Evaluation of the antiangiogenic potential of AQ4N.

Purpose: A number of cytotoxic chemotherapy agents tested at low concentrations show antiangiogenic properties with limited cytotoxicity, e.g., cyclophosphamide, tirapazamine, and mitoxantrone. AQ4N is a bioreductive alkylaminoanthraquinone that is cytotoxic when reduced to AQ4; hence, it can be used to target hypoxic tumor cells. AQ4N is structurally similar to mitoxantrone and was evaluated for antiangiogenic properties without the need for bioreduction.

Experimental Design:The effect of AQ4N and fumagillin on human microvascular endothelial cells (HMEC-1) was measured using a variety ofin vitro assays, i.e., 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide, wound scrape, tubule formation, rat aortic ring, and invasion assays. Low-dose AQ4N (20 mg/kg) was also given in vivo to mice bearing a tumor in a dorsal skin flap.

Results:AQ4N (10-11to10-5mol/L) hadno effect on HMEC-1viability. AQ4N (10-9to10-5mol/L) caused a sigmoidal dose-dependent inhibition of endothelial cell migration in the wound scrape model. Fumagillin showed a similar response over a lower dose range (10-13 to 10-9 mol/L); however, the maximal inhibition was less (25% versus 43% for AQ4N). AQ4N inhibited HMEC-1 cell contacts on Matrigel (10-8 to 10-5 mol/L), HMEC-1 cell invasion, and sprouting in rat aorta explants. Immunofluorescence staining with tubulin, vimentim, dynein, and phalloidin revealed that AQ4N caused disruption to the cell cytoskeleton. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap.

Conclusions:This combination of assays has shown that AQ4N possesses antiangiogenic effects in normoxic conditions, which could potentially contribute to antitumor activity

Investigation of an electron string ion source with field emission cathode

The string mode of operation for an electron beam ion source uses axially oscillating electrons in order to reduce power consumption, also simplifying the construction by omitting the collector with cooling requirements and has been called electron string ion source (ESIS). We have started a project (supported by INTAS and GSI) to use Schottky field emitting cathode tips for generating the electron string. The emission from these specially conditioned tips is higher by orders of magnitude than the focused Brillouin current density at magnetic fields of some Tesla and electron energies of some keV. This may avoid the observed instabilities in the transition from axially oscillating electrons to the string state of the electron plasma, opening a much wider field of possible operating parameters for an ESIS. Besides the presentation of the basic features, we emphasize in this paper a method to avoid damaging of the field, emission tip by backstreaming ions. (C) 2008 American Institute of Physics.

Multiple Evidence for Gold(I)center dot center dot center dot Silver(I) Interactions in Solution

[AuAg3(C6F5)(CF3CO2)(3)(CH2PPh3)](n) (2) was prepared by reaction of [Au(C6F5)(CH2PPh3)] (1) and [Ag(CF3CO2)] (1:3). The crystal structures of complexes I and 2 were determined by X-ray diffraction, and the latter shows a polymeric 2D arrangement built by Au - Ag, Ag - Ag, and Ag - O contacts. The metallophilic interactions observed in 2 in the solid state seem to be preserved in concentrated THF solutions, as suggested by EXAFS, pulsed-gradient spin-echo NMR, and photophysical studies, which showed that the structural motif [AuAg3(C6F5)(CF3CO2)(3)(CH2PPh3)] is maintained under such conditions. Time-dependent DFT calculations agree with the experimental photophysical energies and suggest a metal-to-ligand charge-transfer phosphorescence process. Ab initio calculations give an estimated interaction energy of around 60 kJ mol(-1) for each Au - Ag interaction.

Crystal structures of imidazolium bis(trifluoromethanesulfonyl)imide 'ionic liquid' salts: the first organic salt with a cis-TFSI anion conformation

Crystal structures of two examples of an important class of ionic liquids, 1,3-dimethylimidazolium and 1,2,3-triethylimidazolium bis(trifluoromethanesulfonyl)imide have been characterized by single crystal X-ray diffraction. The anion in the 1,3-dimethylimidazolium example (mp 22 degreesC), adopts an unusual cis-geometry constrained by bifurcated cation-anion C-H...O hydrogen-bonds from the imidazolium cation to the anion resulting in the formation of fluorous layers within the solid-state structure. In contrast, in the 1,2,3-triethylimidazolium salt (mp 57 degreesC), the ions are discretely packed with only weak C-H...O contacts between the ions close to the van der Waals separation distances, and with the anion adopting the twisted conformation observed for all other examples from the limited set of organic bis( trifluoromethanesulfonyl) imide crystal structures. The structures are discussed in terms of the favorable physical properties that bis(trifluoromethanesulfonyl) imide anions impart in ionic liquids.

