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Compounds of formula (I), or a pharmaceutically acceptable salts or solvates thereof : wherein -X- represents a group of formula (a), (b), (c), (d), (e), (f) or (g) : Being selective inhibitors of human MEK (MAPKK) enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive

Bioremediation is a widely accepted technology for the remediation of hydrocarbon-contaminated soil. Treatability studies are usually carried out to assess the biodegradation potential of the contaminants and to design optimal treatments. Laboratory studies measuring soil respiration are often used. One method consists of monitoring the mineralization of a 14C-labeled hydrocarbon surrogate added to the contaminated soil. This study investigates the ability of this method to properly predict the removal of the hydrocarbon contaminants initially found in soils. Mineralization of 14C-labeled hexadecane was monitored in seven soils contaminated with various hydrocarbon mixtures, both fresh and weathered, in microcosm experiments. Reduction of total petroleum hydrocarbon (TPH) concentrations was measured simultaneously in separate microcosms. Both types of microcosms were subjected to the same amendment regimes. For all soils, poor correlation was observed between the mineralization and TPH reduction ...

Background: Calciphylaxis is a rare disorder that is very unusual outside the setting of end-stage kidney disease. Case Summary: A 64-year-old woman with normal renal function presented with painful leg ulcers. She had previously received 300 000 IU of vitamin D3 followed by daily calcium and vitamin D3 supplementation. A skin biopsy was consistent with calciphylaxis, and she was treated with sodium thiosulphate infusions and wound debridement. Conclusion: Calcium and vitamin D3 supplements are widely prescribed. We report a case of calciphylaxis triggered by calcium and vitamin D3 supplementation in a patient with none of the typical risk factors. Our patient had an excellent response to treatment with sodium thiosulphate.

The survival of yeast during a pilot scale production of commercial salami was investigated. A total of 108 distinctive yeast strains were isolated and identified during the processing of the salami. Initially, the number of yeasts remained below 10 3 cfu g −1 but their numbers increased after the 12 th day of maturation, reaching a maximum of 2·0×10 5 cfu g −1 at day 20. During maturation, the pH declined from 5·72 to 4·36, water content from 58% to 43%, while the salt content increased by 1%. The number of lactic acid bacteria remained above 10 5 cfu g −1 throughout processing and maturation. Of the 108 yeast strains isolated, 22 strains were identified as members of the species Debaryomyces hansenii , being present in all samples taken. In descending numbers, Rhodotorula mucilaginosa, Yarrowia lipolytica and Cryptococcus albidus , were also frequently isolated during processing and maturation.

Sediment and water chemistry data were collected from ten lakes within a 110 km radius of Noril'sk in Siberia, the largest smelting complex in the world. Metals showing the most pronounced increase in enrichment near the smelters were Cu, Ni, Co, Ba and Zn. Cu and Ni appear to be as or more enriched in lake sediments around Noril'sk compared with levels previously reported for other locations. Although SO4 concentrations were highly elevated in the areas closest to the smelting complex, lake water pH remained elevated due to high concentrations of base cations in the waters. Sediment mercury enrichment was high in sediments near the smelting complex, but not more so than in other parts of the Arctic, suggesting that Hg either is not a major smelting product at Noril'sk, or that Hg is transported greater distances than other metals due to its longer atmospheric residence time.

The role of adult nutrition in longevity, progeny production, and offspring sex ratio of Trichogramma minutum Riley was examined. On average, honey-fed females lived 26.4 days and produced 260 offspring; unfed females lived 3.5 days and produced 80 offspring. Feeding on fructose or sucrose also significantly increased longevity and fecundity over unfed females (fructose, 23 days and 230 offspring; sucrose, 21 days and 230 offspring) but to a lesser degree than feeding on pure honey. Females fed yeast suspension or water had no significant increases in longevity or fecundity compared to unfed females. Offspring sex ratios of long-lived females were male-biased (50–62% males), those of short-lived females were female-biased (74–82% females). Lifetime reproduction of honey-fed females was highest at 20–25 °C and relative humidities of 20–80%, but short-term offspring production (during the first 2 days after emergence) was highest at 30 °C and 60–80% RH. Females that had access to honey for only a 24-h period did not increase their offspring production over the first 4 days of their lives when compared to unfed females. The potential benefits of feeding adult T. minutum for mass-rearing and field release are discussed.

