The extreme yet transient nature of glacial erosion.

Ice can sculpt extraordinary landscapes, yet the efficacy of, and controls governing, glacial erosion on geological timescales remain poorly understood and contended, particularly across Polar continental shields. Here, we assimilate geophysical data with modelling of the Eurasian Ice Sheet - the third largest Quaternary ice mass that spanned 49°N to 82°N - to decipher its erosional footprint during the entire last ~100 ka glacial cycle. Our results demonstrate extreme spatial and temporal heterogeneity in subglacial erosion, with rates ranging from 0 to 5 mm a-1 and a net volume equating to ~130,000 km3 of bedrock excavated to depths of ~190 m. A hierarchy of environmental controls ostensibly underpins this complex signature: lithology, topography and climate, though it is basal thermodynamics that ultimately regulates erosion, which can be variously protective, pervasive, or, highly selective. Our analysis highlights the remarkable yet fickle nature of glacial erosion - critically modulated by transient ice-sheet dynamics - with its capacity to impart a profound but piecemeal geological legacy across mid- and high latitudes.

Gas hydrate dissociation off Svalbard induced by isostatic rebound rather than global warming.

Methane seepage from the upper continental slopes of Western Svalbard has previously been attributed to gas hydrate dissociation induced by anthropogenic warming of ambient bottom waters. Here we show that sediment cores drilled off Prins Karls Foreland contain freshwater from dissociating hydrates. However, our modeling indicates that the observed pore water freshening began around 8 ka BP when the rate of isostatic uplift outpaced eustatic sea-level rise. The resultant local shallowing and lowering of hydrostatic pressure forced gas hydrate dissociation and dissolved chloride depletions consistent with our geochemical analysis. Hence, we propose that hydrate dissociation was triggered by postglacial isostatic rebound rather than anthropogenic warming. Furthermore, we show that methane fluxes from dissociating hydrates were considerably smaller than present methane seepage rates implying that gas hydrates were not a major source of methane to the oceans, but rather acted as a dynamic seal, regulating methane release from deep geological reservoirs.

Massive blow-out craters formed by hydrate-controlled methane expulsion from the Arctic seafloor.

Widespread methane release from thawing Arctic gas hydrates is a major concern, yet the processes, sources, and fluxes involved remain unconstrained. We present geophysical data documenting a cluster of kilometer-wide craters and mounds from the Barents Sea floor associated with large-scale methane expulsion. Combined with ice sheet/gas hydrate modeling, our results indicate that during glaciation, natural gas migrated from underlying hydrocarbon reservoirs and was sequestered extensively as subglacial gas hydrates. Upon ice sheet retreat, methane from this hydrate reservoir concentrated in massive mounds before being abruptly released to form craters. We propose that these processes were likely widespread across past glaciated petroleum provinces and that they also provide an analog for the potential future destabilization of subglacial gas hydrate reservoirs beneath contemporary ice sheets.

Acute Kidney Injury in Cirrhosis: Baseline Serum Creatinine Predicts Patient Outcomes.

OBJECTIVES: The International Ascites Club (IAC) recently defined Stage 1 acute kidney injury (AKI) for cirrhosis as an acute increase in serum creatinine (SCr) by ≥0.3 mg/dl or by ≥50% in <48 h from a stable value within 3 months. The baseline SCr may influence AKI risk and patient outcomes. The objective of this study is to determine in cirrhosis whether the baseline SCr has any effect on the in-hospital AKI course and patient survival. METHODS: North American Consortium for the Study of End-Stage Liver Disease is a consortium of tertiary-care hepatology centers prospectively enroling non-elective cirrhotic inpatients. Patients with different baseline SCr levels (≤0.5, 0.51-1.0, 1.01-1.5, >1.5 mg/dl) were evaluated for the development of AKI, and compared for AKI outcomes and 30-day survival. RESULTS: 653 hospitalized cirrhotics (56.7±10years, 64% men, 30% with infection) were included. The incidence of AKI was 47% of enrolled patients. Patients with higher baseline SCr were more likely to develop AKI, with significantly higher delta and peak SCr (P<0.001) than the other groups, more likely to have a progressive AKI course (P<0.0001), associated with a significantly reduced 30-day survival (P<0.0001). Multivariate logistic regression showed that the delta SCr during an AKI episode to be the strongest factor impacting AKI outcomes and survival (P<0.001), with a delta SCr of 0.70 mg/dl having a 68% sensitivity and 80% specificity for predicting 30-day mortality. CONCLUSIONS: Admitted cirrhotic patients with higher baseline SCr are at higher risk for in-hospital development of AKI, and more likely to have AKI progression with reduced survival. Therefore, such patients should be closely monitored and treated promptly for their AKI.

