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This article analyzes the unsettling role given to plague in the representational practices of Daniel Defoe's A Journal of the Plague Year (1722). It focuses on how Defoe's combination of discursive frames provides a model for interpreting and understanding his complex world-view. I suggest that, by scrutinizing the mixture of discourses employed to represent plague and its effects, especially those drawn from the fields of natural philosophy, politics and theology, scholars can newly appreciate Defoe's view of the position of the human in a total world economy. By analyzing how plague orders and disturbs notions of the human within those different fields, and how it bridges the divisions among them, I propose that we are able to better understand Defoe's systemic vision of the world. [ABSTRACT FROM AUTHOR]

Back-to-back 1H MRSI scans, using an endorectal and phased-array coil combination, were performed on 18 low-risk patients with prostate cancer at 3 T, employing TEs of 32 and 100 ms in order to compare metabolite visualization at each TE. Outer-volume suppression of lipid signals was performed using regional saturation (REST) slabs and the quantification of spectra at both TEs was achieved with the quantitation using quantum estimation (QUEST) routine. Metabolite nulling experiments in an additional five patients found that there were negligible macromolecule background signals in prostate spectra at TE = 32 ms. Metabolite visibility was judged using the criterion Cramér-Rao lower bound (CRLB)/amplitude < 20%, and metabolite concentrations were corrected for relaxation effects and referenced to the data acquired in corresponding water-unsuppressed MRSI scans. For the first time, the prostate metabolites spermine and myo-inositol were quantified individually in vivo, together with citrate, choline and creatine. All five metabolite visibilities were higher in TE = 32 ms MRSI than in TE = 100 ms MRSI. At TE = 32 ms, citrate was visible in 99.0% of lipid-free spectra, whereas, at TE = 100 ms, no metabolite simulation of citrate matched the in vivo peaks. Spermine, choline and creatine were visualised separately in 30.4% more spectra at TE = 32 ms than at TE = 100 ms, and myo-inositol in 72.5% more spectra. T2 values were calculated for spermine (53 ± 16 ms), choline (62 ± 17 ms) and myo-inositol (90 ± 48 ms). Data from the TE = 32 ms spectra showed that the concentrations of citrate and spermine secretions were positively correlated in both the peripheral zone and central gland ( R2 = 0.73 and R2 = 0.43, respectively), and that the citrate content was significantly higher in the former at 64 ± 22 m m than in the latter at 32 ± 16 m m ( p = 0.01). However, lipid contamination at TE = 32 ms was substantial; therefore, to make clinical use of the greater visualisation of prostate metabolites at TE = 32 ms rather than at TE = 100 ms, three-dimensional MRSI at TE = 32 ms with effective lipid suppression must be implemented. ©2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

31P magnetic resonance spectroscopy (31P MRS) can measure intracellular pH (pHi) using the chemical shift difference between pH-dependent inorganic phosphate (Pi) and a pH-independent reference peak. This study compared three different frequency reference peaks [phosphocreatine (PCr), α resonance of adenosine triphosphate (αATP) and water (using 1H MRS)] in a cohort of 10 volunteers and eight patients with non-Hodgkin's lymphoma (NHL). Well-resolved chemical shift imaging (CSI) spectra were acquired on a 1.5T scanner for muscle, liver and tumour. The pH was calculated for all volunteers and patients using the available methods. The consistency of the resulting pH was evaluated. The direct Pi-PCr method was best for those spectra with a very well-defined PCr, such as muscle (pH=7.05 ± 0.02). In liver, the Pi-αATP method gave more consistent results (pH=7.30 ± 0.06) than the calibrated water-based method (pH=7.27 ± 0.11). In NHL nodes, the measured pH using the Pi-αATP method was 7.25 ± 0.12. Given that the measured range includes some biological variation in individual patients, treatment-related changes of the order of 0.1 pH units should be detectable. