Hydrothermal impacts on trace element and isotope ocean biogeochemistry.

Hydrothermal activity occurs in all ocean basins, releasing high concentrations of key trace elements and isotopes (TEIs) into the oceans. Importantly, the calculated rate of entrainment of the entire ocean volume through turbulently mixing buoyant hydrothermal plumes is so vigorous as to be comparable to that of deep-ocean thermohaline circulation. Consequently, biogeochemical processes active within deep-ocean hydrothermal plumes have long been known to have the potential to impact global-scale biogeochemical cycles. More recently, new results from GEOTRACES have revealed that plumes rich in dissolved Fe, an important micronutrient that is limiting to productivity in some areas, are widespread above mid-ocean ridges and extend out into the deep-ocean interior. While Fe is only one element among the full suite of TEIs of interest to GEOTRACES, these preliminary results are important because they illustrate how inputs from seafloor venting might impact the global biogeochemical budgets of many other TEIs. To determine the global impact of seafloor venting, however, requires two key questions to be addressed: (i) What processes are active close to vent sites that regulate the initial high-temperature hydrothermal fluxes for the full suite of TEIs that are dispersed through non-buoyant hydrothermal plumes? (ii) How do those processes vary, globally, in response to changing geologic settings at the seafloor and/or the geochemistry of the overlying ocean water? In this paper, we review key findings from recent work in this realm, highlight a series of key hypotheses arising from that research and propose a series of new GEOTRACES modelling, section and process studies that could be implemented, nationally and internationally, to address these issues.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.

Endovascular management of coarctation of the aorta.

Untreated thoracic aortic coarctation leads to early death predominantly because of hypertension and its cardiovascular sequelae. Surgical treatment has been available for > 50 years and has improved hypertension and survival. More recently, endovascular techniques have offered a minimally invasive alternative to traditional open repair. Early and intermediate results suggest angioplasty and stenting have an important role in the management of aortic coarctation, particularly in adults and older children.

A role for alphabeta T cells in the resistant phase of the Brown Norway rat model of vasculitis.

Administration of mercuric chloride (HgCl(2)) to Brown Norway rats causes Th2 dominated autoimmunity including a caecal vasculitis. Disease peaks 14 days after starting HgCl(2) after which animals immunoregulate spontaneously. In a third phase, if animals are rechallenged with HgCl(2) 6 weeks later they appear resistant, developing only attenuated disease. Previous studies suggested a role for CD8(+) cells as partial mediators of resistance but no groups had studied the role of alphabeta T cells, gammadelta T cells or natural killer (NK) cells in resistance. We used adoptive transfer and in vitro cell depletion to show that alphabeta T cells are also partially responsible for resistance. Donor animals were treated with HgCl(2) or saline and killed 21 days later. Cells from donor spleens were transferred into recipient animals which were challenged with HgCl(2) and killed 14 days later. Test recipients received spleen cells from HgCl(2)-treated donors after in vitro depletion of one subset of cells. Recipients receiving spleen cells from saline-treated donors remained susceptible to HgCl(2)-induced vasculitis; those receiving spleen cells from HgCl(2)-treated donors were resistant. Animals receiving alphabeta T-cell-depleted spleen cells from HgCl(2)-treated donors showed partial reversal of resistance. Our results suggest a role for alphabeta T cells in the resistant phase of the Brown Norway rat model of vasculitis.

Clinical implications of ST-segment non-resolution after thrombolysis for myocardial infarction.

Failed reperfusion after thrombolytic therapy for acute myocardial infarction is common and signifies a poor prognosis. We investigated the clinical consequences of non-resolution of the ST segment after thrombolytic therapy for acute ST-elevation myocardial infarction, in 85 consecutive patients admitted to a coronary care unit lacking rapid access to angioplasty. Failed thrombolysis was defined as <50% ST-segment resolution 180 minutes after the start of thrombolytic treatment. Outcomes were measured in terms of in-hospital adverse events, length of hospital stay, and mortality at 6 weeks and 1 year. Thrombolysis was successful, in terms of ST-segment resolution, in 45 patients (53%). After adjustment for other factors, ST resolution was the only independent predictor of an uncomplicated recovery in hospital (odds ratio 6.8, 95% confidence interval 2.3 to 19.9; P<0.001). At 6 weeks and 1 year, overall mortality was lower in the ST resolution group, though these differences became non-significant on multivariate analysis. In patients who survived to hospital discharge, median length of stay was greater in successfully thrombolysed patients (9 days versus 8 days) despite their lower rate of complications. ST-segment resolution is a useful marker of successful thrombolysis and relates to clinical outcome. If assessed routinely it might assist, along with other clinical markers, in the identification of low-risk patients who can be discharged early.