Management of Hepatitis B virus infection during pregnancy.

Hepatitis B virus (HBV) infects over 2 billion people worldwide, with approximately 360 million chronically infected. It results in substantial morbidity and mortality, with an estimated 600,000 deaths per year. In endemic areas, mother to child transmission (MTCT) is the most important source of new infections, but even in areas with low endemicity, over 1/3 of infections can still be attributed to this route. Although very effective active-passive immunoprophylaxis with hepatitis B immune globulin (HBIG) and HBV vaccine is available, even with full compliance, failure can be seen in highly viremic mothers who are positive for hepatitis B e antigen. Potential means of reducing the risk of MTCT include nucleotide/nucleoside antiviral agents, interferon in very select cases, and mode of delivery. Determining the optimal therapy and its timing, and preventing both obstetric and liver related complications remains a challenge, but is also an important opportunity to reduce chronic hepatitis B infection. In this review, we provide an overview of issues associated with hepatitis B and its treatment during pregnancy, and suggest an algorithm for management.

Providing solid angle formalism for skyshine calculations.

We detail, derive and correct the technical use of the solid angle variable identified in formal guidance that relates skyshine calculations to dose-equivalent rate. We further recommend it for use with all National Council on Radiation Protection and Measurements (NCRP), Institute of Physics and Engineering in Medicine (IPEM) and similar reports documented. In general, for beams of identical width which have different resulting areas, within ± 1.0 % maximum deviation the analytical pyramidal solution is 1.27 times greater than a misapplied analytical conical solution through all field sizes up to 40 × 40 cm². Therefore, we recommend determining the exact results with the analytical pyramidal solution for square beams and the analytical conical solution for circular beams.

Radiation skyshine from a 6 MeV medical accelerator.

This study assesses the dose level from skyshine produced by a 6 MeV medical accelerator. The analysis of data collected on skyshine yields professional guidance for future investigators as they attempt to quantify and qualify radiation protection concerns in shielding therapy vaults. Survey measurements using various field sizes and at varying distances from a primary barrier have enabled us to identify unique skyshine behavior in comparison to other energies already seen in literature. In order to correctly quantify such measurements outside a shielded barrier, one must take into consideration the fact that a skyshine maximum may not be observed at the same distance for all field sizes. A physical attribute of the skyshine scatter component was shown to increase to a maximum value at 4.6 m from the barrier for the largest field size used. We recommend that the largest field sizes be used in the field for the determination of skyshine effect and that the peak value be further analyzed specifically when considering shielding designs.

Endogenous versus exogenous fatty acid availability affects lysosomal acidity and MHC class II expression.

Although the immune system, inflammation, and cellular metabolism are linked to diseases associated with dyslipidemias, the mechanism(s) remain unclear. To determine whether there is a mechanistic link between lipid availability and inflammation/immune activation, we evaluated macrophage cell lines incubated under conditions of altered exogenous and endogenous lipid availability. Limiting exogenous lipids results in decreased lysosomal acidity and decreased lysosomal enzymatic activity. Both lysosomal parameters are restored with the addition of oleoyl-CoA, suggesting that fatty acids play a role in the regulation of lysosomal function. Cell surface expression of major histocompatibility complex (MHC)-encoded molecules is also decreased in the absence of exogenous lipids. Additionally, we observe decreased gamma-interferon stimulation of cell surface MHC class II. Using cerulenin to limit the endogenous synthesis of fatty acids results in decreased cell surface expression of MHC class II but does not appear to alter lysosomal acidity, suggesting that lysosomal acidity is dependent on exogenous, but not endogenous, fatty acid availability. Testing these conclusions in an in vivo mouse model, we observed statistically significant, diet-dependent differences in lysosomal acidity and MHC class II cell surface expression. Collectively, these data demonstrate a mechanistic link between lipid availability and early events in the immune response.

Neutron and capture gamma along the mazes of linear accelerator vaults.

Neutron and photon dose equivalents at various points along the mazes of the vaults for two 15 MV linear accelerators were measured. The measurements were made with the machines set at various gantry angles with and without the scattering phantom, and with the collimators set at the maximum and the minimum field sizes. Neutron dose equivalent measurements were made for five other accelerator vaults. Empirical equations were used to fit the dose data at points along the center of the maze, at 1 m above floor level, with the primary radiation beam pointing downward. It is reported here that both the capture gamma and the neutron dose attenuations along the maze are in agreement with the literature. The neutron dose is dependent on the square root of the ratio of the cross-sectional areas of the inner maze entrance and the maze. The tenth value distance (T(N)) is proportional to the square root of the cross-sectional area of the maze.

