Ring-fencing a budget for cancer drugs: is it fair?

Ring-fencing is defined as protecting funds for use in a specific area. In the NationalHealth Service in the UK, various methods to ring-fence cancer have beenemployed over the years; more recently the Cancer Drugs Fund in England hasenabled cancer drugs that would not normally be considered cost-effective to beprovided to patients. This has created variation in provision between England andthe devolved countries. While some would argue that ring-fencing allows majoradvances to be made in the treatment of a particular condition, others wouldargue that it is intrinsically unfair. In this debate, Graham and Cassidy have writtenan article arguing the affirmative position and Hughes and Duerden were invitedto respond directly to their arguments. As with all the RCPE's 'Currentcontroversies', the authors have been asked to take a deliberately polarisedposition and so the views they express may be somewhat overstated

The search for novel analgesics: re-examining spinal cord circuits with new tools

In this perspective, we propose the absence of detailed information regarding spinal cord circuits that process sensory information remains a major barrier to advancing analgesia. We highlight recent advances showing that functionally discrete populations of neurons in the spinal cord dorsal horn play distinct roles in processing sensory information. We then discuss new molecular, electrophysiological, and optogenetic techniques that can be employed to understand how dorsal horn circuits process tactile and nociceptive information. We believe this information can drive the development of entirely new classes of pharmacotherapies that target key elements in spinal circuits to selectively modify sensory function and blunt pain

Ecosystem uptake and transfer of Sellafield-derived radiocarbon (14C). Part 1. The Irish Sea

Ecosystem uptake and transfer processes of Sellafield-derived radiocarbon (14C) within the Irish Sea were examined. Highly variable activities in sediment, seawater and biota indicate complex 14C dispersal and uptake dynamics. All east basin biota exhibited 14C enrichments above ambient background while most west basin biota had 14C activities close to background, although four organisms including two slow-moving species were significantly enriched. The western Irish Sea gyre is a suggested pathway for transfer of 14C to the west basin and retention therein. Despite ongoing Sellafield 14C discharges, organic sediments near Sellafield were significantly less enriched than associated benthic organisms. Rapid scavenging of labile, 14C-enriched organic material by organisms and mixing to depth of 14C-enriched detritus arriving at the sediment/water interface are proposed mechanisms to explain this. All commercially important fish, crustaceans and molluscs showed 14C enrichments above background; however, the radiation dose from their consumption is extremely low and radiologically insignificant

Contrasting alterations to synaptic and intrinsic properties in upper-cervical superficial dorsal horn neurons following acute neck muscle inflammation

Background: Acute and chronic pain in axial structures, like the back and neck, are difficult to treat, and have incidence as high as 15%. Surprisingly, most preclinical work on pain mechanisms focuses on cutaneous structures in the limbs and animal models of axial pain are not widely available. Accordingly, we developed a mouse model of acute cervical muscle inflammation and assessed the functional properties of superficial dorsal horn (SDH) neurons.<p></p> Results: Male C57/Bl6 mice (P24-P40) were deeply anaesthetised (urethane 2.2?g/kg i.p) and the rectus capitis major muscle (RCM) injected with 40??l of 2% carrageenan. Sham animals received vehicle injection and controls remained anaesthetised for 2?hrs. Mice in each group were sacrificed at 2?hrs for analysis. c-Fos staining was used to determine the location of activated neurons. c-Fos labelling in carrageenan-injected mice was concentrated within ipsilateral (87% and 63% of labelled neurons in C1 and C2 segments, respectively) and contralateral laminae I - II with some expression in lateral lamina V. c-Fos expression remained below detectable levels in control and sham animals. In additional experiments, whole cell recordings were obtained from visualised SDH neurons in transverse slices in the ipsilateral C1 and C2 spinal segments. Resting membrane potential and input resistance were not altered. Mean spontaneous EPSC amplitude was reduced by ~20% in neurons from carrageenan-injected mice versus control and sham animals (20.63???1.05 vs. 24.64???0.91 and 25.87???1.32 pA, respectively). The amplitude (238???33 vs. 494???96 and 593???167 pA) and inactivation time constant (12.9???1.5 vs. 22.1???3.6 and 15.3???1.4?ms) of the rapid A type potassium current (IAr), the dominant subthreshold current in SDH neurons, were reduced in carrageenan-injected mice.<p></p> Conclusions: Excitatory synaptic drive onto, and important intrinsic properties (i.e., IAr) within SDH neurons are reduced two hours after acute muscle inflammation. We propose this time point represents an important transition period between peripheral and central sensitisation with reduced excitatory drive providing an initial neuroprotective mechanism during the early stages of the progression towards central sensitisation

