Amustaline-glutathione pathogen-reduced red blood cell concentrates for transfusion-dependent thalassaemia

Transfusion-dependent thalassaemia (TDT) requires red blood cell concentrates (RBCC) to prevent complications of anaemia, but carries risk of infection. Pathogen reduction of RBCC offers potential to reduce infectious risk. We evaluated the efficacy and safety of pathogen-reduced (PR) Amustaline-Glutathione (A-GSH) RBCC for TDT. Patients were randomized to a blinded 2-period crossover treatment sequence for six transfusions over 8–10 months with Control and A-GSH-RBCC. The efficacy outcome utilized non-inferiority analysis with 90% power to detect a 15% difference in transfused haemoglobin (Hb), and the safety outcome was the incidence of antibodies to A-GSH-PR-RBCC. By intent to treat (80 patients), 12·5 ± 1·9 RBCC were transfused in each period. Storage durations of A-GSH and C-RBCC were similar (8·9 days). Mean A-GSH-RBCC transfused Hb (g/kg/day) was not inferior to Control (0·113 ± 0·04 vs. 0·111 ± 0·04, P = 0·373, paired t-test). The upper bound of the one-sided 95% confidence interval for the treatment difference from the mixed effects model was 0·005 g/kg/day, within a non-inferiority margin of 0·017 g/kg/day. A-GSH-RBCC mean pre-transfusion Hb levels declined by 6·0 g/l. No antibodies to A-GSH-RBCC were detected, and there were no differences in adverse events. A-GSH-RBCCs offer potential to reduce infectious risk in TDT with a tolerable safety profile

Pharmaceutical care for elderly patients shared between community pharmacists and general practitioners: a randomised evaluation. RESPECT (Randomised Evaluation of Shared Prescribing for Elderly people in the Community over Time) [ISRCTN16932128]

Background: This trial aims to investigate the effectiveness and cost implications of 'pharmaceutical care' provided by community pharmacists to elderly patients in the community. As the UK government has proposed that by 2004 pharmaceutical care services should extend nationwide, this provides an opportunity to evaluate the effect of pharmaceutical care for the elderly. Design: The trial design is a randomised multiple interrupted time series. We aim to recruit 700 patients from about 20 general practices, each associated with about three community pharmacies, from each of the five Primary Care Trusts in North and East Yorkshire. We shall randomise the five resulting groups of practices, pharmacies and patients to begin pharmaceutical care in five successive phases. All five will act as controls until they receive the intervention in a random sequence. Until they receive training community pharmacists will provide their usual dispensing services and so act as controls. The community pharmacists and general practitioners will receive training in pharmaceutical care for the elderly. Once trained, community pharmacists will meet recruited patients, either in their pharmacies (in a consultation room or dispensary to preserve confidentiality) or at home. They will identify drug-related issues/problems, and design a pharmaceutical care plan in conjunction with both the GP and the patient. they will implement monitor, and update this plan monthly. the primary outcome measure is the 'Medication Appropriateness Index'. Secondary measures include adverse events, quality of life, and patient knowledge and compliance. We shall also investigate the cost of pharmaceutical care to the NHS, to patients and to society as a whole

Off the Couch and Onto the Streets: Toward an Ethnographic Psychoanalysis

Psychoanalysis has much to gain by incorporating ethnographic methods into its repertoire. Recent works in ethnographic psychoanalysis demonstrate how psychoanalysis stands to function better as both community intervention and participatory action research. This article describes the historical convergence between psychoanalysis and cultural anthropology and situates ethnographic psychoanalysis within interdisciplinary theory and practice

Differential Control of Yersinia pestis Biofilm Formation In Vitro and in the Flea Vector by Two c-di-GMP Diguanylate Cyclases

Yersinia pestis forms a biofilm in the foregut of its flea vector that promotes transmission by flea bite. As in many bacteria, biofilm formation in Y. pestis is controlled by intracellular levels of the bacterial second messenger c-di-GMP. Two Y. pestis diguanylate cyclase (DGC) enzymes, encoded by hmsT and y3730, and one phosphodiesterase (PDE), encoded by hmsP, have been shown to control biofilm production in vitro via their opposing c-di-GMP synthesis and degradation activities, respectively. In this study, we provide further evidence that hmsT, hmsP, and y3730 are the only three genes involved in c-di-GMP metabolism in Y. pestis and evaluated the two DGCs for their comparative roles in biofilm formation in vitro and in the flea vector. As with HmsT, the DGC activity of Y3730 depended on a catalytic GGDEF domain, but the relative contribution of the two enzymes to the biofilm phenotype was influenced strongly by the environmental niche. Deletion of y3730 had a very minor effect on in vitro biofilm formation, but resulted in greatly reduced biofilm formation in the flea. In contrast, the predominant effect of hmsT was on in vitro biofilm formation. DGC activity was also required for the Hms-independent autoaggregation phenotype of Y. pestis, but was not required for virulence in a mouse model of bubonic plague. Our results confirm that only one PDE (HmsP) and two DGCs (HmsT and Y3730) control c-di-GMP levels in Y. pestis, indicate that hmsT and y3730 are regulated post-transcriptionally to differentially control biofilm formation in vitro and in the flea vector, and identify a second c-di-GMP-regulated phenotype in Y. pestis

A new Raman metric for the characterisation of graphene oxide and its derivatives

