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IN order to describe accurately the kinetics of nucleophilic substitutions carried out under alkaline conditions in aqueous alcoholic solutions, in which both hydroxy and alkoxy groups are introduced, it is necessary to know the equilibrium constant (K) of the reaction: in order to calculate the respective concentrations of the two ions.

EAG, ERG and ELK are members of the Ether-a-go-go voltage-gated potassium channel family. Each channel possesses a C-terminal domain that is homologous to the cyclic nucleotide-binding domain (CNBD) of CNG/HCN channels but insensitive to cyclic nucleotides. X-ray crystallography of EAG suggests the side chains of two residues, Y699 and L701, interact in a manner analogous to the two moieties of a cyclic nucleotide in the binding pocket of bona fide CNBDs. Using two-electrode voltage clamp of channel proteins expressed in Xenopus oocytes, we found that alanine substitutions of Y699 and L701 (“AA”) dramatically slowed activation and shifted the g-V curve by +15 mV. Mutagenesis of both residues were required to elicit an effect, as if the “apo” configuration required the loss of both side chains. Thus, the intrinsic ligand of the CNB homology domain (CNBhD) reduces the stability of the closed state relative to the open state. To determine whether the AA mutant phenotype represents a loss of function, we deleted the CNBhD. In contrast to the AA mutant, the deletion gave rise to faster activation kinetics but a more dramatic g-V shift of +40 mV. This finding indicates that, unlike HCN channel, in which the unliganded CNBD mimics the CNBD deletion, the AA mutant phenotype is not a loss of function of the CNBhD. Instead, both the intrinsically-liganded and apo conformations communicate with the gating machinery. The current properties can be recapitulated by a 7-state allosteric model, in which the AA mutant alters multiple transitions during channel gating whereas CNBhD deletion affects only the last opening step. We conclude that the EAG1 CNBhD serves a function mechanistically distinct from those of the corresponding domains in channels gated by cyclic nucleotides despite extensive sequence and structural homology.

Recently, Garnick et al. (New Engl.J.Med., 1979, 301,252) observed transient thyroxine-binding-globulin (TBG) deficiency in adults during asparaginase therapy. We have studied 6 children with acute lymphoblastic leukemia who were treated with a combination of L-asparaginase, prednisolone, vincristine and daunomycin for inducing remission. Thyroid function was monitored by measuring total thyroxine (T4), free thyroxine (FT4), triiodothyronine (T3), TSH and TBG with specific RIA. Within 3 weeks T4 fell rapidly from 10.4 ± 1.9 (mean ± SD) to 3.3 ± 2.6/ug/100 ml, FT4 from 1.7 ± 0.55 to 1.0 ± 0.5 ng/100 ml, T3 from 1.0 ± 2.7 to 0.26 ± 0.04 ng/ml and TBG from 28.2 ± 1.9 to 9.4 ± 5.2/ug/ml. TSH exhibited only a moderate decrease within normal limits. While on a maintenance therapy (cyclophosphamide, cytosine arabinoside and 6-mercaptopurine) these values became normal within 2 to 3 weeks. In 2 of 5 patients FT4 was extremely low (< 0.3 and 0.7 ng/100 ml) which is not sufficiently explained by a transient deficiency of TBG. We speculate that some patients might suffer from a special form of transient hypothyroidism during asparaginase therapy caused by acute inhibition of TSH and/or TRH synthesis.

Plasma amino acids were found to deviate extensively from normal in patients with end-stage uremia. Concentrations of all essential amino acids except phenylalanine and methionine were reduced. Progressive impairment of reabsorption of amino acids by the kidney is found as glomerular filtration rate (GFR) falls, renal clearances increasing fivefold to fortyfold at GFR less than 10 ml/min. Impairment of absorption of amino acids by the small intestine may explain the abnormal plasma curves after oral loading with tryptophan. These and other abnormalities may be the basis for development of abnormal protein metabolism in chronic, progressive renal failure in man.