Anatomical and molecular properties of long descending propriospinal neurons in mice

Long descending propriospinal neurons (LDPNs) are interneurons that form direct connections between cervical and lumbar spinal circuits. LDPNs are involved in interlimb coordination and are important mediators of functional recovery after spinal cord injury (SCI). Much of what we know about LDPNs comes from a range of species, however, the increased use of transgenic mouse lines to better define neuronal populations calls for a more complete characterisation of LDPNs in mice. In this study, we examined the cell body location, inhibitory neurotransmitter phenotype, developmental provenance, morphology and synaptic inputs of mouse LDPNs throughout the cervical and upper thoracic spinal cord. LDPNs were retrogradely labelled from the lumbar spinal cord to map cell body locations throughout the cervical and upper thoracic segments. Ipsilateral LDPNs were distributed throughout the dorsal, intermediate and ventral grey matter as well as the lateral spinal nucleus and lateral cervical nucleus. In contrast, contralateral LDPNs were more densely concentrated in the ventromedial grey matter. Retrograde labelling in GlyT2GFP and GAD67GFP mice showed the majority of inhibitory LDPNs project either ipsilaterally or adjacent to the midline. Additionally, we used several transgenic mouse lines to define the developmental provenance of LDPNs and found that V2b positive neurons form a subset of ipsilaterally projecting LDPNs. Finally, a population of Neurobiotin (NB) labelled LDPNs were assessed in detail to examine morphology and plot the spatial distribution of contacts from a variety of neurochemically distinct axon terminals. These results provide important baseline data in mice for future work on their role in locomotion and recovery from SCI

Aerodynamic stability characteristics of the Apollo command module

Wind tunnel test data on static and dynamic stability of Apollo command module configuratio

Serum vitamin D levels, diabetes and cardio-metabolic risk factors in Aboriginal and Torres Strait Islander Australians

Assesses levels of serum 25(OH)D in Aboriginal and Torres Strait Islander Australians and explores relationships between 25(OH)D and cardio-metabolic risk factors and diabetes. Abstract Background: Low levels of serum 25 – hydroxy vitamin D (25(OH)D), have been associated with development of type 2 diabetes and cardiovascular disease (CVD); however there are limited data on serum 25(OH)D in Indigenous Australians, a population at high risk for both diabetes and CVD. We aimed to assess levels of serum 25(OH)D in Aboriginal and Torres Strait Islander Australians and to explore relationships between 25(OH)D and cardio-metabolic risk factors and diabetes. Methods: 592 Aboriginal and/or Torres Strait Islander Australian participants of The eGFR (estimated glomerular filtration rate) Study, a cross-sectional analysis of a cohort study performed in 2007 – 2011, from urban and remote centres within communities, primary care and tertiary hospitals across Northern Territory, Far North Queensland and Western Australia. Assessment of serum 25(OH)D, cardio-metabolic risk factors (central obesity, diabetes, hypertension, history of cardiovascular disease, current smoker, low HDL-cholesterol), and diabetes (by history or HbA1c ≥ 6.5%) was performed. Associations were explored between 25(OH)D and outcome measures of diabetes and number of cardio-metabolic risk factors. Results: The median (IQR) serum 25(OH)D was 60 (45 – 77) nmol/L, 31% had 25(OH)D <50 nmol/L. For participants with 25(OH)D < 50 vs ≥ 50 nmol/L, cardio-metabolic risk profile differed for: diabetes (54%, 36% p < 0.001), past history of cardiovascular disease (16%, 9%, p = 0.014), waist-hip ratio (0.98, 0.92, p < 0.001), urine albumin-creatinine ratio (2.7, 1.5 mg/mmol, p < 0.001). The OR (95% CI) for diabetes was 2.02 (1.03 – 3.95) for people in the lowest vs highest tertiles of 25(OH)D (<53 vs >72 nmol/L, respectively) after adjusting for known cardio-metabolic risk factors. Conclusion: The percentage of 25(OH)D levels <50 nmol/L was high among Aboriginal and Torres Strait Islander Australians from Northern and Central Australia. Low 25(OH)D level was associated with adverse cardio-metabolic risk profile and was independently associated with diabetes. These findings require exploration in longitudinal studies

