Assessment of increasing intravenous adenosine dose in fractional flow reserve.

BACKGROUND: Effects of increased adenosine dose in the assessment of fractional flow reserve (FFR) were studied in relation to FFR results, hemodynamic effects and patient discomfort. FFR require maximal hyperemia mediated by adenosine. Standard dose is 140 µg/kg/min administrated intravenously. Higher doses are commonly used in clinical practice, but an extensive comparison between standard intravenous dose and a high dose (220 µg/kg/min) has previously not been performed. METHODS: Seventy-five patients undergoing FFR received standard dose adenosine, followed by high dose adenosine. FFR, mean arterial pressure (MAP) and heart rate (HR) were analyzed. Patient discomfort measured by Visual Analogue Scale (VAS) was assessed. RESULTS: No significant difference was found between the doses in FFR value (0.85 [0.79-0.90] vs 0.85 [0.79-0.89], p = 0.24). The two doses correlated well irrespective of lesion severity (r = 0.86, slope = 0.89, p = <0.001). There were no differences in MAP or HR. Patient discomfort was more pronounced using high dose adenosine (8.0 [5.0-9.0]) versus standard dose (5.0 [2.0-7.0]), p = <0.001. CONCLUSIONS: Increased dose adenosine does not improve hyperemia and is associated with increased patient discomfort. Our findings do not support the use of high dose adenosine. TRIAL REGISTRATION: Retrospective Trial registration: Current Controlled Trials ISRCTN14618196 . Registered 15 December 2016.

Fractionation of wheat and barley straw to access high-molecular-mass hemicelluloses prior to ethanol production.

The cost efficiency of the biorefining process can be improved by extracting high-molecular-mass hemicelluloses from lignocellulosic biomass prior to ethanol production. These hemicelluloses can be used in several high-value-added applications and are likely to be important raw materials in the future. In this study, steam pretreatment in an alkaline environment was used to pretreat the lignocellulosic biomass for ethanol production and, at the same time, extract arabinoxylan with a high-molecular-mass. It was shown that 30% of the arabinoxylan in barley straw could be extracted with high-molecular-mass, without dissolving the cellulose. The cellulose in the solid fraction could then be hydrolysed with cellulase enzymes giving a cellulose conversion of about 80-90% after 72 h. For wheat straw, more than 40% of the arabinoxylan could be extracted with high-molecular-mass and the cellulose conversion of the solid residue after 72 h was about 70-85%. The high cellulose conversion of the pretreated wheat and barley straw shows that they can be used for ethanol production without further treatment. It is therefore concluded that it is possible to extract high-molecular-mass arabinoxylan simultaneously with the pretreatment of biomass for ethanol production in a single steam pretreatment step.

Extraction of water-soluble hemicelluloses from barley husks.

Heat treatment of barley husks was performed to extract arabinoxylan with high yield and high weight-averaged molecular mass (M(W)). Microwave irradiation was employed for initial screening of suitable residence times (2-15 min), temperatures (120-210 degrees C) and initial pH (3-13) of the reaction slurry. Microwave irradiation was shown to be a good method for predicting the effects of heat treatment on a larger scale using steam pretreatment. A M(W) of about 40,000 Da was achieved without the addition of chemicals, by both microwave irradiation and steam pretreatment, with a yield of about 9%. The yield was significantly increased by slightly increasing the severity factor. However, the M(W) decreased below 20,000 Da at severity factors above 3.7. Arabinosyl side groups were enzymatically hydrolysed from the arabinoxylan by alpha-L-arabinofuranosidase to a degree of 47%, demonstrating the ability to specifically alter the side group substitution of arabinoxylans with the use of enzymes.

Pyrazole carboxamides and carboxylic acids as protein kinase inhibitors in aberrant eukaryotic signal transduction: induction of growth arrest in MCF-7 cancer cells.

Densely functionalised pyrazole carboxamides and carboxylic acids were synthesised in an expedient manner through saponification and transamidation, respectively, of ester-functionalised pyrazoles. This synthetic protocol allowed for three diversifying steps in which appendages on the pyrazole scaffold were adjusted to optimise inhibition of protein kinases. Thirty-five analogues were tested in CK2, AKT1, PKA, PKCalpha, and SAPK2a (p38) kinase inhibition bioassays. Blocking of these kinases may lead to effective therapies for treating inflammatory diseases and cancer. In order to investigate potential biological activity, MCF-7 human breast cancer cells were incubated with the most promising derivatives. Two analogues caused changes in MCF-7 cell growth, one of them through cell cycle arrest demonstrated by cell cycle analysis.

Economic evaluation of isolation of hemicelluloses from process streams from thermomechanical pulping of spruce.

