The multidrug-resistant cancer cell lines NCI/AdR RES and MES-SA/DX-5 have higher glycolipid levels and higher P-glycoprotein expression than the chemosensitive cell lines MCF7-wt and MES-SA. Inhibiting glycolipid biosynthesis by blocking glucosylceramide synthase has been proposed to reverse drug resistance in MDR cells by causing an increased accumulation of proapoptotic ceramide during treatment of cells with cytotoxic drugs. We treated both multidrug-resistant cell lines with the glucosylceramide synthase inhibitors PDMP (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol), C 9 DGJ (N-nonyl-deoxygalactonojirimycin) or C 4 DGJ (N-butyl-deoxygalactonojirimycin). PDMP achieved a significant reversal of drug resistance in agreement with previous reports. However, the Nalkylated iminosugars C 9 DGJ and C 4 DGJ, which are more selective glucosylceramide synthase inhibitors than PDMP, failed to cause any reversal of drug resistance despite depleting glycolipids to the same extent as PDMP. Our results suggest that (a) inhibition of glucosylceramide synthase does not reverse multidrug resistance and (b) the chemosensitization achieved by PDMP cannot be caused by inhibition of glucosylceramide synthase alone.A major limitation in chemotherapy for cancer is multidrug resistance (MDR), 1 an innate or acquired phenotype, which allows cancer cells to resist a broad spectrum of chemotherapeutic drugs. One of the most extensively studied and clinically relevant mechanisms of drug resistance is the overexpression by cancer cells of the transmembrane multidrug transporter P-glycoprotein (MDR1, ABCB1, EC 3.6.3.44) (1). However, a drug resistance phenotype comprises many, often interacting, mechanisms of resistance (2). These include increased DNA repair, altered target sensitivity, decreased apoptotic response and numerous aberrant signal transduction pathways. Elevated levels of glycolipids have been correlated with multidrug resistance in cancer (3, 4). Manipulation of glycolipid levels in some MDR cancer cells was able to reverse drug resistance (5-12). This led to the hypothesis that elevated glucosylceramide synthase (GCS, EC 2.4.1.80) activity is a novel form of multidrug resistance and that inhibition of GCS is a promising therapeutic strategy for combating multidrug resistance. The biochemical basis is that an elevated GCS activity prevents the accumulation of ceramide, which is thought to precede, and trigger, apoptosis in response to some cytotoxic drugs (13-16). Therefore, inhibition of GCS activity will promote the accumulation of pro-apoptotic ceramide and enhance cell death in response to cytotoxic agents (17-21).This hypothesis rests largely on three lines of evidence. The first is that multidrug resistance correlates with elevated glycolipid levels (4), which is unfortunately hindered by the small number of samples analyzed and the fact that variability of glycolipid levels in cancers remains unknown.Second, genetic manipulation of the GCS enzyme in MCF7 cells can affect their sensitivity to various cytot...

Introduction: Thames Valley Air Ambulance have carried two units of red blood cells on board both the aircraft and rapid response car since 2014. Methods: A retrospective database narrative review of patients receiving blood was carried out. Results: Data were analysed for 63 patients, the age range was 13 years to 89 years and 74.6% were male. Blunt trauma was the mechanism of injury in 84%. Overall, 16% of patients died at scene, 32% died either in the Emergency Department or as a hospital inpatient and 52% survived to discharge. There were no survivors from traumatic cardiac arrest who received blood products. Injury Severity Scores (ISS) ranged from 4 to 75, and 95% of the patients for whom data were available had an Injury Severity Scores greater than 15. Discussion: Patients who received pre-hospital blood transfusions were overwhelmingly those with high Injury Severity Scores and the majority who survived to hospital received additional blood products on arrival. This suggests that our pre-hospital blood transfusions were correctly targeted to severely injured patients who had a need for blood transfusion in hospital.

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Oxford Cases in Medicine and Surgery, second edition, teaches students a logical step-by-step diagnostic approach to common patient presentations. This approach mirrors that used by successful clinicians on the wards, challenging students with questions at each stage of a case (history-taking, examination, investigation, management). In tackling these questions, students understand how to critically analyse information and learn to integrate their existing knowledge to a real-life scenario from start to finish. Each chapter focuses on a common presenting symptom (e.g. chest pain). By starting with a symptom, mirroring real life settings, students learn to draw on their knowledge of different physiological systems - for example, cardiology, respiratory, gastroenterology - at the same time. All the major presenting symptoms in general medicine and surgery are covered, together with a broad range of pathologies. This book is an essential resource for all medicine students, and provides a modern, well-rounded introduction to life on the wards. Ideal for those starting out in clinical medicine and an ideal refresher for those revising for OSCEs and finals.