Integral Field Spectroscopy of 23 Spiral Bulges

We have obtained Integral Field Spectroscopy for 23 spiral bulges using INTEGRAL on the William Herschel Telescope and SPIRAL on the Anglo-Australian Telescope. This is the first 2D survey directed solely at the bulges of spiral galaxies. Eleven galaxies of the sample do not have previous measurements of the stellar velocity dispersion (sigma*). These data are designed to complement our Space Telescope Imaging Spectrograph program for estimating black hole masses in the range 10^6-10^8M_sun using gas kinematics from nucleated disks. These observations will serve to derive the stellar dynamical bulge properties using the traditional Mgb and CaII triplets. We use both Cross Correlation and Maximum Penalized Likelihood to determine projected sigma* in these systems and present radial velocity fields, major axis rotation curves, curves of growth and sigma* fields. Using the Cross Correlation to extract the low order 2D stellar dynamics we generally see coherent radial rotation and irregular velocity dispersion fields suggesting that sigma* is a non-trivial parameter to estimate.Comment: 11 pages, 30 figures, accepted for publication in ApJ

Reassessing the status of antiphospholipid syndrome in systemic lupus erythematosus.

The antiphospholipid syndrome was initially described in 1986. To reassess the validity of antiphospholipid antibodies in systemic lupus erythematosus (SLE), 95 patients with SLE were studied. Their antiphospholipid antibody profile was analysed and correlated with clinical findings such as thrombosis, abortions, or thrombocytopenia. A low prevalence of these antibodies was found (13 patients; 14%) with a high specificity for thrombosis (92%) and abortions (92%). The importance of anticardiolipin antibodies as a risk factor for thrombosis or abortions, or both, in patients with SLE is reaffirmed by this work

Akt regulates centrosome migration and spindle orientation in the early Drosophila melanogaster embryo

Correct positioning and morphology of the mitotic spindle is achieved through regulating the interaction between microtubules (MTs) and cortical actin. Here we find that, in the Drosophila melanogaster early embryo, reduced levels of the protein kinase Akt result in incomplete centrosome migration around cortical nuclei, bent mitotic spindles, and loss of nuclei into the interior of the embryo. We show that Akt is enriched at the embryonic cortex and is required for phosphorylation of the glycogen synthase kinase-3β homologue Zeste-white 3 kinase (Zw3) and for the cortical localizations of the adenomatosis polyposis coli (APC)–related protein APC2/E-APC and the MT + Tip protein EB1. We also show that reduced levels of Akt result in mislocalization of APC2 in postcellularized embryonic mitoses and misorientation of epithelial mitotic spindles. Together, our results suggest that Akt regulates a complex containing Zw3, Armadillo, APC2, and EB1 and that this complex has a role in stabilizing MT–cortex interactions, facilitating both centrosome separation and mitotic spindle orientation