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims: To examine molecular and metabolic consequences of HPV-16 viral- protein E6, which targets p53 for degradation, in A2780 (ovarian cancer) cells. Methods: Isogenic derivatives of A2780 cells, with empty-vector (E6-) or E6 (E6+) transfection, were cultured. Intracellular metabolites, fatty acids, and the flux of glutamine, glucose, alanine and lactate in proliferation (Day 2) and confluence (Day 4) were determined using MRS. Western blotting confirmed p53 status, protein expressions related to AKT, ERK and mTOR signalling, and phospholipid metabolism. Results: Growth rate was slower in E6+ cells compared with E6-, resulting in reduced glycolysis, amino acid uptake and fatty acid synthesis. Glutamine metabolism, glycerophosphocholine (GPC), and protein expressions of cytosolic PLA2 (cPLA2) and p-cPLA2 increased in E6+ cells. Despite decreased ERK and AKT signalling, expression of S6RP and p-S6RP downstream of mTOR remained unaffected in E6+ cells. E6+ cells were more invasive and migrate faster than the E6- cells. Conclusion: E6+ had slower growth than E6- cells with reduced metabolism, but E6+ cells maintained cellular homeostasis through glutamine metabolism when compared with E6- at Day 2. The ability to migrate and form larger colonies may provide the E6+ cells with a growth advantage. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Rapid induction of CD8+ cytotoxic T lymphocyte (CTL) responses is critical to combat acute infection with intracellular pathogens. CD4+ T cells help prime antigen-specific CTLs in secondary lymphoid organs after infection in the periphery. Although the frequency of naïve precursors is very low, the immune system is able to efficiently screen for cognate CTLs through mechanisms that are not well understood. Here we examine the role of CD4+ T cells in early phases of the immune response. We show that CD4+ T cells help optimal CTL expansion by facilitating entry of naïve polyclonal CD8+ T cells into the draining lymph node (dLN) early after infection or immunization. CD4+ T cells also facilitate input of naïve B cells into reactive LNs. Such "help" involves expansion of the arteriole feeding the dLN and enlargement of the dLN through activation of dendritic cells. In an antigen and CD40-dependent manner, CD4+ T cells activate dendritic cells to support naïve lymphocyte recruitment to the dLN. Our results reveal a previously unappreciated mode of CD4+ T-cell help, whereby they increase the input of naïve lymphocytes to the relevant LN for efficient screening of cognate CD8+ T cells. [ABSTRACT FROM AUTHOR]

The aim of this work was to investigate the effect of experimental conditions on the visibility of polyamines. In solution the chemical shift of the three groups of peaks (at approximately 1.8, 2.1 and 3.1 ppm) were found to be pH dependent. Relaxation times in aqueous solution at pH 7.0, 298 K and 11.74 T were measured to be: putrescine (T1 = 2.49 s, T2 = 2.07 s), spermidine (T1 = 1.27 s, T2 = 1.05 s) and spermine (T1 = 1.02 s, T2 = 0.82 s). Simple spin-echo sequences could not be used to measure T2 as the spins also experience phase evolution from homonuclear coupling which imposes a modulation on the T2 decay curve. This modulation is eliminated by using CPMG sequences with an echo spacing of <500 µs. Relaxation times for spermine in solution in presence of metal ions and protein showed that metal ions had little effect on T2; however, addition of 15 mg/ml bovine serum albumin reduced T2 of spermine (0.41 s at 298 K and 0.19 s at 277 K) but was not as short as the T2 of the polyamine peak in prostatic tissue (0.03 s at 277 K). The MR visibility of polyamines in prostate cell extracts, PC-3 xenograft (intact as well as extracted) and intact human prostatic tissues were investigated. Polyamines were not detected in methanol/chloroform extracts, but were visible in perchloric acid extracts of prostate tumour cells. No polyamines were detected in the HR MAS spectra of three samples of whole PC-3 xenograft tissue studied. In summary, the chemical shift of polyamine species is pH dependent, while protein binding causes peak broadening and reduction in T2. Perchloric acid extraction improves visibility of intracellular polyamines, but whole tissue polyamines are not seen in xenografts without epithelial/ ductal structure. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Carboxypeptidase G2 (CPG2) is a bacterial enzyme that is currently employed in a range of targeted cancer chemotherapy strategies such as gene-directed enzyme prodrug therapy (GDEPT). Employing dynamic nuclear polarization (DNP) and natural abundance 13C magnetic resonance spectroscopy (MRS), we observed the CPG2-mediated conversion of a novel hyperpolarized reporter probe 3,5-difluorobenzoyl-L-glutamic acid (3,5-DFBGlu) to 3,5-difluorobenzoic acid (3,5-DFBA) and L-glutamic acid (L-Glu) in vitro. Isotopic labeling of the relevant nuclei with 13C in 3,5-DFBGlu or related substrates will yield a further factor of 100 increase in the signal-to-noise. We discuss the feasibility of translating these experiments to generate metabolic images of CPG2 activity in vivo. