Tunable near-infrared Gires-Tournois resonators based on vanadium dioxide on gold film.

Vanadium dioxide (VO2) has been proposed as a phase-change material in tunable photonic and optoelectronic devices. In such devices, a thin layer of VO2 is typically deposited on metallic or insulating surfaces. In this Letter, we report the reflectance spectra of a subwavelength structure consisting of a thin layer of VO2 deposited on a gold film in the near-infrared spectral range, particularly near the wavelength of 1550 nm, which is significant for telecommunication applications. Our results indicate that in the insulating phase of VO2, the air/VO2/Au structure can be considered as a Gires-Tournois resonant cavity whose maximum absorption wavelength can be tuned by adjusting the thickness of the VO2 layer. In contrast, in the metallic phase of VO2, the reflectance of the structure increases by an amount of the order of a few tens of units. The proposed structure can prospectively lead to new design concepts in tunable photonic and optoelectronic devices.

Subwavelength resolution scanning diffracted-light microscopy using plasmonic ultra-thin condensers.

We used a rotating slit placed at the back focal plane of the microscope's objective lens to scan the light diffracted by a plasmonic crystal, which had a period smaller than the resolution limit of the optical microscope. A set of images were collected at different orientations of the slit. A high-resolution image of the plasmonic crystal was obtained by processing the experimental images using a numerical Fourier ptychographic algorithm. Supporting simulations of the experiments are also presented.

Scanning diffracted-light microscopy.

Scanning the direction of the light that is diffracted by a sample permits the achievement of image diversity, which is necessary for implementing the Fourier ptychographic microscopy technique (FPM) using only perpendicular illumination. We also demonstrated that the same method allows for implementation of the illumination-direction-multiplexing FPM technique when the sample is illuminated using a ring-shaped condenser.

Scanning diffracted-light photography using white-light and thermal radiation sources.

A 4-f imaging arrangement of lenses with a camera and a rotating slit placed at the Fourier plane of the system was used to obtain the optical disturbance produced by a macroscopic sample. The sample was illuminated by collimated beams from white-light and thermal radiation sources. The agreement between simulated and experimental results, obtained by processing the captured images using a Fourier ptychographic algorithm, demonstrates that scanning with the slit the direction of the light diffracted by the sample permits achieving the image diversity necessary for successful implementation of the scanning diffracted-light imaging technique.

Fourier ptychographic microscopy using an infrared-emitting hemispherical digital condenser.

Fourier ptychographic microscopy is demonstrated in the near-infrared spectral range using a computer-controlled hemispherical digital condenser comprising multiple 940 nm wavelength light emitting diodes. This technique was used to image periodic patterned samples (photonic crystals). Experimental and simulated results using a phase retrieval algorithm were found to be in excellent correspondence. We show that for samples with a single period in each direction, the resolution of the obtained high-resolution near-infrared images is limited by the Rayleigh criteria.

Hemispherical digital optical condensers with no lenses, mirrors, or moving parts.

We present a simple method for obtaining direct non-scanning images in the far-field with subwavelength resolution. Our approach relies on the use of a digital optical condenser comprised of an array of light emitting diodes uniformly distributed inside of a hollow hemisphere. We demonstrate experimental observation of minimum feature sizes of the order of λ/6 with the proposed technique. Although our experiments were performed at visible frequencies, we anticipate that the proposed approach to subwavelength resolution can be extended to the ultraviolet and infrared spectral regions.

Fundaments of optical far-field subwavelength resolution based on illumination with surface waves.

We present a general discussion about the fundamental physical principles involved in a novel class of optical superlenses that permit to realize in the far-field direct non-scanning images with subwavelength resolution. Described superlenses are based in the illumination of the object under observation with surface waves excited by fluorescence, the enhanced transmission of fluorescence via coupling with surface waves, and the occurrence of far-field coherence-related fluorescence diffraction phenomena. A Fourier optics description of the image formation based on illumination with surface waves is presented, and several recent experimental realizations of this technique are discussed. Our theoretical approach explains why images with subwavelength resolution can be formed directly in the microscope camera, without involving scanning or numerical post-processing. While resolution of the order of λ/7 has been demonstrated using the described approach, we anticipate that deeper optical subwavelength resolution should be expected.