Genomic instability in scleroderma.

Scleroderma is an enigmatic rheumatic disorder of uncertain etio-pathogenesis. Cancer has an approximately two-fold higher incidence in scleroderma patients than in the general population. There are preliminary data of acquired genetic damage in scleroderma but the significance of these observations are uncertain. To determine somatic mutation frequency at the glycophorin-A (GPA) locus in patients with limited and diffuse cutaneous scleroderma. The GPA assay measures the total somatic mutation frequency (Vf), composed of gene inactivating mutations (NO) and mutations arising from mitotic recombination (NN) in individuals heterozygous for the GPA MN blood group. Mutation frequency was determined using a validated GPA flow cytometric assay using fluorescent labeled monoclonal antibodies specific for the GPA blood groups M and N. This assay detects and enumerates progeny of red blood cell (rbc) precursor cells which have acquired genetic damage resulting in a loss of expression of one of the GPA alleles. It was found that patients with scleroderma (n = 23) had significantly elevated Vf as compared with young healthy controls (p < 0.001) and elderly controls (p = 0.03). Patients with diffuse scleroderma had higher mean Vf as compared with limited scleroderma (p = 0.055). In comparison with controls, patients with scleroderma exhibit a higher proportion of mitotic recombinant mutations than inactivating mutations (p < 0.002). There was no correlation between Vf and disease duration, age at onset or autoantibody status. We have documented evidence of acquired genetic damage at the GPA locus in scleroderma. Evidence of acquired genetic damage in this disorder may be importance in explaining both the etio-pathogenesis of scleroderma and the association of scleroderma with cancer.

Resistance to re-challenge in the Brown Norway rat model of vasculitis is not always complete and may reveal separate effector and regulatory populations.

Administration of mercuric chloride to Brown Norway rats results in T helper type 2 (Th2)- dominated autoimmunity characterized by high immunoglobulin E (IgE) concentrations, the production of multiple IgG autoantibodies, including those to glomerular basement membrane (GBM), arthritis and caecal vasculitis. After 14 days animals immunoregulate and auto-immunity resolves even if mercuric chloride injections are continued. In a third phase, if animals are re-challenged with mercuric chloride 6 weeks later, they show only attenuated autoimmunity with lower anti-GBM antibody concentrations and arthritis scores. Resistance to the induction of anti-GBM antibodies can also be achieved following an initial challenge with low-dose (one-tenth standard dose) mercuric chloride. We have now studied this resistant phase in more detail. We have shown, first, that following an initial full-dose mercuric chloride challenge, resistance also affects susceptibility to caecal vasculitis. Second, following an initial full-dose mercuric chloride challenge, the IgE response upon re-challenge is initially accelerated but subsequently enters a resistant phase and third, following an initial challenge with low-dose mercuric chloride, resistance is also seen to the induction of caecal vasculitis but is not seen in IgE serology (where results suggest competing effector and regulatory cell populations). Studying such regulatory phases in animal models of autoimmunity may be of benefit in the future in designing new therapies for human vasculitis.

Unusual causes of colonic wall thickening on computed tomography.

Computed tomography (CT) appearances in "colitis" are often non-specific, and include mural thickening and mesenteric fat stranding. In the western world, the majority of cases will have, or be subsequently diagnosed with, inflammatory bowel disease, pseudomembranous colitis or ischaemic colitis. However, other rare conditions may also produce these rather non-specific signs. We present a number of cases demonstrating colonic wall thickening on CT due to rarer diagnoses, which are correlated with the histopathological features. Some of these CT appearances have not been described previously in the literature.

The Th2-response in mercuric chloride-induced autoimmunity requires continuing costimulation via CD28.

Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway (BN) rats is a highly polarized polyclonal Th2-driven autoimmune response with increased IgE production, lymphoproliferation, vasculitis and proteinuria. The increase in serum IgE concentration is clearly measurable by day 4 after the first HgCl2 injection and peaks between days 15 and 20. Treatment with CD80 and CD86 antibodies prior to administration of HgCl2 completely suppresses the autoimmune process. To determine whether interruption of CD28 signalling after initial stimulation of the Th2-response would be suppressive, antibody treatment was delayed. BN rats were given 5 doses of HgCl2 subcutaneously on alternate days. CD80 and CD86 antibodies, or an isotype control, were given daily for 3 days and then on alternate days until day 12 commencing either on the day of the first HgCl2 injection (day 0) or on days 4 or 8. Treatment from day 0 reduced serum IgE concentrations to below baseline (median 9.34 microg/ml on day 0 versus 4.6 microg/ml, on day 5, P = 0.03) suggesting that ongoing costimulation via CD28 is required to maintain basal serum IgE production. Delaying treatment until day 4 or day 8 after the first HgCl2 injection resulted in significant inhibition of IgE secretion, lymphoproliferation, and vasculitis, although less markedly than when treatment was commenced on day 0. These data indicate that CD28-mediated costimulation is not only required for the initiation of the Th2-response but is required for maintenance of a maximal response, making this an attractive therapeutic target for antibody-mediated autoimmune diseases.

Significance of kinetics for sorption on inorganic colloids: modeling and experiment interpretation issues.

A two-site kinetic model for solute sorption on inorganic colloids is developed. The model quantifies linear first-order sorption on two types of sites ("fast" and "slow") characterized by two pairs of rates (forward and reverse). We use the model to explore data requirements for long-term predictive calculations of colloid-facilitated transport and to evaluate laboratory kinetic sorption data of Lu et al.. Five batch sorption data sets are considered with plutonium as the tracer and montmorillonite, hematite, silica, and smectite as colloids. Using asymptotic results applicable on the time scale of limited duration experiments, a robust estimation procedure is developed for the fast-site partitioning coefficient K(C) and the slow forward rate alpha. The estimated range of K(C) is 1.1-76 L/g, and the range for alpha is 0.0017-0.02 1/h. The fast reverse rate k(r) is estimated in the range 0.012-0.1 1/h. Comparison of one-site and two-site sorption interpretations reveals the difficulty in discriminating between the two models for montmorillonite and to a lesser extent for hematite. For silica and smectite, the two-site model clearly provides a better representation of the data as compared with a single site model. Kinetic data for silica are available for different colloid concentrations (0.2 g/L and 1 g/L). For the range of experimental conditions considered, alpha appears to be independent of colloid concentration.

CD80(B7.1) and CD86(B7.2) do not have distinct roles in setting the Th1/Th2 balance in autoimmunity in rats.

Some data suggest that the interaction between CD28 and CD80 (B7.1) stimulates Th1-responses and that CD28 and CD86 (B7.2) stimulates Th2-responses, however this is controversial. We addressed this issue by using mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway (BN) rats as a highly polarized Th2 model and experimental autoimmune encephalomyelitis (EAE) in Lewis rats as a highly polarized Th1 model. Monoclonal antibodies (MoAbs) to CD80 and CD86, given singly, had little effect in either model, however when given together they almost completely suppressed the HgCl2-induced autoimmunity: the peak immunoglobulin (Ig)E concentration was 3.25 microg/ml in treated animals versus 2770 microg/ml in controls (P < 0.0001); caecal vasculitis was suppressed with a median vasculitis score of 0 in treated animals versus 6 in controls (P < 0.0001); and new germinal centre formation was significantly suppressed. A combination of the antibodies also markedly reduced the severity of clinical EAE; from a median aggregate clinical score of 9 to 3 (P = 0.02) and delayed the onset from a median of 12.5 days to 16 days after immunization (P = 0.006). We have demonstrated profound suppression of both Th1 and Th2-driven autoimmunity in rats by a combination of anti-CD80 and CD86, but have been unable to demonstrate any clear differential effects.

Effect of heterogeneity on radionuclide retardation in the alluvial aquifer near Yucca Mountain, Nevada.