Alkaline pH changes in the cerebellum of asymptomatic HIV-infected individuals.

Human immunodeficiency virus (HIV) infection of the brain causes a complex cascade of cellular events involving several different cell types that eventually leads to neuronal cell death and the manifestation of the AIDS-associated dementia complex (ADC). Upon autopsy HIV-infected individuals show lesions within subcortical regions of the brain, including the cerebellum. Previously we have demonstrated, in primary and cell culture models of rat and human astrocytes, a change in intracellular pH (pH(i)) due to increased Na(+)/H(+) exchange following exposure to inactivated virus or gp120, the major HIV envelope glycoprotein. To further investigate whether any such in vivo pH(i) changes occur in human brains subsequent to HIV infection, we measured the pH(i) of the cerebellum in eight HIV-positive individuals and nine healthy volunteers using (31)P magnetic resonance spectroscopy imaging (MRSI) at high field strength (4.1 T). The results showed a significant difference between the age-adjusted mean pH(i) in the cerebellum in control group and patient groups (7.11 +/- 0.03 vs 7.16 +/- 0.04), and further HIV-infected individuals displayed a significant increase in the number of cerebellar volume elements that were alkaline. We hypothesize that this propensity towards alterations in cerebellar pH(i) may portend later neurological involvement resulting from HIV infection.

gp120-induced alterations of human astrocyte function: Na(+)/H(+) exchange, K(+) conductance, and glutamate flux.

Many human immunodeficiency virus (HIV)-infected patients suffer from impaired neurological function and dementia. This facet of the disease has been termed acquired immunodeficiency syndrome (AIDS)-associated dementia complex (ADC). Several cell types, including astrocytes and neurons, are not productively infected by virus but are involved in ADC pathophysiology. Previous studies of rat astrocytes showed that an HIV coat protein (gp120) accelerated astrocyte Na(+)/H(+) exchange and that the resultant intracellular alkalinization activated a pH-sensitive K(+) conductance. The present experiments were conducted to determine whether gp120 affected human astrocytes in the same fashion. It was found that primary human astrocytes express a pH-sensitive K(+) conductance that was activated on intracellular alkalinization. Also, gp120 treatment of whole cell clamped human astrocytes activated this conductance specifically. Furthermore, gp120 inhibited glutamate uptake by primary human astrocytes. These altered physiological processes could contribute to pathophysiological changes in HIV-infected brains. Because the gp120-induced cell physiological changes were partially inhibited by dimethylamiloride (an inhibitor of Na(+)/H(+) exchange), our findings suggest that modification of human astrocyte Na(+)/H(+) exchange activity may provide a means of addressing some of the neurological complications of HIV infection.

Functional expression of a truncated Ca(2+)-activated Cl- channel and activation by phorbol ester.

We have isolated a niflumic acid-insensitive, Ca(2+)-activated Cl- channel (CaCC) from bovine trachea that migrates at 38 kDa (p38) on reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. However, a cloned CaCC isolated from a tracheal cDNA expression library by screening with an antibody raised against p38 has a primary cDNA transcript of 2712 base pairs that codes for a 100-kDa protein and is not susceptible to dithiothreitol reduction. To test the hypothesis that the functional channel may be a much smaller posttranslationally processed form of the 100-kDa protein, we generated a mutant construct (CaCCX, 42.5-kDa protein) truncated at the NH2 and COOH termini. The whole cell currents of wild-type (wt) CaCC and CaCCX expressed in Xenopus oocytes were 10-fold higher than those of water-injected oocytes and were further increased by ionomycin or A-23187 and inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and dithiothreitol. Whole cell currents in wtCaCC- and CaCCX-expressing oocytes could also be activated by phorbol 12-myristate 13-acetate and could be inhibited by chelerythrine chloride, suggesting that the cloned CaCC is regulated by protein kinase C. These results suggest that a smaller form of the full-length CaCC can form a functional channel.

Identification of an amiloride binding domain within the alpha-subunit of the epithelial Na+ channel.