Tunable dual-band terahertz metamaterial bandpass filters.

We report metamaterial terahertz (THz) bandpass filters with tunable dual-band selectivity. The shift in the center frequency of the device is achieved by actively modifying the effective length of the resonators. This was realized by introducing vanadium dioxide (VO2) bridges interconnecting specific regions of each resonator. Raising the temperature across the phase transition shifted the resonance frequency by ~32% due to changes in the electrical conductivity of the VO2. Measured THz transmission response of the proposed dual-band filter was in good correspondence with simulations.

Imaging nanoscale features with plasmon-coupled leakage radiation far-field superlenses.

Optical images from nano-scale features were obtained by collection of leakage radiation coupled to surface plasmon polaritons excited by near-field fluorescence. Plasmonic crystals with spatial periods as small as 190 nm and non-periodic features separated by 80 nm, corresponding to ~λ/7, were clearly visible in the real plane images using this far-field technique. We show that the leaked light from the investigated samples carries detailed information to the far-field which is not present in the images obtained with conventional optical microscopy.

Terahertz bandpass filters using double-stacked metamaterial layers.

Bandpass filters are reported based on double-stacked metamaterial layers separated by an air gap for operation at terahertz frequencies. Several stacking configurations were investigated designed for a ~0.5 THz center frequency. The filters exhibited improved spectral transmission properties when compared with conventional ones based on single metamaterial layers. 3 dB bandwidth of ~78 GHz and sidelobe suppression ratio >16 dB were determined when symmetric or asymmetric double layers were stacked. We demonstrate that superior frequency selectivity can be achieved when metamaterial layers with different unit cells are used. Good agreement was found between measured and simulated transmission response.

Improvement in vesicoureteral reflux grade on serial imaging predicts resolution.

PURPOSE: When children are initially diagnosed with vesicoureteral reflux most undergo a period of antibiotic prophylaxis followed by serial imaging. Although improvement in reflux grade through time presumably predicts eventual resolution, the significance of changing grade through time is unknown. We examined whether improvement in reflux on serial imaging predicts resolution. MATERIALS AND METHODS: We retrospectively reviewed 1,761 children diagnosed with vesicoureteral reflux, of whom 965 had a minimum of 2 years of followup. We examined initial reflux grade and grade on serial imaging up to 5 years after the original diagnosis. For each child it was determined whether reflux was resolved, eventually resolved or never resolved. Groups were further stratified by clinical characteristics. RESULTS: Multivariate analysis revealed that male gender (HR 1.33, p = 0.05), age younger than 1 year at diagnosis (HR 1.35, p = 0.004), lower grade at presentation (grade I HR 2.2, grade II HR 1.96, grade III HR 1.33; p <0.001) and unilateral reflux (HR 1.39, p = 0.001) were all independent predictors of reflux resolution. Multivariate analysis also showed that reflux improvement on imaging 1 year after diagnosis (HR 3.14, p <0.0001) and improvement from the previous year at any point during followup (HR 1.8, p = 0.009) were independent predictors of reflux resolution. CONCLUSIONS: Consistent with previous findings, male gender, lower reflux grade at presentation, age less than 1 year at presentation and unilateral reflux were all predictive of reflux resolution. Our analysis also demonstrated that improvement in reflux grade on imaging study 1 year after diagnosis was predictive of resolution, and that reflux improvement from the previous year at any point during followup was an independent predictor of resolution. This information will prove valuable in clinical counseling and therapeutic decision making.

Role of transport proteins in drug discovery and development: a pharmaceutical perspective.

1. This review will explore, from a pharmaceutical industry perspective, the evidence and consequences of transport protein involvement in pharmacokinetic variability and safety of drugs in humans. With the preclinical and clinical evidence available, the transport proteins that are considered to be the most important in respect of pharmacokinetic variability and safety in humans will be highlighted. 2. A large number of transport proteins have been identified, at both the genetic and the cellular level, which have been suggested to play some role in the absorption, distribution or elimination of endogenous, xenobiotic or drug substrates. 3. The weight of evidence suggests that only a small number of transport proteins need to be routinely considered in the drug-discovery setting driven by the magnitude of their impact on tissue distribution, pharmacokinetic variability and drug-drug interactions. 4. For the majority of candidate drugs, an assessment of the role of transporter proteins in their disposition and safety need only be assessed if in vivo properties suggest that active transport is likely to be a significant factor, if transport proteins are implicated in a particular therapeutic target area or if the disposition and safety of a likely co-medication are known to be significantly modulated by transport proteins.

