Implications of Antiphospholipid and Antineutrophilic Cytoplasmic Antibodies in the Context of Postinfectious Glomerulonephritis.

While antineutrophil cytoplasmic antibody (ANCA) positivity has been documented in some patients with postinfectious glomerulonephritis (PIGN) and is associated with more severe disease, antiphospholipid antibodies (APA) are not known to be a common occurrence. We describe a child with severe acute kidney injury who was noted to have prolonged positivity of both ANCA and APA; a renal biopsy showed noncrescentic immune complex mediated glomerulonephritis with subepithelial deposits compatible with PIGN. He recovered without maintenance immunosuppressive therapy and at last follow-up had normal renal function. We discuss the cooccurrence and implications of ANCA and APA in children with PIGN

Rationale and design of the GUIDE-IT study: Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure.

OBJECTIVES: The GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study is designed to determine the safety, efficacy, and cost-effectiveness of a strategy of adjusting therapy with the goal of achieving and maintaining a target N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of BACKGROUND: Elevations in natriuretic peptide (NP) levels provide key prognostic information in patients with HF. Therapies proven to improve outcomes in patients with HF are generally associated with decreasing levels of NPs, and observational data show that decreases in NP levels over time are associated with favorable outcomes. Results from smaller prospective, randomized studies of this strategy thus far have been mixed, and current guidelines do not recommend serial measurement of NP levels to guide therapy in patients with HF. METHODS: GUIDE-IT is a prospective, randomized, controlled, unblinded, multicenter clinical trial designed to randomize approximately 1,100 high-risk subjects with systolic HF (left ventricular ejection fraction ≤40%) to either usual care (optimized guideline-recommended therapy) or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of CONCLUSIONS: The GUIDE-IT study is designed to definitively assess the effects of an NP-guided strategy in high-risk patients with systolic HF on clinically relevant endpoints of mortality, hospitalization, quality of life, and medical resource use. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840)

Effect of Natriuretic Peptide-Guided Therapy on Hospitalization or Cardiovascular Mortality in High-Risk Patients With Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ( guided therapy ) with inconsistent results. Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF). Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care. Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group. Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events. Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups. Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes. Trial Registration: clinicaltrials.gov Identifier: NCT01685840

A water column study of methane around gas flares located at the West Spitsbergen continental margin

In the Arctic Seas, the West Spitsbergen continental margin represents a prominent methane seep area. In this area, free gas formation and gas ebullition as a consequence of hydrate dissociation due to global warming are currently under debate. Recent studies revealed shallow gas accumulation and ebullition of methane into the water column at more than 250 sites in an area of 665 km2. We conducted a detailed study of a subregion of this area, which covers an active gas ebullition area of 175 km2 characterized by 10 gas flares reaching from the seafloor at~245 m up to 50 m water depth to identify the fate of the released gas due to dissolution of methane from gas bubbles and subsequent mixing, transport and microbial oxidation. The oceanographic data indicated a salinity-controlled pycnocline situated ~20 m above the seafloor. A high resolution sampling program at the pycnocline at the active gas ebullition flare area revealed that the methane concentration gradient is strongly controlled by the pycnocline. While high methane concentrations of up to 524 nmol L−1 were measured below the pycnocline, low methane concentrations of less than 20 nmol L−1 were observed in the water column above. Variations in the δ13CCH4 values point to a 13C depleted methane source (~−60‰ VPDB) being mainly mixed with a background values of the ambient water (~−37.5‰ VPDB). A gas bubble dissolution model indicates that ~80% of the methane released from gas bubbles into the ambient water takes place below the pycnocline. This dissolved methane will be laterally transported with the current northwards and most likely microbially oxidized in between 50 and 100 days, since microbial CH4 oxidation rates of 0.78 nmol d−1 were measured. Above the pycnocline, methane concentrations decrease to local background concentration of ~10 nmol L−1. Our results suggest that the methane dissolved from gas bubbles is efficiently trapped below the pycnocline and thus limits the methane concentration in surface water and the air–sea exchange during summer stratification. During winter the lateral stratification breaks down and fractions of the bottom water enriched in methane may be vertically mixed and thus be potentially an additional source for atmospheric methane