Foxp3+ T cells induce Perforin-Dependent Dendritic Cell Death in Tumor-Draining Lymph Nodes.

Regulatory T (Treg) cells limit the onset of effective antitumor immunity, through yet-ill-defined mechanisms. We showed the rejection of established ovalbumin (OVA)-expressing MCA101 tumors required both the adoptive transfer of OVA-specific CD8(+) T cell receptor transgenic T cells (OTI) and the neutralization of Foxp3(+) T cells. In tumor-draining lymph nodes, Foxp3(+) T cell neutralization induced a marked arrest in the migration of OTI T cells, increased numbers of dendritic cells (DCs), and enhanced OTI T cell priming. Using an in vitro cytotoxic assay and two-photon live microscopy after adoptive transfer of DCs, we demonstrated that Foxp3(+) T cells induced the death of DCs in tumor-draining lymph nodes, but not in the absence of tumor. DC death correlated with Foxp3(+) T cell-DC contacts, and it was tumor-antigen and perforin dependent. We conclude that Foxp3(+) T cell-dependent DC death in tumor-draining lymph nodes limits the onset of CD8(+) T cell responses.

A RCT of peer-mentoring for first-time mothers in socially disadvantaged areas (the moments study)

Objective: Interventions to reduce health inequalities for young children and their mothers are important: involving peers is recommended, but evidence of value for this approach is limited. The authors aimed to examine the effect of an innovative tailored peer-mentoring programme, based on perceived needs, for first-time mothers in socio-economically deprived communities. Design: Randomised controlled trial; parallel qualitative study with purposive samples using semistructured interviews. Setting: Socio-economically disadvantaged areas, Belfast. Participants: Primigravidae, aged 16-30 years, without significant co-morbidity. Intervention: Peer-mentoring by a lay-worker fortnightly during pregnancy and monthly for the following year, tailored to participants' wishes (home visits/telephone contacts), additional to usual care. Main outcome measures: Infant psychomotor and mental development (Bayley Scales of Infant Development (BSID-II)) at 1 year, assessed by an observer blinded to group allocation. Mothers' health at 1 year postnatal (SF-36). Results: Of 534 women invited, 343(64%) participated; 85%, with their children, completed outcome assessments (140 of 172 intervention; 152 of 171 controls). Intervention and control groups did not differ in BSID-II psychomotor (mean difference 1.64, 95% CI -0.94 to 4.21) or mental (-0.81, -2.78 to 1.16) scores, nor SF-36 physical functioning (-5.4, -11.6 to 0.7) or mental health (-1.8, -6.1 to 2.6). Women valued advice given in context of personal experience of child-rearing. Mentors gained health-related knowledge, personal skills and new employment opportunities. Conclusions: Despite possible longer-term social advantage, this peer-mentoring programme showed no benefit for infant development or maternal health at 1 year. Further rigorous evaluation of important outcomes of complex interventions promoting health for children in socially disadvantaged communities is warranted. Trial registration no: ISRCTN 55055030.

Interstitial Cells in the Urinary Bladder-Localization and Function

Aims: This review summarizes the currently available literature on the localization and proposed functions of a novel group of cells in the urinary bladder known as interstitial cells or interstitial cells of Cajal (ICC).

Methods: On-line searches of "Pubmed" for bladder, c-Kit, ICC, interstitial cell and myofibroblast were performed to identify relevant studies for the review.

Results: The literature contains substantial data that several sub-populations of ICC are present in the wall of the mammalian urinary bladder. These are located in the lamina propria and within the detrusor with distinctive cell shapes and morphological arrangements. Bladder ICC are identified with transmission electron microscopy or by immunohistochemical labeling using antibodies to the Kit receptor which is an established ICC marker. Lamina propria-ICC form a loose network connected via Cx43 gap junctions and are associated with mucosal nerves. Detrusor ICC track the smooth muscle bundles and make frequent contacts with intramural nerves. Both groups of ICC exhibit spontaneous electrical and Ca²⁺-signalling and also respond to application of neurotransmitter substances including ATP and carbachol. There is emerging evidence that the expression of ICC is upregulated in pathophysiological conditions including the overactive bladder.