Anthraflavic acid is a potent and specific inhibitor of cytochrome P-448 activity.

Consideration of the computer-optimised dimensions of anthraflavic acid indicates that it is essentially a planar molecule with a large area/depth ratio, that would preferentially interact with the polycyclic aromatic hydrocarbon-induced family of cytochrome P-450 proteins (cytochromes P-448). Anthraflavic acid was a potent inhibitor of the O-deethylations of ethoxycoumarin and ethoxyresorufin, both catalysed primarily by cytochromes P-448, in Arochlor-1254-induced hepatic microsomes. Similarly anthraflavic acid markedly inhibited the mutagenicity of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (Glu-P-I) in the Ames test. In contrast, it has no effect on the dealkylation of pentoxyresorufin, a reaction catalysed primarily by the phenobarbital-induced cytochromes P-450, and NADPH-dependent reduction of cytochrome c. It is concluded that anthraflavic acid is a potent and specific inhibitor of cytochrome P-448 activity.

Versatile optical microscopy using a reconfigurable hemispherical digital condenser.

We present a computer-controlled hemispherical digital condenser and demonstrate that a single device can be used to implement a variety of both well established and novel optical microscopy techniques. We verified the condenser capabilities by imaging fabricated periodic patterned structures and biological samples.

Induction of the cytochrome P450 I and IV families and peroxisomal proliferation in the liver of rats treated with benoxaprofen. Possible implications in its hepatotoxicity.

Administration of the non-steroidal anti-inflammatory drug benoxaprofen to rats gave rise to significant increases in the hepatic O-dealkylations of ethoxyresorufin and methoxyresorufin and in the 12-hydroxylation of lauric acid but, in contrast, the N-demethylation of dimethylnitrosamine was inhibited. Immunoblot studies employing solubilized microsomes from benoxaprofen-treated rats revealed that benoxaprofen increased the apoprotein levels of P450 IA1 and A2 and of P450 IVA1. The same treatment with benoxaprofen increased the beta-oxidation of palmitoyl CoA determined in liver homogenates, and immunoblot analysis showed an increase in the apoprotein levels of the trans-2-enoyl CoA hydratase bifunctional protein. It is concluded that benoxaprofen is a peroxisomal proliferator which selectively induces the hepatic cytochrome P450 I and IV families. The possible implications of these findings to the well-known hepatotoxicity of this drug are discussed.

Induction of the rat hepatic microsomal mixed-function oxidases by two aza-arenes. A comparison with their non-heterocyclic analogues.

The ability of the aza-aromatic polycyclic aromatic hydrocarbons 10-azobenz(a)pyrene and benz(a)acridine to induce the rat hepatic microsomal mixed-function oxidases was compared to that of their non-heterocyclic analogues benz(a)pyrene and benz(a)anthracene respectively. All four hydrocarbons markedly increased the O-deethylations of ethoxyresorufin and ethoxycoumarin, the non-heterocyclic analogues being the more potent. A more modest increase was seen in the O-dealkylation of pentoxyresorufin. All four hydrocarbons induced proteins recognised by antibodies to cytochrome P-450IAI but no increase was seen when antibodies to cytochrome P-450IIB1 were employed. The metabolic activation of benz(a)pyrene and Glu-P-1 to mutagenic intermediates in the Ames test was enhanced by all pretreatments. It is concluded that the aza-aromatic polycyclic hydrocarbons, like their non-heterocyclic analogues, selectively induce the cytochrome P-450I family of proteins.

The interaction of omeprazole with rat liver cytochrome P450-mediated monooxygenase reactions in vitro and in vivo.