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Development and evaluation of new anticancer drugs are expedited when minimally invasive biomarkers of pharmacokinetic and pharmacodynamic behaviour are available. Gene-directed enzyme prodrug therapy (GDEPT) is a suicide gene therapy in which the anticancer drug is activated in the tumor by an exogenous enzyme previously targeted by a vector carrying the gene. GDEPT has been evaluated in various clinical trials using several enzyme/prodrug combinations. The key processes to be monitored in GDEPT are gene delivery and expression, as well as prodrug delivery and activation. {4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoyl}-L-glutamic acid, a prodrug for the GDEPT enzyme carboxypeptidase-G2 (CPG2; Km = 1.71 µM; kcat = 732 s−1), was measured with 19F magnetic resonance spectroscopy (MRS). The 1 ppm chemical shift separation found between the signals of prodrug and activated drug (4-[bis(2-chloroethyl)amino]-3,5-difluorobenzoic acid) is sufficient for the detection of prodrug activation in vivo. However, these compounds hydrolyze rapidly, and protein binding broadens the MR signals. A new CPG2 substrate was designed with hydroxyethyl instead of chloroethyl groups ( Km = 3.5 µM, kcat = 747 s−1). This substrate is nontoxic and stable in solution, has a narrow MRS resonance in the presence of bovine and foetal bovine albumin, and exhibits a 1.1 ppm change in chemical shift upon cleavage by CPG2. In cells transfected to express CPG2 in the cytoplasm (MDA MB 361 breast carcinoma cells and WiDr colon cancer cells), well-resolved 19F MRS signals were observed from clinically relevant concentrations of the new substrate and its nontoxic product. The MRS conversion half-life (470 min) agreed with that measured by HPLC (500 min). This substrate is, therefore, suitable for evaluating gene delivery and expression prior to administration of the therapeutic agent. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Choline metabolites are widely studied in cancer research as biomarkers of malignancy and as indicators of therapeutic response. However, endogenous phosphocholine levels are determined by a number of processes that confound the interpretation of these measurements, including membrane transport rates and a series of enzyme catalysed reactions in the Kennedy pathway. Employing a dynamic 31P NMR assay that is specific to choline kinase (ChoK) we have measured the rates of this enzyme reaction in cell lysates of MDA-MB-231 breast, PC-3 prostate and HeLa cervical cancer cells and in solutions of purified human ChoK. The rates are sensitive to inhibition by hemicholinium-3 (HC-3), a competitive ChoK inhibitor, and to N-[2-bromocinnamyl(amino)ethyl]-5-isoquinolinesulphonamide (H-89), an agent commercialized as a specific cyclic-AMP-dependent protein kinase A (PKA) inhibitor. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the metabolic changes in the transition from pre-invasive to invasive cervical cancer using high-resolution magic angle spinning (HR-MAS) MRS. Biopsy specimens were obtained from women with histologically normal cervix (n = 5), cervical intraepithelial neoplasia (CIN; mild, n = 5; moderate/severe, n = 40), and invasive cancer (n = 23). 1H HR-MAS MRS data were acquired using a Bruker Avance 11.74 T spectrometer (Carr-Purcell-Meiboom-Gill sequence; TR = 4.8 s; TE = 135 ms; 512 scans; 41 min acquisition). 31P HR-MAS spectra were obtained from the normal subjects and cancer patients only (as acetic acid applied before tissue sampling in patients with CIN impaired spectral quality) using a 1H-decoupled pulse-acquire sequence ( TR = 2.82 s; 2048 scans; 96 min acquisition). Peak assignments were based on values reported in the literature. Peak areas were measured using the AMARES algorithm. Estimated metabolite concentrations were compared between patient diagnostic categories and tissue histology using independent samples t tests. Comparisons based on patient category at diagnosis showed significantly higher estimated concentrations of choline (P = 0.0001) and phosphocholine (P = 0.002) in tissue from patients with cancer than from patients with high-grade dyskaryosis, but no differences between non-cancer groups. Division by histology of the sample also showed increases in choline (P = 0.002) and phosphocholine (P = 0.002) in cancer compared with high-grade CIN tissue. Phosphoethanolamine was increased in cancer compared with normal tissue (P = 0.0001). Estimated concentrations of alanine (P = 0.01) and creatine (P = 0.008) were significantly reduced in normal tissue from cancer patients compared with normal tissue from non-cancer patients. The estimated concentration of choline was significantly increased in CIN tissue from cancer patients compared with CIN tissue from non-cancer patients (P = 0.0001). Estimated concentrations of choline-containing metabolites increased from pre-invasive to invasive cervical cancer. Concurrent metabolite depletion occurs in normal tissue adjacent to cancer tissue. