Heterogeneous melting near the Thwaites Glacier grounding line.

Thwaites Glacier represents 15% of the ice discharge from the West Antarctic Ice Sheet and influences a wider catchment1-3. Because it is grounded below sea level4,5, Thwaites Glacier is thought to be susceptible to runaway retreat triggered at the grounding line (GL) at which the glacier reaches the ocean6,7. Recent ice-flow acceleration2,8 and retreat of the ice front8-10 and GL11,12 indicate that ice loss will continue. The relative impacts of mechanisms underlying recent retreat are however uncertain. Here we show sustained GL retreat from at least 2011 to 2020 and resolve mechanisms of ice-shelf melt at the submetre scale. Our conclusions are based on observations of the Thwaites Eastern Ice Shelf (TEIS) from an underwater vehicle, extending from the GL to 3 km oceanward and from the ice-ocean interface to the sea floor. These observations show a rough ice base above a sea floor sloping upward towards the GL and an ocean cavity in which the warmest water exceeds 2 °C above freezing. Data closest to the ice base show that enhanced melting occurs along sloped surfaces that initiate near the GL and evolve into steep-sided terraces. This pronounced melting along steep ice faces, including in crevasses, produces stratification that suppresses melt along flat interfaces. These data imply that slope-dependent melting sculpts the ice base and acts as an important response to ocean warming.

cGMP signaling inhibits platelet shape change through regulation of the RhoA-Rho Kinase-MLC phosphatase signaling pathway.

Essentials Platelet shape change requires cytoskeletal rearrangement via myosin-mediated actin contraction. We investigated whether nitric oxide (NO) affected thrombin-induced platelet shape change. NO inhibits shape change, RhoA/ROCK signalling and myosin light chain (MLC) phosphorylation. NO promotes MLC phosphatase activity, thus prevents MLC phosphorylation and shape change. SUMMARY: Background Platelet shape change, spreading and thrombus stability require activation of the actin cytoskeleton contractile machinery. The mechanisms controlling actin assembly to prevent unwanted platelet activation are unclear. Objectives We examined the effects of nitric oxide on the signaling pathways regulating platelet actin-myosin activation. Results S-nitrosoglutathione (GSNO) inhibited thrombin-induced platelet shape change and myosin phosphorylation of the myosin light chain (MLC). Because thrombin stimulates phospho-MLC through the RhoA/ ROCK dependent inhibition of MLC phosphatase (MLCP) we examined the effects of NO on this pathway. Thrombin caused the GTP loading and activation of RhoA, leading to the ROCK-mediated phosphorylation of MLCP on threonine 853 (thr853 ), which is known to inhibit phosphatase activity. Treatment of platelets with GSNO blocked ROCK-mediated increases in phosphoMLCP-thr853 induced by thrombin. This effect was mimicked by the direct activator of protein kinase G, 8-pCPT-PET-cGMP, and blocked by the inhibition of guanylyl cyclase, but not inhibitors of protein kinase A. Further exploration of the mechanism demonstrated that GSNO stimulated the association of RhoA with protein kinase G (PKG) and the inhibitory phosphorylation (serine188) of RhoA in a cGMP-dependent manner. Consistent with these observations, in vitro experiments revealed that recombinant PKG caused direct phosphorylation of RhoA. The inhibition of RhoA by GSNO prevented ROCK-mediated phosphorylation and inhibition of MLCP activity. Conclusions These data suggest novel crosstalk between the NO-cGMP-PKG and RhoA/ROCK signaling pathways to control platelet actin remodeling.

Three-year audit and cost assessment of open abdominal aortic aneurysm repair in a district general hospital.

INTRODUCTION: The aims of this study were to audit the outcome of elective open abdominal aortic aneurysm (AAA) repair in a district general hospital, as well as investigate the true costs for this procedure in relation to the national tariff. PATIENTS AND METHODS: A database is maintained on AAA surgery in the trust. Data were supplemented by drawing information from blood bank and clinical notes. Patients with symptomatic or emergency aneurysms were excluded. Data from January 2005 to December 2007 were obtained on demographics, morbidity, 30-day mortality and blood usage. Costs were obtained from the trust finance department. RESULTS: Between January 2005 and December 2007, 79 elective AAA procedures were undertaken. Median age was 75 years (range, 52-85 years), median aneurysm size was 63 mm (range, 42-105 mm) and median ITU stay was 3 days (range, 1-41 days). Major morbidity rate was 20.3% (16 of 79 patients) and 30-day mortality overall was 5.1% (4 of 79 patients). Average cost per case was pound15,012.91 (range, pound4,040.03- pound82,158.00), when National Tariff is pound6,722.00 ( pound5,649.00 x local Market Forces Factor of 1.19). Loss per case for our trust was pound8,290.91 with a total annual loss of pound218,299.56. CONCLUSIONS: Morbidity and mortality in this district general hospital compare well with national studies; however, the total cost is far in excess of the national tariff.

Fluvastatin reduces oxidative damage in human vascular endothelial cells by upregulating Bcl-2.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been widely used in clinical practise and their efficacy in reducing cardiovascular risk has been well described. OBJECTIVES: To investigate the effect of low doses of fluvastatin (nanomolar) on H(2)O(2)-induced cell damage and the underlying mechanism. METHODS AND RESULTS: Primary cultures of human umbilical vein endothelial cells were used, and the effects of fluvastatin on H(2)O(2)-induced apoptosis, necrosis, and proliferation were observed. H(2)O(2) at a concentration of 100 mum significantly induced apoptotic cell death after 24-h cell culture. Fluvastatin at low concentrations (10-100 nm) prevented H(2)O(2)-induced apoptosis, as determined by a DNA fragmentation assay and by cell counting with trypan blue and Hoechst 33342 nuclei staining. The protective effect of fluvastatin was mediated by the upregulation of Bcl-2 expression as probed by real-time polymerase chain reaction and Western blotting. Using siRNA to knock down the expression of Bcl-2, the protective effect of fluvastatin was abolished. Fluvastatin had no direct effect on the H(2)O(2)-sensitive TRPM2 calcium channel. CONCLUSIONS: These results suggest that fluvastatin has a potent protective effect against H(2)O(2)-induced apoptosis via upregulation of Bcl-2 expression. The findings provide a new insight into the mechanism by which fluvastatin is able to modulate the influence of oxidative stress on vascular endothelial cells.