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Background Atorvastatin and metformin are known energy restricting mimetic agents that act synergistically to produce molecular and metabolic changes in advanced prostate cancer (PCa). This trial seeks to determine whether these drugs favourably alter selected parameters in men with clinically-localized, aggressive PCa. Methods/design This prospective phase II randomized, controlled window trial is recruiting men with clinically significant PCa, confirmed by biopsy following multiparametric MRI and intending to undergo radical prostatectomy. Ethical approval was granted by the Royal Brisbane and Women's Hospital Human and The University of Queensland Medical Research Ethics Committees. Participants are being randomized into four groups: metformin with placebo; atorvastatin with placebo; metformin with atorvastatin; or placebo alone. Capsules are consumed for 8 weeks, a duration selected as the most appropriate period in which histological and biochemical changes may be observed while allowing prompt treatment with curative intent of clinically significant PCa. At recruitment and prior to RP, participants provide blood, urine and seminal fluid. A subset of participants will undergo 7Tesla magnetic resonance spectroscopy to compare metabolites in-vivo with those in seminal fluid and biopsied tissue. The primary end point is biochemical evolution, defined using biomarkers (serum prostate specific antigen; PCA3 and citrate in seminal fluid and prostatic tissue). Standard pathological assessment will be undertaken. Discussion This study is designed to assess the potential synergistic action of metformin and atorvastatin on PCa tumour biology. The results may determine simple methods of tumour modulation to reduce disease progression.

Bruising of the mesocarp in avocado fruit is an important postharvest issue for the industry. Proton magnetic resonance imaging (H-1-MRI) was used as a non-destructive tool to monitor bruise expression over time in avocado cv. Hass fruit. H-1-MRI clearly identified fruit morphological features and bruised mesocarp tissue. The pixel intensity value of T-2 weighted spin echo H-1-MRI images of avocado fruit pericarp changed over time with fruit softening. Bruised mesocarp tissue in impacted fruit appeared relatively hyperintense (brighter) in T-2 weighted H-1-MRI images. For firm ripe fruit impacted from 25 cm drop height (0.38 J +/- 0.004) and for firm ripe fruit impacted from 50 cm drop height (0.81 J +/- 0.011), hyper-intensity in the mesocarp beneath the impact point was evident immediately after impact. However, visible symptoms of bruising in the form of flesh browning did not appear in parallel serial destructive assessments until after day 1 following impact on day 0. The brown, bruised mesocarp volume in ripe fruit increased progressively over the assessment period of 3 days. This trend was evident in destructive assessments as well as in H-1-MRI images. In hard green mature fruit impacted from 100 cm drop height (1.68 J +/- 0.020), contrast between mesocarp tissue beneath the impact site and surrounding sound mesocarp was evident in T-2 weighted H-1-MRI images from day 0. However, no bruise symptoms were evident as flesh browning upon serial destructive assessments of fruit over the 3 days assessment period. The average pixel intensity values at the impact site in T-2 weighted H-1-MRI images for both firm ripe and hard green mature fruit decreased over the period of assessment. In contrast, the pixel intensities in the T-2 weighted H-1-MRI images of diseased flesh increased over time. (C) 2014 Elsevier B.V. All rights reserved.

An optimal current density map is crucial in magnet design to provide the initial values within search spaces in an optimization process for determining the final coil arrangement of the magnet. A strategy for obtaining globally optimal current density maps for the purpose of designing magnets with coaxial cylindrical coils in which the stored energy is minimized within a constrained domain is outlined. The current density maps obtained utilising the proposed method suggests that peak current densities occur around the perimeter of the magnet domain, where the adjacent peaks have alternating current directions for the most compact designs. As the dimensions of the domain are increased, the current density maps yield traditional magnet designs of positive current alone. These unique current density maps are obtained by minimizing the stored magnetic energy cost function and therefore suggest magnet coil designs of minimal system energy. Current density maps are provided for a number of different domain arrangements to illustrate the flexibility of the method and the quality of the achievable designs.