Limited information is available regarding domains within the epithelial Na+ channel (ENaC) which participate in amiloride binding. We previously utilized the anti-amiloride antibody (BA7.1) as a surrogate amiloride receptor to delineate amino acid residues that contact amiloride, and identified a putative amiloride binding domain WYRFHY (residues 278-283) within the extracellular domain of alpharENaC. Mutations were generated to examine the role of this sequence in amiloride binding. Functional analyses of wild type (wt) and mutant alpharENaCs were performed by cRNA expression in Xenopus oocytes and by reconstitution into planar lipid bilayers. Wild type alpharENaC was inhibited by amiloride with a Ki of 169 nM. Deletion of the entire WYRFHY tract (alpharENaC Delta278-283) resulted in a loss of sensitivity of the channel to submicromolar concentrations of amiloride (Ki = 26.5 microM). Similar results were obtained when either alpharENaC or alpharENaC Delta278-283 were co-expressed with wt beta- and gammarENaC (Ki values of 155 nM and 22.8 microM, respectively). Moreover, alpharENaC H282D was insensitive to submicromolar concentrations of amiloride (Ki = 6.52 microM), whereas alpharENaC H282R was inhibited by amiloride with a Ki of 29 nM. These mutations do not alter ENaC Na+:K+ selectivity nor single-channel conductance. These data suggest that residues within the tract WYRFHY participate in amiloride binding. Our results, in conjunction with recent studies demonstrating that mutations within the membrane-spanning domains of alpharENaC and mutations preceding the second membrane-spanning domains of alpha-, beta-, and gammarENaC alters amiloride's Ki, suggest that selected regions of the extracellular loop of alpharENaC may be in close proximity to residues within the channel pore.

In vitro evidence for a dual role of tumor necrosis factor-alpha in human immunodeficiency virus type 1 encephalopathy.

Microglial cell activation, myelin alteration, and abundant tumor necrosis factor (TNF)-alpha message have been observed in the brains of some human immunodeficiency virus type 1 (HIV-1)-infected and demented patients. We therefore used cultures of purified human microglia and oligodendrocytes derived from adult human brain to examine the role of TNF-alpha in HIV-1 encephalopathy. Human microglia synthesize TNF-alpha message and protein in vitro. When these cells were infected with HIV-1 JrFL and maintained in the presence of TNF-alpha antibodies, soluble TNF-alpha receptors, or the TNF-alpha inhibitor pentoxifylline, viral replication was delayed or strongly inhibited. Both human microglia and oligodendrocytes express the two TNF receptors, TNF-R1, which has been implicated in cytotoxicity, and TNF-R2. While TNF-alpha may enhance HIV-1 replication in an autocrine manner, it is not toxic for microglia. In contrast, recombinant human TNF-alpha causes oligodendrocyte death in a dose-dependent manner. In situ detection of DNA fragmentation in some cells indicated that oligodendrocyte death may occur by apoptosis. Addition of live microglia or medium conditioned by these cells also resulted in 30 to 40% oligodendrocyte death, which was largely prevented by TNF-alpha inhibitors. We propose that TNF-alpha plays a dual role in HIV-1 encephalopathy, enhancing viral replication by activated microglia and damaging oligodendrocytes. Thus, TNF-alpha inhibitors may alleviate some of the neurological manifestations of acquired immunodeficiency syndrome.

Effect of beta blockade on the neurohumoral and cardiopulmonary response to dynamic exercise in cardiac transplant recipients.

OBJECTIVE: To determine the effects of a small dose of beta blocker on neurohumoral and cardiopulmonary responses after cardiac transplantation. BACKGROUND: Cardiac transplant recipients have a reduced exercise capacity and abnormal cardiovascular responses to exercise. The sympathoadrenal response to exercise has been shown to be abnormal with high venous noradrenaline. The effect of beta blockade on these neurohumoral mechanisms has not been defined. METHODS: 10 non-rejecting cardiac transplant recipients were studied. Patients carried out graded exercise to a symptom limited maximum. Blood samples were taken during exercise. Concentrations of noradrenaline, adrenaline, and atrial natriuretic peptide and plasma renin activity were measured. The next day, the exercise and sampling procedure were repeated after an oral dose of propranolol (40 mg). RESULTS: Patients tolerated exercise poorly after beta blockade, which was reflected in the maximum workload reached. Heart rate and blood pressure were significantly higher at rest and during exercise before beta blockade. Although there was no significant difference when resting, mean (SEM) noradrenaline concentrations during peak exercise were higher after beta blockade (16.2 (2) v 23.6 (2.9) nmol/l, p = 0.001). Adrenaline concentrations at peak exercise were also greater after beta blockade (0.89 (0.31) v 1.18 (0.38) nmol/l, p = 0.055). Atrial natriuretic peptide concentrations tended to be higher after beta blockade (118.75 (50.2) v 169.79 (39.3) pmol/l, p = 0.36). There was no significant change in plasma renin activity. CONCLUSIONS: A small oral dose of a competitive beta blocker such as propranolol has an adverse effect on exercise tolerance and cardiovascular response to exercise in cardiac transplant recipients. There are also increased concentrations of circulating noradrenaline and therefore, sympathetic activity during exercise. beta blockers should be used with caution in cardiac transplant recipients.