeneous solution using propylene carbonate as solvent with mixtures of ADPS and pentylamine, benzylamine, and dodecylamine producing a series of well-defined statistical acrylamido sulfobetaine copolymers containing hydrophobic pentyl, benzyl, or dodecylacrylamide comonomers with well-controllable molar composition as evidenced by NMR and FT-IR spectroscopy and size exclusion chromatography.This synthetic strategy was exploited to investigate, for the first time, the influence of hydrophobic modification on the upper critical solution temperature (UCST) of sulfobetaine copolymers in aqueous solution. Surprisingly, incorporation of pentyl groups was found to increase solubility over a wide composition range, whereas benzyl groups decreased solubility—an effect attributed to different entropic and enthalpic contributions of both functional groups. While UCST transitions of polysulfobetaines are typically limited to higher molar mass samples, incorporation of 0–65 mol % of benzyl groups into copolymers with molar masses of 25.5–34.5 kg/mol enabled sharp, reversible transitions from 6 to 82 °C in solutions containing up to 76 mM NaCl, as observed by optical transmittance and dynamic light scattering. Both synthesis and systematic UCST increase of sulfobetaine copolymers presented here are expected to expand the scope and applicability of these smart materials