Conclusions: There is now a convincing body of evidence that specialized ICC are present in the urinary bladder making important associations with other cells that make up the bladder wall and possessing physiological properties consistent with a role of bladder activity modulation. Neurourol. Urodynam. 29: 82–87, 2010. © 2009 Wiley-Liss, Inc.

Barrier height variations and interface properties of PtSi/Si structures

To study some of the interfacial properties of PtSi/Si diodes, Schottky structures were fabricated on (100) crystalline silicon substrates by conventional thermal evaporation of Pt on Si followed by annealing at different temperatures (from 400 degrees C to 700 degrees C) to form PtSi. The PtSi/n-Si diodes, all yielded Schottky barrier (SB) heights that are remarkably temperature dependent. The temperature range (20-290 K) over which the I-V characteristics were measured in the present study is broader with a much lower limit (20 K), than what is usually reported in literature. These variations in the barrier height are adequately interpreted by introducing spatial inhomogeneity into the barrier potential with a Gaussian distribution having a mean barrier of 0.76 eV and a standard deviation of 30 meV. Multi-frequency capacitance-voltage measurements suggest that the barrier is primarily controlled by the properties of the silicide-silicon interface. The forward C-V characteristics, in particular, show small peaks at low frequencies that can be ascribed to interface states rather than to a series resistance effect.

Variable temperature, variable-gap Otto prism coupler for use in a vacuum environment

The field of surface polariton physics really took off with the prism coupling techniques developed by Kretschmann and Raether, and by Otto. This article reports on the construction and operation of a rotatable, in vacuo, variable temperature, Otto coupler with a coupling gap that can be varied by remote control. The specific design attributes of the system offer additional advantages to those of standard Otto systems of (i) temperature variation (ambient to 85 K), and (ii) the use of a valuable, additional reference point, namely the gap-independent reflectance at the Brewster angle at any given, fixed temperature. The instrument is placed firmly in a historical context of developments in the field. The efficacy of the coupler is demonstrated by sample attenuated total reflectance results on films of platinum, niobium, and yttrium barium copper oxide and on aluminum/gallium arsenide (Al/GaAs) Schottky diode structures. (C) 2000 American Institute of Physics. [S0034-6748(00)02411-4].

Utility, Caller, and Patient Profile of a Novel Chemotherapy Telephone Helpline Service Within a Regional Cancer Centre in Northern Ireland

Background: The telephone is an accepted and useful means of communication for the management of patient care. The Chemotherapy Telephone Helpline (CTH) service, located in a large inner-city Trust within the United Kingdom, is a unique nurse-led service within Northern Ireland.

Objective: The objective of the study was to investigate the utility, caller, and patient profile of a novel CTH.

Methods: This was a retrospective study of telephone contacts during 2007 to the CTH. Calls were categorized by caller and patient characteristics, reason for call, and subsequent action.

Results: A total of 7498 calls were made to the CTH during 2007. Of these, 25.6% occurred outside 8AM-4PM. Callers included patients (45.8%), lay carers (31%), and health care professionals (20.5%); 35.2% of calls concerned patients with polysymptomatic problems; 36.8% of calls led directly to patients being medically assessed.

Conclusions: The utility of the CTH service confirms the need of this nurse-led service. This service facilitates access to specialist advice and support for patients, their families, and allied health care professionals.

Implications for Practice: The international significance of these findings for practice includes its demonstration of the multifaceted symptom experience of patients receiving chemotherapy and highlights the importance of rapid access to specialist cancer services for patients and their lay and professional carers. In addition, it demonstrates the capacity of helplines to identify gaps in professional skills and training.

Altered distribution of interstitial cells and innervation in the rat urinary bladder following spinal cord injury