Muon resonance studies show that muonium atoms (Mu) in ethanol add selectively to certain C-sites of aromatic compounds containing -Cl and -OH substituents. The sites chosen seem to be those carrying the lowest electron density. This helps to characterize Mu as a nucleophile in addition reactions and, in this respect, Mu differs from ordinary H-atoms. The study shows no apparentinter-molecular selectivity between a pair of aromatic solutes in an equimolar mixture, but strongintra-molecular selectivity in an ether composed of those two aromatic rings. This difference between intra- and inter-molecular selectivity is interpreted as kinetic in origin — arising from the ‘caging effect’ of the solvent and peculiar to reactions close to the diffusion-controlled limit.

Cydia pomonella (L.), a major pest of apples in Canadian orchards, is susceptible to a granulosis virus (CpGV). Orchard trials with different formulations of CpGV in Ontario, whereC. pomonella has two generations per year, indicated that as many as seven applications of virus would be needed to maintain the percentage of fruit with deep larval entries below 4%. In Nova Scotia, where there is only one generation ofC. pomonella per year, two applications of CpGV usually were needed although, in some cases, one sufficed. The protection of fruit conferred by CpGV equalled that by the organophosphate insecticides, azinphosmethyl or phosmet, in some tests. The advantages of a selective treatment, such as CpGV, over use of broad-spectrum insecticides are discussed.

The chemical speciation of zinc- and tin(II)-containing dentrifices and of the reaction between saliva and such toothpastes has been researched using computer simulation. Pivotal formulation variables have been identified (phosphates, fluorides, citrate, etc.) and optimised to suggest formulations having maximum availability, of antimicrobial metal salts Zn2+ (aq) and soluble tin(II) species. Although the concept of having a single dentifrice in which both the zinc and the soluble tin(II) species are maximised together is desirable, it is concluded that at a single pH value, there cannot be maximal availability for both species, but it is possible to achieve levels of antimicrobial metal salts superior to a dentifrice containing either ingredient alone.

The RET (rearranged-during-transfection protein) protooncogene triggers multiple intracellular signaling cascades regulating cell cycle progression and cellular metabolism. We therefore hypothesized that metabolic imaging could allow noninvasive detection of response to the RET inhibitor vandetanib in vivo.The effects of vandetanib treatment on the full-genome expression and the metabolic profile were analyzed in the human medullary thyroid cancer cell line TT. In vitro, transcriptional changes of pathways regulating cell cycle progression and glucose, dopa, and thymidine metabolism were correlated to the results of cell cycle analysis and the uptake of (3)H-deoxyglucose, (3)H-3,4-dihydroxy-L-phenylalanine, and (3)H-thymidine under vandetanib treatment. In vivo, the tumor metabolism under vandetanib was monitored by small-animal PET of tumor-bearing mice.Vandetanib treatment resulted in the transcriptional downregulation of various effector pathways with consecutive downregulation of cyclin expression and a G(0)/G(1) arrest. In vitro, vandetanib treatment resulted in the decreased expression of genes regulating glucose, 3,4-dihydroxy-L-phenylalanine, and thymidine metabolism, with a subsequent reduction in the functional activity of the corresponding pathways. In vivo, metabolic imaging with PET was able to assess changes in the tumoral glucose metabolism profile as early as 3 d after initiation of vandetanib treatment.We describe a metabolic imaging approach for the noninvasive detection of successful vandetanib treatment. Our results suggest that PET may be useful for identifying patients who respond to vandetanib early in the course of treatment.