Atmospheric methane flux from bubbling seeps: Spatially extrapolated quantification from a Black Sea shelf area

Bubble transport of methane from shallow seep sites in the Black Sea west of the Crimea Peninsula between 70 and 112 m water depth has been studied by extrapolation of results gained through different hydroacoustic methods and direct sampling. Ship-based hydroacoustic echo sounders can locate bubble releasing seep sites very precisely and facilitate their correlation with geological or other features at the seafloor. Here, the backscatter strength of a multibeam system was integrated with single-beam data to estimate the amount of seeps/m2 for different backscatter intensities, resulting in 2709 vents in total. Direct flux measurements by submersible revealed methane fluxes from individual vents of 0.32–0.85 l/min or 14.5–37.8 mmol/min at ambient pressure and temperature conditions. A conservative estimate of 30 mmol/min per site was used to estimate the flux into the water to be 1219–1355 mmol/s. The flux to the atmosphere was calculated by applying a bubble dissolution model taking release depth, temperature, gas composition, and bubble size spectra into account. The flux into the atmosphere (3930–4533 mol/d) or into the mixed layer (6186–6899 mol/d) from the 21.8 km2 large study area is three times higher than independently measured fluxes of dissolved methane for the same area using geochemical methods (1030–2495 mol/d). The amount of methane dissolving in the mixed layer is 2256–2366 mol/d. This close match shows that the hydroacoustic approach for extrapolating the number of seeps/m2 and the applied bubble dissolution model are suitable to extrapolate methane fluxes over larger areas

Methanotropic microbial communities associated with bubble plumes above gas seeps in the Black Sea

Bubbles evolving from active gas seeps can be traced by hydroacoustic imaging up to 1000 m high in the Black Sea water column. Although methane concentrations are not distinguishable between the water column above the deep seep and reference sites, atmospheric noble gas measurements clearly show the constant input of gases (mainly methane) via seepage into the Black Sea. Archaea (ANME-1, ANME-2) and methanotrophic bacteria detected with specific 16S rRNA-targeted oligonucleotide probes are related to active gas seeps in the oxic and anoxic water column. It is suggested that methane seeps have a much greater influence on the Black Sea methane budget than previously acknowledged and that ANME-1 and ANME-2 are injected via gas bubbles from the sediment into the anoxic water column mediating methane oxidation. Our results show further that only minor amounts of methane evolving from Black Sea gas seeps reach the atmosphere due to the very effective microbial barrier. Hence only major thermodynamically and/or tectonically triggered gas hydrate dissociation has the potential to induce rapid climate changes as suggested by the “clathrate gun hypothesis.

Pyrite-induced hydroxyl radical formation and its effect on nucleic acids

BACKGROUND: Pyrite, the most abundant metal sulphide on Earth, is known to spontaneously form hydrogen peroxide when exposed to water. In this study the hypothesis that pyrite-induced hydrogen peroxide is transformed to hydroxyl radicals is tested. RESULTS: Using a combination of electron spin resonance (ESR) spin-trapping techniques and scavenging reactions involving nucleic acids, the formation of hydroxyl radicals in pyrite/aqueous suspensions is demonstrated. The addition of EDTA to pyrite slurries inhibits the hydrogen peroxide-to-hydroxyl radical conversion, but does not inhibit the formation of hydrogen peroxide. Given the stability of EDTA chelation with both ferrous and ferric iron, this suggests that the addition of the EDTA prevents the transformation by chelation of dissolved iron species. CONCLUSION: While the exact mechanism or mechanisms of the hydrogen peroxide-to-hydroxyl radical conversion cannot be resolved on the basis of the experiments reported in this study, it is clear that the pyrite surface promotes the reaction. The formation of hydroxyl radicals is significant because they react nearly instantaneously with most organic molecules. This suggests that the presence of pyrite in natural, engineered, or physiological aqueous systems may induce the transformation of a wide range of organic molecules. This finding has implications for the role pyrite may play in aquatic environments and raises the question whether inhalation of pyrite dust contributes to the development of lung diseases