Raman spectroscopy is among the primary techniques for the characterisation of graphene materials, as it provides insights into the quality of measured graphenes including their structure and conductivity as well as the presence of dopants. However, our ability to draw conclusions based on such spectra is limited by a lack of understanding regarding the origins of the peaks. Consequently, traditional characterisation techniques, which estimate the quality of the graphene material using the intensity ratio between the D and the G peaks, are unreliable for both GO and rGO. Herein we reanalyse the Raman spectra of graphenes and show that traditional methods rely upon an apparent G peak which is in fact a superposition of the G and D’ peaks. We use this understanding to develop a new Raman characterisation method for graphenes that considers the D’ peak by using its overtone the 2D’. We demonstrate the superiority and consistency of this method for calculating the oxygen content of graphenes, and use the relationship between the D’ peak and graphene quality to define three regimes. This has important implications for purification techniques because, once GO is reduced beyond a critical threshold, further reduction offers limited gain in conductivity

Correlation of three immunohistochemically detected markers of neuroendocrine differentiation with clinical predictors of disease progression in prostate cancer

<p>Abstract</p> <p>Background</p> <p>The importance of immuno-histological detection of neuroendocrine differentiation in prostatic adenocarcinoma with respect to disease at presentation and Gleason grade is gaining acceptance. There is limited literature on the relative significance of three commonly used markers of NE differentiation i.e. Chromogranin A (CgA), Neuron specific enolase (NSE) and Synaptophysin (Syn). In the current work we have assessed the correlation of immuno-histological detection of neuroendocrine differentiation in prostatic adenocarcinoma with respect to disease at presentation and Gleason grade and to determine the relative value of various markers.</p> <p>Materials and methods</p> <p>Consecutive samples of malignant prostatic specimens (Transurethral resection of prostate or radical retropubic prostatectomy) from 84 patients between January 1991 and December 1998 were evaluated by immunohistochemical staining (PAP technique) using selected neuroendocrine tumor markers i.e. Chromogranin A (CgA), Neuron specific enolase (NSE), and Synaptophysin (Syn). According to the stage at diagnosis, patients were divided into three groups. Group (i) included patients who had organ confined disease, group (ii) included patients with locally invasive disease, and group (iii) with distant metastasis. NE expression was correlated with Gleason sum and clinical stage at presentation and analyzed using Chi-Square test and one way ANNOVA.</p> <p>Results</p> <p>The mean age of the patients was 70 ± 9.2 years. Group I had 14 patients, group II had 31 patients and group III had 39 patients. CgA was detected in 33 cases, Syn in 8 cases, and NSE in 44 cases. Expression of CgA was seen in 7% of group I, 37% in group II and 35% of group III patients (p 0.059). CgA (p 0.024) and NSE (p 0.006) had a significantly higher expression with worsening Gleason grade.</p> <p>Conclusion</p> <p>CgA has a better correlation with disease at presentation than other markers used. Both NSE and CgA had increasing expression with worsening histological grade this correlation has a potential for use as a prognostic indicator. Limitations in the current work included small number and retrospective nature of work. The findings of this work needs validation in a larger cohort.</p

Dynamics of dental evolution in ornithopod dinosaurs.

Ornithopods were key herbivorous dinosaurs in Mesozoic terrestrial ecosystems, with a variety of tooth morphologies. Several clades, especially the 'duck-billed' hadrosaurids, became hugely diverse and abundant almost worldwide. Yet their evolutionary dynamics have been disputed, particularly whether they diversified in response to events in plant evolution. Here we focus on their remarkable dietary adaptations, using tooth and jaw characters to examine changes in dental disparity and evolutionary rate. Ornithopods explored different areas of dental morphospace throughout their evolution, showing a long-term expansion. There were four major evolutionary rate increases, the first among basal iguanodontians in the Middle-Late Jurassic, and the three others among the Hadrosauridae, above and below the split of their two major clades, in the middle of the Late Cretaceous. These evolutionary bursts do not correspond to times of plant diversification, including the radiation of the flowering plants, and suggest that dental innovation rather than coevolution with major plant clades was a major driver in ornithopod evolution

Microfabricated Physical Spatial Gradients for Investigating Cell Migration and Invasion Dynamics

We devise a novel assay that introduces micro-architectures into highly confining microchannels to probe the decision making processes of migrating cells. The conditions are meant to mimic the tight spaces in the physiological environment that cancer cells encounter during metastasis within the matrix dense stroma and during intravasation and extravasation through the vascular wall. In this study we use the assay to investigate the relative probabilities of a cell 1) permeating and 2) repolarizing (turning around) when it migrates into a spatially confining region. We observe the existence of both states even within a single cell line, indicating phenotypic heterogeneity in cell migration invasiveness and persistence. We also show that varying the spatial gradient of the taper can induce behavioral changes in cells, and different cell types respond differently to spatial changes. Particularly, for bovine aortic endothelial cells (BAECs), higher spatial gradients induce more cells to permeate (60%) than lower gradients (12%). Furthermore, highly metastatic breast cancer cells (MDA-MB-231) demonstrate a more invasive and permeative nature (87%) than non-metastatic breast epithelial cells (MCF-10A) (25%). We examine the migration dynamics of cells in the tapered region and derive characteristic constants that quantify this transition process. Our data indicate that cell response to physical spatial gradients is both cell-type specific and heterogeneous within a cell population, analogous to the behaviors reported to occur during tumor progression. Incorporation of micro-architectures in confined channels enables the probing of migration behaviors specific to defined geometries that mimic in vivo microenvironments