A novel application of ratio spectra derivative spectroscopy for the determination of amphotericin in highly icteric plasma.

Derivative spectroscopy has been utilised for the determination of amphotericin in various biological matrices including plasma, serum, urine and brain tissue. Whilst these methods have all been shown to be suitable for the determination of the drug in these matrices it has been reported that the application fails in the case of highly icteric plasma, this being due to the presence of high concentrations (>50 mu M) of bilirubin. This paper details the application of ratio spectra derivative spectroscopy to overcome the interference of bilirubin with amphotericin in such situations.

HDQ (1-hydroxy-2-dodecyl-4(1H)quinolone), a high affinity inhibitor for mitochondrial alternative NADH dehydrogenase

Alternative NADH dehydrogenases (NADH:ubiquinone oxidoreductases) are single subunit respiratory chain enzymes found in plant and fungal mitochondria and in many bacteria. It is unclear how these peripheral membrane proteins interact with their hydrophobic substrate ubiquinone. Known inhibitors of alternative NADH dehydrogenases bind with rather low affinities. We have identified 1-hydroxy-2-dodecyl-4(1H)quinolone as a high affinity inhibitor of alternative NADH dehydrogenase from Yarrowia lipolytica. Using this compound, we have analyzed the bisubstrate and inhibition kinetics for NADH and decylubiquinone. We found that the kinetics of alternative NADH dehydrogenase follow a ping-pong mechanism. This suggests that NADH and the ubiquinone headgroup interact with the same binding pocket in an alternating fashion.

Fasciola hepatica: Histological changes in the reproductive structures of triclabendazole (TCBZ)-sensitive and TCBZ-resistant flukes after treatment in vivo with TCBZ and the related benzimidazole derivative, Compound Alpha

Twenty-four shed-reared lambs were each infected orally with 250 metacercariae of Fasciola hepatica, using either the triclabendazole (TCBZ)-sensitive Cullompton isolate or the TCBZ-resistant Sligo isolate. Twelve weeks after infection the lambs were treated with TCBZ (10 mg/kg) or with the experimental fasciolicide, Compound Alpha (Cpd alpha), a benzimidazole derivative of TCBZ (15 mg/kg). The lambs were euthanised 48,72 and 96 h after TCBZ treatment, or 24, 48 and 72 h after Cpd a treatment, and flukes were collected from the liver and/or gall bladder of each animal. Untreated animals harbouring 12-week infections were euthanised 24 h after administration of anthelmintic to the treatment groups, and the untreated flukes provided control material. A semi-quantitative assessment of the degree of histological change induced by the two drugs after different times of exposure was achieved by scoring the intensity of three well-defined lesions that developed in the testes and uteri of a representative sample of flukes from each lamb. In general, it was found that in those tissues where active meiosis and/or mitosis occurred (testis, ovary, and vitelline follicles), there was progressive loss of cell content due to apparent failure of cell division to keep pace with expulsion of the mature or effete products. Further, actively dividing cell types tended to become individualised, rounded and condensed, characteristic of apoptotic cell death. Protein synthetic activity was apparently inhibited in the Mehlis' secretory cells. In the uterus, where successful formation of shelled eggs represents the culmination of a complex sequence of cytokinetic, cytological and synthetic activity involving the vitelline follicles, the ovary and the Mehlis' gland, histological evidence indicating failure of ovigenesis was evident from 24 h post-treatment onwards. The development of these lesions may be related to the known antitubulin activity of the benzimidazole class of anthelmintics, to the induction of apoptosis in cells where mitosis or meiosis has aborted due to failure of spindle formation, and to drug-induced inhibition of protein synthesis. The semi-quantitative findings indicated that Cpd a is slightly less efficacious than TCBZ itself in causing histological damage to the reproductive structures of TCBZ-sensitive flukes, and that, like TCBZ, it caused no histological damage in flukes of the TCBZ-resistant isolate. This study illustrates the potential utility of histological techniques for conveniently screening representative samples of flukes in field trials designed to validate instances of drug resistance or to test the efficacy of new products against known drug-resistant and drug-susceptible fluke isolates. It also provides reference criteria for drug-induced histopathological changes in fluke reproductive structures which may aid interpretation of TEM findings. (C) 2009 Elsevier B.V. All rights reserved.

Molecular characterization and phylogenetic analysis of quinolone resistance-determining regions (QRDRs) of gyrA, gyrB, parC and parE gene loci in viridans group streptococci isolated from adult patients with cystic fibrosis

This study demonstrated key resistance genes to fluroquinilones in Streptococcci isolated from sputum of people with CF. This suggests that other bacteria which are sometimes considered commensal may be a resovoir for resistance. Jse designed the study with Moore.

The triazatruxene derivative azatrux binds to the parallel form of the human telomeric G-quadruplex under molecular crowding conditions: Biophysical and molecular modeling studies

The present study has employed a combination of spectroscopic, calorimetric and computational methods to explore the binding of the three side-chained triazatruxene derivative, termed azatrux, to a human telomeric G-quadruplex sequence, under conditions of molecular crowding. The binding of azatrux to the tetramolecular parallel [d(TGGGGT)](4) quadruplex in the presence and absence of crowding conditions, was also characterized. The data indicate that azatrux binds in an end-stacking mode to the parallel G-quadruplex scaffold and highlights the key structural elements involved in the binding. The selectivity of azatrux for the human telomeric G-quadruplex relative to another biologically relevant G-quadruplex (c-Kit87up) and to duplex DNA was also investigated under molecular crowding conditions, showing that azatrux has good selectivity for the human telomeric G-quadruplex over the other investigated DNA structures. (C) 2011 Elsevier Masson SAS. All rights reserved.

Cryptic plasmid pKA22 isolated from the naphthalene degrading derivative of Rhodococcus rhodochrous NCIMB13064

Cryptic plasmids were found in Rhodococcus rhodochrous NCIMB13064 derivatives which had lost the ability to utilize short-chain 1-chloroalkanes (chain length C-3-C-10) and had acquired the ability to degrade naphthalene. The reversions of these derivatives to the original phenotype were accompanied by the loss of the cryptic plasmids. The 4969-bp pKA22 plasmid was cloned in Escherichia coli and sequenced. This plasmid encodes a putative 33,200-Da protein which contains motifs typical of theta replicase proteins and shows a high degree of similarity to a putative theta replicase from Brevibacterium linens plasmid pRBL1 and to a putative protein encoded by ORF1 of the plasmid pAL5000 from Mycobacterium fortuitum. Two sets of long direct repeats were found in pKA22 which may be involved in the replication of the plasmid and recombination processes. (C) 1997 Academic Press.

Optimal proportional-integral-derivative control of shape memory alloy actuators using genetic algorithm and the Preisach model

Shape memory alloy (SMA) actuators, which have the ability to return to a predetermined shape when heated, have many potential applications in aeronautics, surgical tools, robotics, and so on. Although the number of applications is increasing, there has been limited success in precise motion control owing to the hysteresis effect of these smart actuators. The present paper proposes an optimization of the proportional-integral-derivative (PID) control method for SMA actuators by using genetic algorithm and the Preisach hysteresis model.

Ciprofloxacin use and susceptibility of Gram-negative organisms to quinolone and non-quinolone antibiotics

A Trust strategy to reduce ciprofloxacin use was implemented at a University hospital. This study aimed to investigate whether the susceptibility of Gram-negative organisms (GNO) to alternative antimicrobials (co-amoxiclav, doxycycline, aztreonam, piperacillin/tazobactam, meropenem and gentamicin) changed, and whether there was any relationship between GNO susceptibility to these antimicrobials and ciprofloxacin usage.