The U.S. Department of Energy is currently studying Yucca Mountain, Nevada, as a potential site for a geological high-level waste repository. In the current conceptual models of radionuclide transport at Yucca Mountain, part of the transport path to pumping locations would be through an alluvial aquifer. Interactions with minerals in the alluvium are expected to retard the downstream migration of radionuclides, thereby delaying arrival times and reducing ground water concentrations. We evaluate the effectiveness of the alluvial aquifer as a transport barrier using the stochastic Lagrangian framework. A transport model is developed to account for physical and chemical heterogeneities and rate-limited mass transfer between mobile and immobile zones. The latter process is caused by small-scale heterogeneity and is thought to control the macroscopic-scale retardation in some field experiments. A geostatistical model for the spatially varying sorption parameters is developed from a site-specific database created from hydrochemical measurements and a calibrated modeling approach (Turner and Pabalan 1999). Transport of neptunium is considered as an example. The results are sensitive to the rate of transfer between mobile and immobile zones, and to spatial variability in the hydraulic conductivity. Chemical heterogeneity has only a small effect, as does correlation between hydraulic conductivity and the neptunium distribution coefficient. These results illustrate how general sensitivities can be explored with modest effort within the Lagrangian framework. Such studies complement and guide the application of more detailed numerical simulations.

UraniumVI sorption behavior on silicate mineral mixtures.

UraniumVI sorption experiments involving quartz and clinoptilolite, important mineral phases at the proposed US nuclear waste repository at Yucca Mountain, NV, were conducted to evaluate the ability of surface complexation models to predict UVI sorption onto mineral mixtures based on parameters derived from single-mineral experiments. The experiments were conducted at an initial UVI aqueous concentration of approximately 2.0 x 10(-7) mol.l-1 (0.1 mol.l-1 NaNO3 matrix) and over the pH range approximately 2.5 to approximately 9.5. The UVI solutions were reacted with either quartz or clinoptilolite only, or with mixtures of the two minerals. The experiments were carried out under atmospheric pCO2(g) conditions (in loosely capped containers) or under limited pCO2(g) (in capped containers or in a glove box). Data from sorption experiments on quartz at atmospheric pCO2 conditions were used to derive UVI binding constants for a diffuse-layer surface complexation model (DLM). The DLM was then used with surface area as a scaling factor to predict sorption of UVI onto clinoptilolite and clinoptilolite/quartz mixtures under both atmospheric and low pCO2 conditions. The calculations reproduced many aspects of the pH-dependent sorption behavior. If this approach can be demonstrated for natural mineral assemblages, it may be useful as a relatively simple method for improving radionuclide transport models in performance-assessment calculations.

Modeling colloid transport for performance assessment.

The natural system is expected to contribute to isolation at the proposed high-level nuclear waste (HLW) geologic repository at Yucca Mountain, NV (YM). In developing performance assessment (PA) computer models to simulate long-term behavior at YM, colloidal transport of radionuclides has been proposed as a critical factor because of the possible reduced interaction with the geologic media. Site-specific information on the chemistry and natural colloid concentration of saturated zone groundwaters in the vicinity of YM is combined with a surface complexation sorption model to evaluate the impact of natural colloids on calculated retardation factors (RF) for several radioelements of concern in PA. Inclusion of colloids into the conceptual model can reduce the calculated effective retardation significantly. Strongly sorbed radionuclides such as americium and thorium are most affected by pseudocolloid formation and transport, with a potential reduction in RF of several orders of magnitude. Radioelements that are less strongly sorbed under YM conditions, such as uranium and neptunium, are not affected significantly by colloid transport, and transport of plutonium in the valence state is only moderately enhanced. Model results showed no increase in the peak mean annual total effective dose equivalent (TEDE) within a compliance period of 10,000 years, although this is strongly dependent on container life in the base case scenario. At longer times, simulated container failures increase and the TEDE from the colloidal models increased by a factor of 60 from the base case. By using mechanistic models and sensitivity analyses to determine what parameters and transport processes affect the TEDE, colloidal transport in future versions of the TPA code can be represented more accurately.

IL-4 gene expression up-regulated by mercury in rat mast cells: a role of oxidant stress in IL-4 transcription.

