Selective Imaging of Damaged Bone Structure (Microcracks) Using a Targeting Supramolecular Eu(III) Complex As a Lanthanide Luminescent Contrast Agent

The synthesis and photophysical evaluation of a new supramolecular lanthanide complex is described which was developed as a luminescent contrast agent for bone structure analysis. We show that the Eu(III) emission of this complex is not pH dependent within the physiological pH range, and that its steady state emission is not significantly modulated by a series of group I and II as well as d-metal ions, and that this agent can be successfully employed to image mechanically formed cracks (scratches) in bone samples after 4 or 24 hours, using confocal laser-scanning microscopy.

Real time monitoring of the polymerisation of PMMA bone cement using Raman spectroscopy

In this investigation Raman spectroscopy was shown to be a method that could be used to monitor the polymerisation of PMMA bone cement. Presently there is no objective method that orthopaedic surgeons can use to quantify the curing process of cement during surgery. Raman spectroscopy is a non-invasive, non-destructive technique that could offer such an option. Two commercially available bone cements (Palacos® R and SmartSet® HV) and different storage conditions (4 and 22°C) were used to validate the technique. Raman spectroscopy was found to be repeatable across all conditions with the completion of the polymerisation process particularly easy to establish. All tests were benchmarked against current temperature monitoring methods outlined in ISO and ASTM standards. There was found to be close agreement with the standard methods and the Raman spectroscopy used in this study.

Regulation of cyclin D1 RNA stability by SNIP1

Cyclin D1 expression represents one of the key mitogen-regulated events during the G1 phase of the cell cycle, whereas Cyclin D1 overexpression is frequently associated with human malignancy. Here, we describe a novel mechanism regulating Cyclin D1 levels. We find that SNIP1, previously identified as a regulator of Cyclin D1 expression, does not, as previously thought, primarily function as a transcriptional coactivator for this gene. Rather, SNIP1 plays a critical role in cotranscriptional or posttranscriptional Cyclin D1 mRNA stability. Moreover, we show that the majority of nucleoplasmic SNIP1 is present within a previously undescribed complex containing SkIP, THRAP3, BCLAF1, and Pinin, all proteins with reported roles in RNA processing and transcriptional regulation. We find that this complex, which we have termed the SNIP1/SkIP–associated RNA-processing complex, is coordinately recruited to both the 3' end of the Cyclin D1 gene and Cyclin D1 RNA. Significantly, SNIP1 is required for the further recruitment of the RNA processing factor U2AF65 to both the Cyclin D1 gene and RNA. This study shows a novel mechanism regulating Cyclin D1 expression and offers new insight into the role of SNIP1 and associated proteins as regulators of proliferation and cancer.

The effect of increased dietary fruit and vegetable consumption on endothelial activation, inflammation and oxidative stress in hypertensive volunteers

Background and aims

Public health campaigns recommend increased fruit and vegetable (FV) consumption as an effective means of cardiovascular risk reduction. During an 8 week randomised control trial among hypertensive volunteers, we noted significant improvements in endothelium-dependent vasodilatation with increasing FV consumption. Circulating indices of inflammation, endothelial activation and insulin resistance are often employed as alternative surrogates for systemic arterial health. The responses of several such biomarkers to our previously described FV intervention are reported here.
Methods and results

Hypertensive volunteers were recruited from medical outpatient clinics. After a common 4 week run-in period during which FV consumption was limited to 1 portion per day, participants were randomised to 1, 3 or 6 portions daily for 8 weeks. Venous blood samples for biomarker analyses were collected during the pre and post-intervention vascular assessments. A total of 117 volunteers completed the 12 week study. Intervention-related changes in circulating levels of high sensitivity C-reactive protein (hsCRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) did not differ significantly between FV groups. Similarly, there were no significant between group differences of change in homeostasis model assessment (HOMA) scores.
Conclusions

Despite mediating a significant improvement in acetylcholine induced vasodilatation, increased FV consumption did not affect a calculated measure of insulin resistance or concentrations of the circulating biomarkers measured during this study. Functional indices of arterial health such as endothelium-dependent vasomotion are likely to provide more informative cardiovascular end-points during short-term dietary intervention trials.

Alterations in the steroid hormone receptor co-chaperone FKBPL are associated with male infertility: a case-control study

Background: Male infertility is a common cause of reproductive failure in humans. In mice, targeted deletions of the genes coding for FKBP6 or FKBP52, members of the FK506 binding protein family, can result in male infertility. In the case of FKBP52, this reflects an important role in potentiating Androgen Receptor (AR) signalling in the prostate and accessory glands, but not the testis. In infertile men, no mutations of FKBP52 or FKBP6 have been found so far, but the gene for FKBP-like (FKBPL) maps to chromosome 6p21.3, an area linked to azoospermia in a group of Japanese patients.