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Double resonance techniques such as INEPT (insensitive nuclei enhanced by polarization transfer) and JCP ( J cross-polarization) have previously been applied in vitro to enhance the SNR of low-sensitivity nuclei and detect altered metabolism, for example, with 13C magnetic resonance spectroscopy (MRS), where the 1H-13C scalar couplings are of the order of 130 Hz. The aim of the present study was to investigate the potential advantage of using JCP for the detection of phosphomonoesters (PME) and phosphodiesters (PDE) with 31P MRS in vivo. These metabolites are involved in membrane metabolism and their concentration is altered in tumors and other pathologies. JCP has been implemented and compared with INEPT and pulse-and-acquire in vivo both in unlocalized and in localized spectra in order to select the optimum method for in vivo applications for PME and PDE detection. The results suggest that JCP can give up to 20% more signal in the PME region and up to 70% more signal in the PDE region, with 20 to 70% lower power deposition than INEPT. Such enhancement could be used to reduce the measurement times for equivalent signal-to-noise ratios. The JCP sequence is, however, slightly more sensitive than INEPT to RF field inhomogeneities, as predicted from theory. Magn Reson Med, 2005. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Biliary excretion is a significant component in the metabolism of many drugs, but remains difficult to detect and characterise non-invasively. A previous publication recently described the detection of metabolites of ifosfamide in gall bladder in a guinea pig model using in vivo 1H-decoupled 31P 3-D magnetic resonance spectroscopic imaging and a clinical 1.5 T MR scanner.. Here high-resolution 31P magnetic resonance spectroscopy (MRS) of extracted bile identifies peaks as parent ifosfamide (1.19±1.47 mM; mean ± sd), carboxyifosfamide (2.04±1.04 mM) and a major contribution from a previously unreported peak at 16.0 ppm (4.05±2.38 mM). The unknown resonance was identified using liquid chromatography - mass spectrometry (LCMS) as the glutathione conjugate of ifosfamide (MW = 531). This was confirmed by analysing products from the reaction of glutathione with ifosfamide using LCMS and MRS. These results demonstrate how combined in vivo and analytical MRS, together with mass spectrometry, can help identify visceral routes of drug metabolism, thereby aiding understanding of ±drug disposition and mechanisms of action and toxicity. In particular, the distribution of ifosfamide and its metabolites into bile may be related to oxazophosphorine-related cholecystitis reported in patients. [ABSTRACT FROM AUTHOR]

To measure hepatic concentrations of the fluorine-containing antimicrobial, sitafloxacin, usingin vivo19F magnetic resonance spectroscopy (MRS).Data were acquired from eight healthy subjects at 2, 5, 8 and 24 h following doses of 500 mg day−1 for 5 days using a1H/19F surface coil in a 1.5T clinical MR system. Tissue water was used as a reference.Estimated liver concentrations at 2 h were 15.0 ± 4.0 µg ml−1 (mean ± 95% CI), compared with 3.54 ± 0.58 µg ml−1 in plasma (n = 6), and fell below threshold concentrations (2 µg ml−1) by 24 h.19F MRS is able to detect and quantify sitafloxacin in the liver. There was no evidence for the hepatic retention of the drug. [ABSTRACT FROM AUTHOR]

This paper introduces a special issue of Habitat International on land tenure and property rights. It sets the scene for case studies carried out in countries around the world commissioned by the author as part of a research project11‘Progress in the provision of secure tenure for the urban poor’ a research project undertaken by Geoffrey Payne and Associates and an international team of researchers between 2002 and 2003 with funding from the UK Department for International Development (DFID). The views expressed in this issue are not necessarily those of the DFID. updating previous research on innovative approaches to tenure for the urban poor in 16 countries. The research reviewed changes in the selected tenure systems and placed them in a wider context of local land and housing markets.A key feature of the paper is a typological framework which enables policy makers or others to identify the range and distribution of statutory, customary and informal tenure categories in a city, the de facto levels of security provided by each and the various property rights associated with them. The paper demonstrates that tenure systems form a continuum of categories and that policies need to recognise crucial distinctions between these if policy objectives are to be achieved. The role of tenure policy in facilitating or inhibiting security and rights for vulnerable groups, such as tenants and women is discussed and proposals made for implementing a pro-poor tenure policy. The paper concludes by introducing the case study papers. [Copyright &y& Elsevier]