The effect of omeprazole on cytochrome P450-mediated monooxygenase reactions was assessed in rat liver S9 utilising ethylmorphine-N-demethylase (EM) and ethoxycoumarin-O-deethylase (ECOD) activities. The inhibition of EM by omeprazole was judged to be predominantly reversible in mechanism. The average Ki for omeprazole was 40 +/- 27 microM with EM and 76 +/- 6 microM with ECOD in four separate rats. In preparations of rat hepatocytes the intrinsic clearance of diazepam was decreased substantially by 50 microM omeprazole (average inhibition 73%). In comparison 50 microM cimetidine inhibited the intrinsic clearance of diazepam by 50%. The relationship between these two in vitro models for drug interactions is discussed in the context of previously published drug inhibition data. Moreover, repeated administration of omeprazole to adult male rats (500 mg.kg-1, 14 days, p.o.) resulted in statistical increases in liver weight, cytochrome P450 and ECOD activity. Thus omeprazole interacts with the mixed function oxidase system in vitro and in vivo.

A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene.

The contributions of the hepatic microsomal and cytosolic fractions in the metabolic activation of the promutagen 2-aminofluorene into mutagenic intermediates in the Ames test were investigated. Rat hepatic postmitochondrial, microsomal and cytosolic preparations could convert 2-aminofluorene to mutagens, the postmitochondrial preparation being the most and cytosol the least efficient. Pretreatment of the rats with Aroclor 1254 markedly enhanced the cytosol-mediated mutagenicity of the amine but increased microsomal- and postmitochrondrial-mediated mutagenicity only modestly. The cytosol-mediated mutagenicity of 2-aminofluorene was abolished by heat treatment and by incubation with proteinase K, but was unaffected by dialysis emphasising the protein nature of the cytosolic activation system. Oxygen radical generating systems and oxygen radical scavengers did not significantly influence the cytosol-mediated mutagenic response. Similarly incorporation of xanthine or allopurinol into the cytosolic activation system did not modulate the mutagenic response indicating no role for the molybdenum oxygenases. The cytosolic activation of 2-aminofluorene differed from that mediated by the microsomes in cofactor requirement, substrate specificity and sensitivity to DMSO and (+)-catechin. Further centrifugation of the cytosolic fraction to remove any microsomal contamination did not decrease the cytosolic activation of 2-aminofluorene. It is concluded that the hepatic cytosol contains an oxygenase activity capable of activating certain aromatic amines.

Induction of the P-450 I family of proteins by polycyclic aromatic hydrocarbons: possible relationship to their carcinogenicity.

The hypothesis has been put forward that mutagenic polycyclic aromatic hydrocarbons which induce the P-450 I family of cytochromes, the major enzyme system responsible for their activation, are likely to be carcinogenic. In order to test this hypothesis, rats have been pretreated with a number of polycyclic aromatic hydrocarbons of different mutagenic and carcinogenic potency and hepatic P-450 I activity was monitored using chemical probes such as the O-deethylation of ethoxyresorufin and metabolic activation of Glu-P-1 to mutagens, and immunologically employing polyclonal antibodies against purified rat P-450 I A1. All compounds studied enhanced P-450 I activity and induced P-450 I apoproteins but the extent of induction was very markedly different. The results are discussed with reference to the mutagenicity of these chemicals in the Ames test and their carcinogenicity in the classical mouse skin model. A relationship appears to exist between carcinogenicity of polycyclic aromatic hydrocarbons and their ability to induce hepatic P-450 I activity.

Application of liquid chromatography-mass spectrometry(n) analyses to the characterization of novel glyburide metabolites formed in vitro.

The application of bench-top ion-trap atmospheric pressure ionization mass spectrometry in the characterization of in vitro metabolites of glyburide is discussed. The metabolites formed in vitro by rat, dog, monkey and human liver microsomes were separated by reversed-phase high-performance liquid chromatography (HPLC) and characterized by mass spectrometry (MS)n experiments. The utility of data dependent MS1-MS2-MS3 analyses, where the mass spectrometer makes "real-time" decisions about the experiment to be performed, are described using the characterization of two novel metabolites of glyburide as an example. The metabolite profiles from each species were similar. Six cyclohexyl hydroxylation products were detected, as well as two novel monooxygenation products formed via hydroxylation of the ethyl chain at the benzylic position, and alpha to the amide nitrogen. The ion-trap with electrospray ionization proved to be a sensitive and reliable HPLC detection system that provided important chemical structure information.