Marshall and Medley have drawn attention to the possible influence of the cation on the diffusion of acid dyes in nylon1 and express doubts as to the general validity of the explanation offered by McGregor, Peters and Petropoulos2 for the rapid increase with concentration of the diffusion coefficient of an acid dye anion in nylon.

The uncatalysed addition of primary and secondary amines to vinyl sulphones and sulphonamides in polar aprotic solvents has been shown to be of the first order with respect to vinyl groups and of the second order with respect to amine. The reactions are retarded by the addition of a tertiary amine. A mechanism is suggested in which the initial step is the addition of the amine itself to the double bond to form a solvent-stabilised dipolar intermediate which then reacts with a second molecule of amine. The addition of secondary amines is much slower than that of primary, probably for steric reasons.Polymers with high intrinsic viscosities in 90% formic acid have been formed from bifunctional vinyl compounds and hexamethylene-1,6-diamine.

Background:The clinical differentiation between gout, osteoarthritis (OA), and calcium pyrophosphate deposition disease (CPPD) still remains a hurdle in daily practice without imaging or arthrocentesis. Although a plethora of clinical data exists, reliable predictor biomarkers for all but gout are still missing.Objectives:To explore an association between common physical examination, ultrasound and laboratory findings and gout, OA, and CPPD, which can in turn provide reliable diagnostic predictions.Methods:277 patients were retrospectively analysed using ANOVA with Scheffe’s post hoc tests and conditional inference trees regarding biomarkers such as age, sex, body mass index, hypertension, renal status, cumulative affected joint size, number of afflicted joints, double contour sign, intracartiliginous double contour sign, degree of vascularization on ultrasound (DoV), uric acid, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, and leucocyte count. Simple linear regressions were carried out to explore associations between increased inflammatory parameters and the above-mentioned biomarkers. Statistically significant associations were defined as p values < 0.05.Results:The male sex was associated with gout (p value < 0.05 vs CPPD and < 0.05 vs OA). OA affected younger patients than CPPD (mean 64.5 vs 73.1 years, p < 0.05). Hypertension was correlated with gout (p < 0.05) and CPPD (p < 0.05), impaired renal status with gout when compared to OA (p < 0.05) but not compared to CPPD (p 0.21). A higher number of involved joints was associated with gout (mean 2.2 joints) compared to OA (1.0, p < 0.05) and CPPD (1.6, p 0.01). The double contour sign was not able to differentiate gout and CPPD with a sensitivity/specificity of 71%/55% for gout and 59%/39% for CPPD. The intracartilaginous double contour sign was specific for CPPD (99%) but with a low sensitivity of 26%. DoV was significantly associated with gout (vs OA, p < 0.05) and CPPD (vs OA, p < 0.05). Unsurprisingly, uric acid was associated with gout while ESR and CRP were increased in gout and CPPD, but not in OA. Some associations were statistically significant but arguably clinically unimportant. Conditional inference trees were able to exclude OA (specificity 97.5%) and CPPD (specificity 94.0%) as possible differentials based on just uric acid, CRP, hypertension, and sex, and diagnose gout with a sensitivity of 95.1%, summarized in Figure 1. Linear regressions demonstrated an elevated CRP response in people suffering from type II diabetes, higher cumulative joint points score, number of affected joints, as well as elevated uric acid, ESR, and leucocyte count.Figure 1.Conditional inference tree using unbiased recursive partitioning to reliably differentiate between gout, osteoarthritis, and calcium pyrophosphate deposition disease.Conclusion:Gout can be reliably diagnosed, simultaneously excluding OA and CPPD as differential diagnoses by conditional inference trees using just four biomarkers. A correlation between inflammatory reaction severity based on CRP levels was found in patients suffering from type II diabetes, more or larger joint involvement and elevated uric acid levels. The double contour sign remains a questionable differentiator between gout and CPPD with a sensitivity/specificity of 71%/55% for gout and 59%/39% for CPPD, similar to findings reported by Löffler et al (1) with a sensitivity/specificity of only 64%/52% for gout.References:[1]Löffler C, Sattler H, Peters L, Löffler U, Uppenkamp M, Bergner R. Distinguishing gouty arthritis from calcium pyrophosphate disease and other arthritides. J Rheumatol 2015; 42(3):513–20.Disclosure of Interests:Dmitrij Kravchenko Shareholder of: Pfizer, Raoul Bergner: None declared, Charlotte Behning: None declared, Valentin Schäfer Speakers bureau: AbbVie, Novartis, BMS, Chugai, Celgene, Medac, Sanofi, Lilly, Hexal, Pfizer, Janssen, Roche, Schire, Onkowissen, Royal College London, Consultant of: Novartis, Chugai, AbbVie, Celgene, Sanofi, Lilly, Hexal, Pfizer, Amgen, BMS, Roche, Gilead, Medac, Grant/research support from: Novartis, Hexal, Lilly, Roche, Celgene, Universität Bonn.