Human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) catalyses the synthesis of the purine nucleoside monophosphates, IMP and GMP, by the addition of a 6-oxopurine base, either hypoxanthine or guanine, to the 1-beta-position of 5-phospho-U-D-ribosyl-1-pyrophosphate (PRib-PP). The mechanism is sequential, with PRib-PP binding to the free enzyme prior to the base. After the covalent reaction, pyrophosphate is released followed by the nucleoside monophosphate. A number of snapshots of the structure of this enzyme along the reaction pathway have been captured. These include the structure in the presence of the inactive purine base analogue, 7-hydroxy [4,3-d] pyrazolo pyrimidine (HPP) and PRib-PP. Mg2+, and in complex with IMP or GMP. The third structure is that of the immucillinHP.Mg2+.PPi complex, a transition-state analogue. Here, the first crystal structure of free human HGPRT is reported to 1.9 angstrom resolution, showing that significant conformational changes have to occur for the substrate(s) to bind and for catalysis to proceed. Included in these changes are relative movement of subunits within the tetramer, rotation and extension of an active-site alpha-helix (D137-D153), reorientation of key active-site residues K68, D137 and K165, and the rearrangement of three active-site loops (100-128, 165-173 and 186-196). Toxoplasina gondii HGXPRT is the only other 6-oxopurine phosphoribosyltransferase structure solved in the absence of ligands. Comparison of this structure with human HGPRT reveals significant differences in the two active sites, including the structure of the flexible loop containing K68 (human) or K79 (T gondii). (c) 2005 Elsevier Ltd. All rights reserved.

Ultem irradiated up to 10.0 MGy has been analysed using C-13, H-1 and D-2 proton-carbon and proton-proton correlation NMR spectroscopy to shed light on the formation of new structures. Chemical shifts and correlation data were used to determine the structure or partial structures of several new components. The spectra indicated the presence of new groups and structures involving the isopropylidene group, the imide ring, and hydrogen-abstraction reactions. Possible pathways for formation of the new structures are proposed and the G-values for their formation have been estimated. (C) 2003 Elsevier Science Ltd. All rights reserved.

The aim of this work is to develop 3-acyl prodrugs of the potent analgesic morphine-6-sulfate (M6S). These are expected to have higher potency and/or exhibit longer duration of analgesic action than the parent compound. M6S and the prodrugs were synthesized, then purified either by recrystallization or by semi-preparative HPLC and the structures confirmed by mass spectrometry, IR spectrophotometry and by detailed 1- and 2-D NMR studies. The lipophilicities of the compounds were assessed by a combination of shake-flask, group contribution and HPLC retention methods. The octanol-buffer partition coefficient could only be obtained directly for 3-heptanoylmorphine-6-sulfate, using the shake-flask method. The partition coefficients (P) for the remaining prodrugs were estimated from known methylene group contributions. A good linear relationship between log P and the HPLC log capacity factors was demonstrated. Hydrolysis of the 3-acetyl prodrug, as a representative of the group, was found to occur relatively slowly in buffers (pH range 6.15-8.01), with a small buffer catalysis contribution. The rates of enzymatic hydrolysis of the 3-acyl group in 10% rat blood and in 10% rat brain homogenate were investigated. The prodrugs followed apparent first order hydrolysis kinetics, with a significantly faster hydrolysis rate found in 10% rat brain homogenate than in 10% rat blood for all compounds. (C) 1998 Elsevier Science B.V. All rights reserved.

Conducting dielectric samples are often used in high-resolution experiments at high field. It is shown that significant amplitude and phase distortions of the RF magnetic field may result from perturbations caused by such samples. Theoretical analyses demonstrate the spatial variation of the RF field amplitude and phase across the sample, and comparisons of the effect are made for a variety of sample properties and operating field strengths. Although the effect is highly nonlinear, it tends to increase with increasing field strength, permittivity, conductivity, and sample size. There are cases, however, in which increasing the conductivity of the sample improves the homogeneity of the amplitude of the RF field across the sample at the expense of distorted RF phase. It is important that the perturbation effects be calculated for the experimental conditions used, as they have the potential to reduce the signal-to-noise ratio of NMR experiments and may increase the generation of spurious coherences. The effect of RF-coil geometry on the coherences is also modeled, with the use of homogeneous resonators such as the birdcage design being preferred. Recommendations are made concerning methods of reducing sample-induced perturbations. Experimental high-field imaging and high-resolution studies demonstrate the effect.

The structures of haliclonacyclamines A (1) and B (2), and their methiodide salts (3) and (4), were investigated by 1D- and 2D-NMR experiments, notably DQFCOSY, HMBC, HMQC-HOHAHA, and HOHAHA. The relative stereochemistry and position of alkene substituents were determined by single crystal x-ray study at low temperature. The parent haliclonacyclamines show pronounced cytotoxic, antibacterial and antifungal activity.