In the Brown Norway (BN) rat, chemical compounds [mercuric chloride (HgCl2), D-penicillamine or gold salts] induce a T(h)2-dominated autoimmune syndrome with tissue injury in the form of a vasculitis and arthritis. An early phase of vasculitis in the model occurs within 24 h of an injection of HgCl2, is alphabeta T cell independent and involves the mast cell. In addition, HgCl2 induces IL-4 mRNA in mast cells from BN rats. Our recent work has demonstrated that the balance of oxidative/antioxidative influences plays an important role in the modulation of mast cell function (degranulation) in chemically induced autoimmunity. The aim of this study was to determine, in mast cells, whether oxidative status influences IL-4 transcription and translation, which is required for the development of a T(h)2 response. Exposure of the mast cell line RBL-2H3 to HgCl2 enhanced both IL-4 mRNA and its promoter activity. Oxidative stress by hydrogen peroxide mimicked the effects of HgCl2 in enhancing IL-4 promoter activity. The enhancement of IL-4 gene expression by HgCl2 was significantly reduced by antioxidants (both sulphydryl and non-sulphydryl containing). The same pattern of regulation was also observed on IL-4 protein expression in the mast cells. These data suggest a novel mechanism of IL-4 transcriptional up-regulation by oxidative stress. Our results provide evidence to support our hypothesis that alterations in intracellular reactive oxygen species production modulate both IL-4 gene expression and mast cell function.

Initial experience using the Palmaz Corinthian stent for right ventricular outflow obstruction in infants and small children.

The original Palmaz balloon expandable stent has been used extensively for the treatment of vascular stenoses in older children and young adults. Placement of the Palmaz stent in infants and small children, however, is limited by stent inflexibility, large delivery sheath size, and concerns about creating fixed obstructions after the placement of small diameter stents in growing patients. New Palmaz Corinthian stents were placed through 6 French sheaths in four high-risk patients with postoperative right ventricular outflow obstruction. Patients were not considered candidates for surgical repair. Median patient age and weight were 17 months (range 5-32 months) and 7.7 kg (range 4.6-11.1 kg), respectively. Median fluoroscopy time was 58.2 min (range 55.2-172 min). No complications were encountered. In each case, successful stent placement was achieved, and surgery with cardiopulmonary bypass was avoided. Palmaz Corinthian stents are more flexible, require a smaller delivery sheath, have equal or increased radial strength, and can be maximally expanded to a greater cross sectional area when compared to the original Palmaz stent. These characteristics make the Palmaz Corinthian stent a reasonable alternative for use in a select group of infants and small children who are not candidates for surgical repair of postoperative right ventricular outflow obstruction.

The role of endogenous steroid hormones in the generation of T helper 2-mediated autoimmunity in mercuric chloride-treated Brown-Norway rats.

Injection of Brown-Norway rats with mercuric chloride (HgCl2) activates a T helper type 2 (Th2) autoimmune response, with production of a number of autoantibodies and vasculitis primarily affecting the gut. Glucocorticoids have been shown to suppress Th1 and to promote the development of Th2-type responses. Conversely dehydroepiandrosterone (DHEA) promotes Th1 responses with suppression of Th2 responses. This study set out to define the role of these hormones in this animal model. Rats were adrenalectomized (Adx) with no steroid replacement (n = 11), Adx with basal steroid replacement given by a 25 mg corticosterone pellet inserted subcutaneously (n = 13), or sham-Adx (n = 14) prior to administration of HgCl2. In both groups of Adx animals there was a delay in the production of immunoglobulin E (IgE) and serum concentrations on day 9 were marginally lower (P = 0.035, repeated measures ANOVA). All of the animals Adx with no steroid replacement and two Adx animals with steroid replacement died between 10 and 14 days after HgCl2 challenge. There was no difference in the severity of caecal vasculitis between the groups. A significant increase in adrenal size was noted following administration of HgCl2. Administration of subcutaneous DHEA implants (100 mg and 200 mg) had no significant effect on IgE concentrations or severity of vasculitis. These observations do not support the hypothesis that corticosterone and DHEA play a central role in setting the Th1/Th2 balance in this experimental Th2-mediated autoimmune disease; in contrast with the Th1-mediated autoimmune disease experimental allergic encephalomyelitis where corticosterone plays a key role in immunoregulation.

The contribution of exogenous and endogenous mutagens to in vivo mutations.

There is abundant evidence of the potential for exogenous agents to cause cancer but the proportion of human cancers attributable to defined external agents is uncertain. With rare exceptions it is difficult to demonstrate a role for exogenous agents in increasing mutation above background rates. There are many sources of endogenous mutation including physico-chemical processes, free radicals and enzymatic processes controlling DNA damage and repair. Evidence for the role of diet and genetic factors as major determinants of endogenous mutagenesis is reviewed with reference to the spontaneous spectrum of mutations in human cells and the quantitative measurement of mutation frequency in dietary restriction and the senescence-accelerated mouse.