Peroxisome proliferator-activated receptor alpha (PPARalpha)is a nuclear receptor for various fatty acids, eicosanoids, and hypolipidemic drugs. In the presence of ligand, this transcription factor increases expression of target genes that are primarily associated with lipid homeostasis. We have previously reported PPARalpha as a nuclear receptor of the inflammatory mediator leukotriene B(4) (LTB(4)) and demonstrated an anti-inflammatory function for PPARalpha in vivo (Devchand, P. R., Keller, H., Peters, J. M., Vazquez, M., Gonzalez, F. J., and Wahli, W. (1996) Nature 384, 39-43). LTB(4) also has a cell surface receptor (BLTR) that mediates proinflammatory events, such as chemotaxis and chemokinesis (Yokomizo, T., Izumi, T., Chang, K., Takuwa, Y., and Shimizu, T. (1997) Nature 387, 620-624). In this study, we report on chemical probes that differentially modulate activity of these two LTB(4) receptors. The compounds selected were originally characterized as synthetic BLTR effectors, both agonists and antagonists. Here, we evaluate the compounds as effectors of the three PPAR isotypes (alpha, beta, and gamma) by transient transfection assays and also determine whether the compounds are ligands for these nuclear receptors by coactivator-dependent receptor ligand interaction assay, a semifunctional in vitro assay. Because the compounds are PPARalpha selective, we further analyze their potency in a biological assay for the PPARalpha-mediated activity of lipid accumulation. These chemical probes will prove invaluable in dissecting processes that involve nuclear and cell surface LTB(4) receptors and also aid in drug discovery programs.

Roth H., Peters-Gerth P. and Lucas K., 1992. Experimental vapor-liquid equilibria in the systems R 22-R 23, R 22-CO 2 , CS 2 -R 22, R 23-CO 2 , CS 2 -R 23 and their correlation by equations of state. Fluid Phase Equilibria , 73: 147-166. Vapor-liquid equilibria in systems with polar molecules tend to show a rather complex phase behavior. In order to investigate the phase boundaries in mixtures of dipolar and quadrupolar components five binary systems of the components R 22, R 23, CO 2 and CS 2 have been selected. Experimental VLE data for the systems R 22-R 23, R 22-CO 2 , CS 2 -R 22, R 23-CO 2 and CS 2 -R 23 are reported in this paper at temperatures between 254 and 473 K and pressures up to 25 MPa. The data were correlated with one empirical and one semi-empirical equation of state.

A method of determining the dependence on dye concentration of the diffusion coefficient of dyes in fibrous substrates has been developed, based on an approximation method of Crank, in which the amount of dye adsorbed by the fibre is measured colorimetrically as a function of time. The method has been applied to two dyeing systems, the direct dye Chlorazol Sky Blue FF (C. I. Direct Blue 1) on rayon and the acid dye Naphthalene Scarlet 4R (C. I. Acid Red 18) on nylon 6. 6. The results are in good agreement with those of R. H. Peters et al. for the same dyes and substrates, although Peters used films and not fibres and determined diffusion coefficients by an experimentally more complex method that appears impractical for fibres, the film being sectioned and the dye concentration measured as a function of distance with a microdensitometer.