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

Moisture-Activated Rheological Structuring of Nonaqueous Poloxamine–Poly(Acrylic Acid) Systems Designed as Novel Biomedical Implants

This study reports the formulation/characterisation of novel polymeric platforms designed to behave as low-viscosity systems in the nonaqueous state, however, following uptake of aqueous ?uids, exhibit rheological structuring and mucoadhesion. The rheological/mechanical and mucoadhesive properties of platforms containing poly(acrylic acid) (PAA, 1%, 3%, 5%, w/w) and poloxamines (Tetronic 904, 901, 704, 701, 304), both in the absence and presence of phosphate buffered saline (PBS, pH 7.4) are described. With the exception of Tetronic 904, all formulations exhibited Newtonian ?ow in the nonaqueous state, whereas, all aqueous formulations displayed pseudoplastic ?ow. The consistency and viscoelastic properties were dependent on the concentrations of PAA and PBS and Tetronic grade. PBS signi?cantly increased the consistency, viscoelasticity and mucoadhesion, reaching a maximum at a de?ned concentration of PBS that was dependent on PAA concentration and Tetronic grade. Formulations containing Tetronic 904 exhibited greatest consistency and elasticity both prior to and after dilution with PBS. Increasing PAA concentration enhanced the mucoadhesive properties. Prolonged drug release of metronidazole was observed from formulations containing 10% (w/w) PBS, 3% and, particularly, 5% (w/w) PAA. It is suggested that the physicochemical properties of formulations containing 3% or 5% (w/w) PAA and Tetronic 904, would render them suitable platforms for administration to body cavities.

Lacustrine evidence of Holocene environmental change from three Faroese lakes: a multiproxy XRF and stable isotope study

The vegetation history of the Faroe Islands has been investigated in numerous studies all broadly showing that the early-Holocene vegetation of the islands largely consisted of fellfield with gravely and rocky soils formed under a continental climate which shifted to an oceanic climate around 10,000 cal yr BP when grasses, sedges and finally shrubs began to dominant the islands. Here we present data from three lake sediment cores and show a much more detailed history from geochemical and isotope data. These data show that the Faroe Islands were deglaciated by the end of Younger Dryas (11,700 10,300 cal yr BP), at this time relatively high sedimentation rates with high delta C-13 imply poor soil development. delta C-13, Ti and chi data reveal a much more stable and warm mid-Holocene until 7410 cal yr BP characterised by increasing vegetation cover and build up of organic soils towards the Holocene thermal maximum around 7400 cal yr BP. The final meltdown of the Laurentide ice sheet around 7000 cal yr BP appears to have impacted both ocean and atmospheric circulation towards colder conditions on the Faroe Islands. This is inferred by enhanced weathering and increased deposition of surplus sulphur (sea spray) and erosion in the highland lakes from about 7400 cal yr BP. From 4190 cal yr BP further cooling is believed to have occurred as a consequence for increased soil erosion due to freeze/thaw sequences related to oceanic and atmospheric variability. This cooling trend appears to have advanced further from 3000 cal yr BR A short period around 1800 cal yr BP appears as a short warm and wet phase in between a general cooling characterised by significant soil erosion lasting until 725 cal yr BP. Interestingly, increased soil erosion seems to have begun at 1360 cal yr BP, thus significantly before the arrival of the first settlers on the Faroe Island around 1150 cal yr BP, although additional erosion took place around 1200 cal yr BP possibly as a consequence of human activities. Hence it appears that if humans caused a change in the Faroe landscape in terms of erosion they in fact accelerated a process that had already started. Soil erosion was a dominant landscape factor during the Little Ice Age, but climate related triggers can hardly be distinguished from human activities. (c) 2010 Elsevier Ltd. All rights reserved.

Potential Rôle of Hares in the Spread of Liver Fluke in the Netherlands.

Hares (Lepus europeanus) sharing pasture with cattle from six locations in the Netherlands were examined for the presence of liver fluke (Fasciola hepatica) and shown to have prevalences of infection ranging from zero to 41%. The mitochondrial haplotypes of liver flukes present in the hare populations were determined and compared with those found in cattle from a farm where triclabendazole resistance has been reported. Phylogenetic analysis indicated that the flukes present in the hares belonged to the same clades as those present in the cattle. A consideration of the life cycle of the liver fluke and the seasonal breeding pattern and ecology of hares supports the suggestion that hares may act as a refugia for liver fluke and as a vector for the spread of drug-resistant genotypes.

Modelling non-adiabatic processes using correlated electron-ion dynamics

Here we survey the theory and applications of a family of methods (correlated electron-ion dynamics, or CEID) that can be applied to a diverse range of problems involving the non-adiabatic exchange of energy between electrons and nuclei. The simplest method, which is a paradigm for the others, is Ehrenfest Dynamics. This is applied to radiation damage in metals and the evolution of excited states in conjugated polymers. It is unable to reproduce the correct heating of nuclei by current carrying electrons, so we introduce a moment expansion that allows us to restore the spontaneous emission of phonons. Because of the widespread use of Non-Equilibrium Green's Functions for computing electric currents in nanoscale systems, we present a comparison of this formalism with that of CEID with open boundaries. When there is strong coupling between electrons and nuclei, the moment expansion does not converge. We thus conclude with a reworking of the CEID formalism that converges systematically and in a stable manner.

Guidelines for the measurement of BCR-ABL1 transcripts in chronic myeloid leukaemia

Molecular testing for the BCR-ABL1 fusion gene by real time quantitative polymerase chain reaction (RT-qPCR) is the most sensitive routine approach for monitoring the response to therapy of patients with chronic myeloid leukaemia. In the context of tyrosine kinase inhibitor (TKI) therapy, the technique is most appropriate for patients who have achieved complete cytogenetic remission and can be used to define specific therapeutic milestones. To achieve this effectively, standardization of the laboratory procedures and the interpretation of results are essential. We present here consensus best practice guidelines for RT-qPCR testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 21 testing laboratories in the United Kingdom and Ireland in accordance with the procedures of the UK Clinical Molecular Genetics Society.