A variety of robust and model-dependent genetic linkage methods were applied to log transformed lipid levels from a large pedigree in which the LDL receptor defect has been shown to segregate by molecular biologic techniques. Applicationof the Haseman-Elston and avariance-components based test for linkage identified LDL and cholesterol as cosegregating with the marker C3, which is genetically linked to the LDL receptor defect. Consideration of lipid fractions as a multivariate response identified (0.723×cholesterol)-(0.55 1×triglycerides) as most strongly supporting evidence for linkage with C3. Subsequent segregation and linkage analyses provided support for an autosomal dominant major gene influencing either LDL or the function of cholesterol and triglycerides

Synthesis of the terminally disubstituted rigid rod molecules, [n]staffane-3,3 (n-1) -dithiols, n = 1-4, and their singly functionalized derivatives carrying and acetyl or a pentaammineruthenium(II), [Ru(NH 3 ) 5 ] 2+ , substituent is described. Self-assembled monolayers of the neat [n]staffane derivatives and of their mixtures with n-alkyl thiols were prepared on polycrystalline gold electrodes

Previous results of the comparison of colors given by indicators in alkaline buffers and pure aqueous sodium hydroxide have been repeated and confirmed. The electrometric determinations show that the sodium hydroxide was pure and gave theoretical values for the concentration of hydroxyl ion. The slight but distinct neutralising effect of dilute solutions of alkali has been measured electrometrically and the allowances to be made are recorded graphically. It is found that whereas alizarin yellow G, tropæolin O and thymol violet may be used without appreciable error (in accordance with our previous communication) the grave discrepancies remain for phenolphthalein, o-cresol phthalein and thymol blue and phenol red which must be ascribed to salt error in the alkaline buffer itself.

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Gemcitabine (2′,2′-difluorodeoxycytidine, dFdC) and cytosine arabinoside (cytarabine, ara-C) represent a class of nucleoside analogs used in cancer chemotherapy. Administered as prodrugs, dFdC and ara-C are transported across cell membranes and are converted to cytotoxic derivatives through consecutive phosphorylation steps catalyzed by endogenous nucleoside kinases. Deoxycytidine kinase (DCK) controls the rate-limiting step in the activation cascade of dFdC and ara-C. DCK activity varies significantly among individuals and across different tumor types and is a critical determinant of tumor responses to these prodrugs. Current assays to measure DCK expression and activity require biopsy samples and are prone to sampling errors. Noninvasive methods that can detect DCK activity in tumor lesions throughout the body could circumvent these limitations. Here, we demonstrate an approach to detecting DCK activity in vivo by using positron emission tomography (PET) and 18 F-labeled 1-(2′-deoxy-2′-fluoroarabinofuranosyl) cytosine] ([ 18 F]FAC), a PET probe recently developed by our group. We show that [ 18 F]FAC is a DCK substrate with an affinity similar to that of dFdC. In vitro, accumulation of [ 18 F]FAC in murine and human leukemia cell lines is critically dependent on DCK activity and correlates with dFdC sensitivity. In mice, [ 18 F]FAC accumulates selectively in DCK-positive vs. DCK-negative tumors, and [ 18 F]FAC microPET scans can predict responses to dFdC. We suggest that [ 18 F]FAC PET might be useful for guiding treatment decisions in certain cancers by enabling individualized chemotherapy.

The toxicity of the insecticides permethrin, azinphosmethyl, and methomyl to adult Pholetesor ornigis (Weed) and P. pedias Nixon was evaluated in laboratory bioassays. Older P. pedias (2 and 3 days old) were more susceptible than younger parasites (1 day old) to permethrin. Azinphosmethyl was slightly more toxic to female P. ornigis than to male P. ornigis or to P. pedias. There was no consistent difference in the response of adult P. ornigis compared with P. pedias exposed to permethrin or methomyl on treated paper disks. Methomyl was twice as toxic as either azinphosmethyl or permethrin. Male P. ornigis were less susceptible than female P. ornigis to permethrin, but the difference was significant in only one of four populations tested. Male P. ornigis were less susceptible than females to azinphosmethyl. In 1986, populations of P. ornigis which had been exposed previously to pyrethroid insecticides were less susceptible to permethrin than P. ornigis from orchards where pyrethroids had never been applied. The response of both Pholetesor spp. to permethrin varied significantly from 1986 to 1987.