Proton magnetic resonance imaging (MRI) was used to observe disinfestation heat treatment-induced injury in the mesocarp of ripening mango cv. Kensington Pride. Injured areas were characterised by relatively low water levels (low signal intensity) corresponding to air filled cavities and “islands” of starchy mesocarp. Heat treatment-induced lesions started to develop on the day of treatment (day 0) and were maximally evident in fruit held at 22°C by day 4. Nondestructive proton MRI was shown to be a sensitive method for detecting and monitoring the progress of heat treatment-induced injury in mango fruit.

R. J. Lewis, R. S. Norton, I. M. Brereton and C. D. Eccles . Ciguatoxin-2 is a diastereomer of ciguatoxin-3. Toxicon 31, 637–643, 1993.—Ciguatoxin-2, a major ciguatoxin present in the flesh and viscera of ciguateric fishes, has been shown by 1H nuclear magnetic resonance studies (2-dimensional homonuclear Hartman Hahn, nuclear Overhauser effect and decoupling difference experiments) to be a diastereomer of ciguatoxin-3, differing only in stereochemistry at carbon 52 (a quaternary carbon). This difference accounts for the significant changes in the chemical shift of resonances for protons in this region of ciguatoxin-2. Differences between ciguatoxin-1, -2 and -3 involve modifications at only one end of the ciguatoxins (ring M) and modest differences in potency, indicating that this ring contributes to, but is not critical for, high affinity binding of the ciguatoxins to voltage-dependent sodium channels. It is proposed that ciguatoxin-2 originates from a different precursor to the precursor (presumably gambiertoxin-4b) for ciguatoxin-1 and -3, and that both precursors are produced by a common biosynthetic pathway in Gambierdiscus toxicus .

Motion of abdominal organs with respiration is a major problem in NMR spectroscopy and imaging thereof. Triggering each phase-encoding step with respiration or gating a number of phase-encoding steps is one approach to the problem. The design of a sensor for small animal experiments has not been as simple. An optical device, implemented with polymer optical fibres is described, along with associated hardware and electronics which can act as a trigger for small animal NMR experiments. A brief description of a similar device for human application is also given. 2DFT spin-echo and B0 susceptibility images, both triggered and untriggered, are presented to validate the technique.

The gradient-enhanced, heteronuclear, chemical-shift correlation experiment, which provides F 1 quadrature detection in a single acquisition, is analyzed in terms of product operators. Spectral distortions due to eddy-current effects can be avoided by judicial placement of gradient episodes with respect to the incremented evolution period as illustrated by an alternative gradient sequence. The analysis demonstrates the gradient selection of coherences and shows that the relative value of the gradients for N-type or P-type selection now depends upon the value of the ratio of gyromagnetic ratios, rather than on its sign. The new sequence is experimentally demonstrated by the acquisition of a 2D heteronuclear 1 H 3 C correlation spectrum of strychnine.

The SPACE volume-selection technique has been used to acquire high-resolution 1H spectra from the brain of neonate mice at 11.7 T (500 MHz). Spectra were acquired from voxels smaller than 20 μl. The spectra display elevated intensities of resonances arising from taurine and reduced intensities of those arising from N-acetylaspartate, when compared to those of mature animals, correlating well with in vitro studies. An integrated probe design consisting of separate transmission and reception RF coils and linear gradient coils is described. Comments are made concerning the advantages and disadvantages of performing gradient-encoded localized spectroscopy at this field strength.

The improved understanding and control of induced eddy current effects has led to the increased application of pulsed field gradients in high-resolution 2D NMR spectroscopy. Of particular interest is the ability to select specific coherences in a single acquisition with concomitant "quadrature detection" in the F1 dimension. A product-operator analysis of this effect for an AX spin system which describes the selection of N-type or P-type signals using appropriate gradient episodes in the COSY and 2D double-quantum experiments is presented.