In its effort to fight poverty, the Royal Government of Cambodia has emphasised the importance of providing land titles to its population. This aim has been widely supported both financially and technically by the World Bank and German Technical Assistance (GTZ) as well as foreign governments such as Finland. The World Bank''s Regional Land Policy Workshop in Asia held in Phnom Penh in April 200211Minister''s speech, April 2002. sought to kick off the process of a country-wide land titling programme which also covers Phnom Penh city.Even though this heavily budgeted project looks set to produce more than a million22The total target of land titles to be issued is varied from one executive year to another, i.e., 12,000 in 2002, 102,000 in 2003, 192,000 in 2004, 300,000 in 2005, 330,000 in 2006, and only 66,000 in 2007 (The World Bank, 2002, p. 43). land titles within approximately 5 years, it will face many difficulties and challenges related to land tenure due to overlapping claims and border demarcation disputes.This paper addresses the types of land tenure existing in Phnom Penh which will present problems to the land titling programme and suggests that an alternative approach may be preferable. It is based on a field survey of households in a range of informal and formal low-income settlements of 10 areas in Phnom Penh, Cambodia. It also involved interviews with a number of key stakeholders in government agencies, the private sector, NGOs and representatives of international agencies. A total of 700 householders were interviewed and an additional 70 informal case studies were completed to obtain qualitative information to complement the quantitative data obtained through the survey. [Copyright &y& Elsevier]

Intermolecular multiple-quantum coherences (iMQCs) have been reported to offer a sensitivity to sample structure at a specific user-defined length scale down to the order of 10 μm. When assessing this novel contrast mechanism in controlled phantom experiments, we have observed three different mechanisms whereby residual single-quantum coherences (SQCs) arising from intense high spatial frequencies, stimulated echoes and strong spatially encoding gradients can produce significant changes in signal contrast at particular length scales. These changes which only appear when components arising from SQCs and iMQCs are both present in the detected signal, are similar to changes previously attributed to iMQCs alone. We demonstrate each mechanism by which these residual SQCs arise and describe methods for their suppression. [Copyright &y& Elsevier]

Histamine increases the permeability of capillaries and venules but little is known of its precapillary actions on the control of tissue perfusion. Using gene ablation and pharmacological interventions, we tested whether histamine could increase muscle blood flow through stimulating nitric oxide (NO) release from microvascular endothelium. Vasomotor responses to topical histamine were investigated in second-order arterioles in the superfused cremaster muscle of anesthetized C57BL6 mice and null platelet endothelial cell adhesion molecule-1 (PECAM-1[sup -/-]) and null endothelial NO synthase (eNOS[sup -/-]) mice aged 8-12 wk. Neither resting (17 ± 1 µm) nor maximum diameters (36 ± 2 µm) were different between groups, nor was the constrictor response (∼5 ± 1 µm) to elevating superfusate oxygen from 0 to 21%. For arterioles of C57BL6 and PECAM1[sup -/-] mice, cumulative addition of histamine to the superfusate produced vasodilation (1 nM-1 µM; peak response, 9 ± 1 µm) and then vasoconstriction (10-100 µM; peak response, 12 ± 2 µm). In eNOS[sup -/-] mice, histamine produced only vasoconstriction. In C57BL6 and PECAM-1[sup -/-] mice, vasodilation was abolished with N[sup ω]-nitro-L-arginine (30 µM); in all mice, vasoconstriction was abolished with nifedipine (1 µM). Vasomotor responses were eliminated with pyrilamine (1 µM; H1 receptor antagonist) yet remained intact with cimetidine (1 µM; H[sub 2] receptor antagonist). These findings illustrate that the biphasic vasomotor response of mouse cremaster arterioles to histamine is mediated through H[sub 1] receptors on endothelium (NO-dependent vasodilation) as well as smooth muscle (Ca[sup 2+] entry and constriction). Thus histamine can increase as well as decrease muscle blood flow, according to local concentration. However, when NO production is compromised, only vasoconstriction and flow reduction occur. [ABSTRACT FROM AUTHOR]