Introduction Changes in the distribution of interstitial cells (IC) are reportedly associated with dysfunctional bladder. The present study investigated whether spinal cord injury (SCI) resulted in changes to IC subpopulations (vimentin-positive with the ultrastructural profile of IC), smooth muscle and nerves within the bladder wall and correlated cellular remodelling with functional properties. Methods Bladders from SCI (T8/9 transection) and sham-operated rats five-weeks post-injury were used for ex vivo pressure-volume experiments or processed for morphological analysis with transmission electron microscopy (TEM) and light/confocal microscopy. Results Pressure-volume relationships revealed low-pressure, hypercompliance in SCI bladders indicative of decompensation. Extensive networks of vimentin-positive IC were typical in sham lamina propria and detrusor but were markedly reduced post-SCI; semi-quantitative analysis showed significant reduction. Nerves labelled with anti-neurofilament and anti-vAChT were notably decreased post-SCI. TEM revealed lamina propria IC and detrusor IC which formed close synaptic-like contacts with vesicle-containing nerve varicosities in shams. Lamina propria and detrusor IC were ultrastructurally damaged post-SCI with retracted/lost cell processes and were adjacent to areas of cellular debris and neuronal degradation. Smooth muscle hypertrophy was common to SCI tissues. Conclusions IC populations in bladder wall were decreased five weeks post-SCI, accompanied with reduced innervation, smooth muscle hypertrophy and increased compliance. These novel findings indicate that bladder wall remodelling post-SCI affects the integrity of interactions between smooth muscle, nerves and IC, with compromised IC populations. Correlation between IC reduction and a hypercompliant phenotype suggests that disruption to bladder IC contribute to pathophysiological processes underpinning the dysfunctional SCI bladder.

Pilgrimstad revisited - a multi-proxy reconstruction of Early/Middle Weichselian climate and environment at a key site in central Sweden

The site Pilgrimstad in central Sweden has often been cited as a key locality for discussions of ice-free/ice-covered intervals during the Early and Middle Weichselian. Multi-proxy investigations of a recently excavated section at Pilgrimstad now provide a revised picture of the climatic and environmental development between similar to 80 and 36 ka ago. The combination of sedimentology, geochemistry, OSL and 14C dating, and macrofossil, siliceous microfossil and chironomid analyses shows: (i) a lower succession of glaciofluvial/fluvial, lacustrine and glaciolacustrine sediments; (ii) an upper lacustrine sediment sequence; and (iii) Last Glacial Maximum till cover. Microfossils in the upper lacustrine sediments are initially characteristic for oligo- to mesotrophic lakes, and macrofossils indicate arctic/sub-arctic environments and mean July temperatures > 8 degrees C. These conditions were, however, followed by a return to a low-nutrient lake and a cold and dry climate. The sequence contains several hiatuses, as shown by the often sharp contacts between individual units, which suggests that ice-free intervals alternated with possible ice advances during certain parts of the Early and Middle Weichselian.

Molecular dynamics studies of the STAT3 homodimer:DNA complex: relationships between STAT3 mutations and protein-DNA recognition.

Signal Transducers and Activators of Transcription (STAT) proteins are a group of latent cytoplasmic transcription factors involved in cytokine signaling. STAT3 is a member of the STAT family and is expressed at elevated levels in a large number of diverse human cancers and is now a validated target for anticancer drug discovery.. Understanding the dynamics of the STAT3 dimer interface, accounting for both protein-DNA and protein-protein interactions, with respect to the dynamics of the latent unphosphorylated STAT3 monomer, is important for designing potential small-molecule inhibitors of the activated dimer. Molecular dynamics (MD) simulations have been used to study the activated STAT3 homodimer:DNA complex and the latent unphosphorylated STAT3 monomer in an explicit water environment. Analysis of the data obtained from MD simulations over a 50 ns time frame has suggested how the transcription factor interacts with DNA, the nature of the conformational changes, and ways in which function may be affected. Examination of the dimer interface, focusing on the protein-DNA interactions, including involvement of water molecules, has revealed the key residues contributing to the recognition events involved in STAT3 protein-DNA interactions. This has shown that the majority of mutations in the DNA-binding domain are found at the protein-DNA interface. These mutations have been mapped in detail and related to specific protein-DNA contacts. Their structural stability is described, together with an analysis of the model as a starting-point for the discovery of novel small-molecule STAT3 inhibitors.

Interface mediated resistive switching in epitaxial NiO nanostructures

We report on the non-volatile resistive switching properties of epitaxial nickel oxide (NiO) nanostructures, 10-100 nm wide and up to 30 nm high grown on (001)-Nb:SrTiO3 substrates. Conducting-atomic force microscopy on individual nano-islands confirms prominent bipolar switching with a maximum ON/OFF ratio of similar to 10(3) at a read voltage of similar to+0.4V. This ratio is found to decrease with increasing height of the nanostructure. Linear fittings of I-V loops reveal that low and high resistance states follow Ohmic-conduction and Schottky-emission mechanism, respectively. The switching behavior (dependence on height) is attributed to the modulation of the carrier density at the nanostructure-substrate interface due to the applied electric field.