Exploitation of mu ltiple-quantum (MQ) and zero-quantum (ZQ) coherences generated between scalar-coupled nuclei for selective spectral editing of metabolite signals has recently received much attention (I-4). Perhaps the ma in disadvantages associated with reported methods are their reliance on accurate subtraction ( 1)) a ma jor concern for in vivo applications where dominant water and lipid resonances may interfere, and the need for two-dimensional spectroscopy to extract the metabolite signal (2). In a one-dimensional method (3, 4)) selective excitation and pulsed field gradients were emp loyed to select ZQ coherence exclusively, giving good spectral editing and solvent suppression in a single scan. However, these methods suffer significant signal-to-noise loss since both ZQ and MQ coherences are generated but only one is eventually converted to an observable single-quantum (SQ) signal, the other being dephased by a field gradient or eliminated by phase cycling. In the case of ZQ coherence selection, a maximum of one-quarter of the coherence is available following gradient application and the efficiency of a desired MQ coherence formation may be dependent upon the mu ltiplicity of the spin-spin coupling, for example, in ethanol, where SQ and triple-quantum (TQ) components are lost (4). Selective polarization transfer methods have also been proposed but these also result in reduced signal due to the direction of the transfer (5) or through the dependency of the polarization transfer efficiency on RF pulse angle (4) and may require extensive phase cycling (6). Here we describe a procedure, ECZOTIC (editing via correlated z order with total inherent coherence), in which all metabolite coherence is selectively converted to correlated z order, or longitudinal two-spin order ( 7)) in a manner similar to that of the INEPT experiment (8), and, following pulsed field gradient dephasing of other signals, is converted to observable SQ coherence with maximum signal return. The insensitivity of ZQ coherence to field inhomogeneity is well known and is the basis of the editing techniques ment ioned above (2-4). However, correlated z order, like all longitudinal magnetization, is also invariant in the presence of a field gradient and provides an alternative approach to spectral editing. The method is readily applied

Water-suppression techniques can be divided into two types, those that result in zero net excitation of the water resonance and those in which the water magnetization is randomized prior to observation of the spectrum of interest. The randomization mechanism may involve selective irradiation, use of natural spin relaxation, or application of a homospoil gradient pulse to dephase selectively excited transverse spin coherence. Destruction techniques considered in this paper will involve the latter of these processes. Nonexcitation methods usually involve a binomial-type pulse cluster which results in off-resonance excitation but zero net rotation on resonance ( 1). Although the water-suppression factor of these methods is usually high ( > 1000)) they suffer from the major limitation that the spectral response is either not flat and/ or there is a large linear phase distortion of the spectrum. Destruction techniques are attractive because the final read pulse can be a hard 90” pulse which ensures uniform excitation of the spectrum with minimal phase distortion. The aim of these methods is the establishment of (S,) = (3,) = (&) = 0 over some selective band in frequency space. For those that utilize a pulsed field gradient, selectivity is achieved by the application of a shaped RF pulse which generates transverse spin coherence over a narrow band and the coherence is dephased by the field gradient. In a previous paper (2) we discussed the difficulties of maintaining high-resolution conditions (Au < 1 Hz) during data acquisition following a field gradient pulse. The major problems can be overcome by preemphasis of the gradient pulse and by applying a correction current through the Z0 coil during data acquisition to ensure that the static magnetic field is stable. Decoupling of the gradient coils from the magnet, shim set, and bore tubes by shielding and isolation may also alleviate these induced eddy current problems. In this paper we consider the nature of the shaped pulse to achieve the optimum water suppression. As well, we introduce a new mechanism to achieve water suppression using a pulsed field gradient and a selective noise pulse. All spectra were obtained on a Bruker MSL-200 spectrometer interfaced to an Oxford Instruments 4.7 T, 13 cm vertical bore magnet. Gradient pulses and Z0 correction were controlled by a Bruker MSL preemphasis unit and were applied to the

The apparent stability constants (K) of the cryptates [AgβC21C5]+ and [Na·C21C5]+ (C21C5 = 4,7,13-trioxa-1,10-diazabicyclo[8.5.5]eicosane) have been determined in a range of solvents. For [Na·C21C5]+ log (K/dm3 mol−1) = 2.87, 3.72, 3.76, 3.98, 5.08 and 5.12 at 298.2 K in dimethylformamide, pyridine, methanol, acetone, acetonitrile and propylene carbonate, respectively, in the presence of 0.05 mol dm−3 tetraethylammonium perchlorate supporting electrolyte. These values are substantially lower than those observed for [Na·C211]+ (C211 = 4,7,13,18-tetraoxa-1,10-diazabicyclo[8.5.5]eicosane) and this is attributed to the presence of one less oxygen atom in C21C5 than in C211. A similar relationship is observed for [Ag·C211]+ and [Ag·C21C5]+, where, for the latter cryptate, log (K/dm3 mol−1) = 5.19

Natural abundance deuterium NMR spectroscopy can be used to characterise in vivo2H signals arising from water and fat in mice, with acquisition times of less than two minutes. Administration of D2O (10% V V ) in the drinking water enhances these signals so that excellent spectra can be obtained with one scan. Using these procedures the in vivo turnover of 2H in water and fat in mice has been determined. This procedure may be of particular importance in studies of fat turnover in obesity.