Hemicelluloses, which are abundant in nature and have potential use in a wide variety of applications, may make an important contribution in helping relieve society of its dependence on petrochemicals. However, cost-efficient methods for the isolation of hemicelluloses are required. This article presents an economic evaluation of a full-scale process to isolate hemicelluloses from process water from a thermomechanical pulp mill. Experimental data obtained in laboratory scale were used for the scale up of the process by computer simulation. The isolation method consisted of two process steps. The suspended matter in the process water was removed by microfiltration and thereafter the hemicelluloses were concentrated by ultrafiltration, and at the same time, separated from smaller molecules and ions in the process water. The isolated hemicelluloses were intended for the production of oxygen barriers for food packaging, an application for which they have been shown to have suitable properties. The solution produced contained 30 g hemicelluloses/L with a purity (defined as the ratio between the hemicelluloses and the total solids) of approx 80%. The evaluation was performed for a plant with a daily production of 4 metric tonnes (t) of hemicelluloses, which is the estimated future need of barrier films at Tetra Pak (Lund, Sweden). The production cost was calculated to be 670 euros/t of hemicelluloses. This is approx 9 times lower than the price of ethylene vinyl alcohol, which is produced by petrochemicals and is currently used as an oxygen barrier in fiber-based packaging materials. This indicates that it is possible to produce oxygen barriers made of hemicelluloses at a price that is competitive with the materials used today.

Comparison of diafiltration and size-exclusion chromatography to recover hemicelluloses from process water from thermomechanical pulping of spruce.

Hemicelluloses constitute one of the most abundant renewable resources on earth. To increase their utilization, the isolation of hemicelluloses from industrial biomass side-streams would be beneficial. A method was investigated to isolate hemicelluloses from process water from a thermomechanical pulp mill. The method consists of three steps: removal of solids by microfiltration, preconcentration of the hemicelluloses by ultrafiltration, and purification by either size-exclusion chromatography (SEC) or diafiltration. The purpose of the final purification step is to separate hemicelluloses from small oligosaccharides, monosaccharides, and salts. The ratio between galactose, glucose, and mannose in oligo- and polysaccharides after preconcentration was 0.8:1:2.8, which is similar to that found in galactoglucomannan. Continuous diafiltration was performed using a composite fluoro polymer membrane with cutoff of 1000 Da. After diafiltration with four diavolumes the purity of the hemicelluloses was 77% (gram oligo- and polysaccharides/gram total dissolved solids) and the recovery was 87%. Purification by SEC was performed with 5, 20, and 40% sample loadings, respectively and a flow rate of 12 or 25 mL/min (9 or 19 cm/h). The purity of hemicelluloses after SEC was approx 82%, and the recovery was above 99%. The optimal sample load and flow rate were 20% and 25 mL/min, respectively. The process water from thermomechanical pulping of spruce is inexpensive. Thus, the recovery of hemicelluloses is not of main importance. If the purity of 77%, obtained with diafiltration, is sufficient for the utilization of the hemicelluloses, diafiltration probably offers a less expensive alternative in this application.

Synthesis of N-methoxy-N-methyl-beta-enaminoketoesters: new synthetic precursors for the regioselective synthesis of heterocyclic compounds.

[Structure: see text] Weinreb amides react with the lithium or sodium acetylide of ethyl propynoate in a hitherto unexplored acyl substitution-conjugate addition sequence to furnish (E)-N-methoxy-N-methyl-beta-enaminoketoesters. This approach provides a diverse entry to densely functionalized heterocyclic compounds, including pyrazoles through regioselective cyclocondensations with hydrazines in a microwave-assisted reaction.

Quorum sensing inhibition: targeting chemical communication in gram-negative bacteria.

Quorum sensing (QS) systems comprise a new therapeutic target potentially substitutive or complementary to traditional antibiotic treatment of chronic diseases. One route to disrupt the previously established interrelationship between pathogenesis and QS is by blocking the dual functioning signal/receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural analogs of the native signaling molecules and the other compounds lacking structural resemblance. Biological activity is rationalized on the basis of structure-activity relationships and structural insight into the target protein.

Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic.

Parallel solution-phase synthesis of sulfide AHL analogues (10a-s) by one-pot or a sequential approach is reported. The corresponding sulfoxides 13a-e and sulfones 14a-e were prepared to expand the diversity of the 19-member array of sulfides . Likewise, dithianes 12a-c were prepared with similarity both to sulfides 10a-s and to bioactive structures from garlic. Design and biological screening of all compounds presented in this work targeted inhibition of quorum-sensing comprising competitive inhibition of transcriptional regulators LuxR and LasR. The design was based on critical interactions within the binding-site and structural motifs in molecular components isolated from garlic, 7 and 8, shown to be quorum-sensing inhibitors but not antibiotics. A potent quorum-sensing inhibitor N-(heptylsulfanylacetyl)-l-homoserine lactone (10c) was identified. Together with data collected for the other analogues, the resulting structure-activity relationship led to a hypothesis in which competitive binding was assumed.

Synthesis of furanone-based natural product analogues with quorum sensing antagonist activity.

The synthesis of 5- and 3-(1'-hydroxyalkyl)-substituted 5H-furan-2-ones 4a-d and 8a-d as well as 5-alkylidene-5H-furan-2-ones 5a-d is described. A study of the structure-activity relationship of these furanone-based natural product analogues towards two different quorum sensing systems is reported. Although the synthesized compounds are not as potent quorum sensing inhibitors as some natural counterparts and a synthetic analogue hereof, interesting structure-activity relationships are seen.