The protection of apples against damage by the codling moth,Laspeyresia pomonella (L.), by applications of the granulosis virus ofL. pomonella was assessed in apple orchard tests at 4 locations in Canada in 1974–1978. Sprays containing 3×109 to 4×1010 granules/litre, applied 2 or 3 times per generation of codling moth larvae, reduced injury to apples by 44 to 85% compared to reductions of 72 to 98% by applications of azinphos-methyl or phosmet. Applications of the virus did not reduce numbers of arthropods predaceous on pest insects and mites.

A strain of Trichogramma minutum Riley collected from codling moth (CM) Cydia pomonella (L.) in southern Ontario was studied to assess its potential as a biological control agent for that species. The threshold temperature and degree-days (°D) far development were found ta be 128°D10.2 Feeding the wasps diluted honey increased fecundity 6-fold and longevity 9-fald aver unfed wasps. Unmated females lived longer than the mated females but their fecundities were not significantly different. Longevity and fecundity at 25°C were 25.5 days and 236.8 eggs per female. Longevity varied inversely, while daily fecundity varied directly with temperatures between 15 and 35°C. At 35°C, however, fecundity decreased considerably, signifying an adverse effect of high temperature. T. minutum preferred eggs of CM and ariental fruit moth, Grapholitha molesta (Busck), to those of Mediterranean flour moth (MFM), Anagasta kuehniella (Zeller), and oblique-banded leaf-roller, Choristoneura rosaceana Harris, even though they had been reared on MFM eggs for about 22 generations. Parasitism of CM eggs depended on the age of the eggs and density of the parasitoid. Residues af the insecticides permethrin and phosmet on apple leaves significantly lowered rates of parasitization by T. minutum on eggs of CM far mare than 16 days. Residues af azinphosmethyl and phosalone, however, were virtually nontoxic 16 days after application.

The effects of the administration of oestrogens on the activity of hepatic tryptophan oxygenase have been assessed both directly (by measurement of enzyme activity in vitro) and indirectly (by measurement of urinary excretion of tryptophan metabolites) in rats, and indirectly in menopausal women receiving hormone replacement therapy. Intraperitoneal administration of 500 micrograms of oestradiol or ethinyl oestradiol/kg body wt had no effect on the activity of tryptophan oxygenase in homogenates of liver from mature (13-week-old) female rats. Both adrenalectomy and ovariectomy led to a reduction in the activity of tryptophan oxygenase in homogenates of liver from mature rats; again there was no effect of giving 500 micrograms of oestradiol/kg body wt by intraperitoneal injection. Intraperitoneal administration of 210 micrograms of oestrone sulphate/kg body wt for 1 or 2 days before killing, or its incorporation in the diet for up to 8 weeks at an equivalent dose rate, had no effect on the activity of tryptophan oxygenase in homogenates of liver from ovariectomized 6-14-week-old female rats. Intraperitoneal administration of 500 micrograms oestradiol/kg body wt to intact mature female rats together with 500 mg tryptophan/kg body wt caused a reduction in the urinary excretion of xanthurenic and kynurenic acids, kynurenine and N1-methyl nicotinamide. When peri- and post-menopausal women were treated with ethinyl oestradiol (20 micrograms/day) or piperazine oestrone sulphate (3 mg/day) for 3 months, there was an increase in the concn of tryptophan in plasma, with no change in the urinary excretion of xanthurenic and kynurenic acids and kynurenine. This study provides no evidence for the induction of tryptophan oxygenase by oestrogens in rats or human beings.

TEN years ago we found that two portions of the same solution of soap could be brought into the states of either sol or typically transparent jelly respectively at the same temperature, and that such significant properties as conductivity, lowering of vapour pressure, concentration of sodium ion as measured with the sodium amalgam electrode, etc., were identical in both these states. Sol and jelly differed only in mechanical properties such as rigidity and elasticity. We therefore drew the obvious conclusion that the rigid structure of the jelly must be built up by progressive linkings together of the particles which pre-existed in the sol (Trans. Ghem. Soc, London, 117, 1506; 1920).