B-type natriuretic levels in critically ill patients: critically misleading?

Although B-type natriuretic peptide (BNP) has been used for the diagnosis of congestive heart failure in many clinical settings, its diagnostic role in critically ill patients remains uncertain. The body of literature suggests that BNP and N-terminal pro-BNP levels are not useful for the diagnosis of systolic or diastolic heart failure in the critically ill, including in patients with brain hemorrhage, due to poor specificity. However, these cardiac peptides may have a more promising prognostic role in this patient population

Computational Insights into Sulfur Redox Chemistry in Enzymology

In biochemistry, sulfur-containing biomolecules enrich the chemical diversity in cells. This occurs via their participation in several reactions including disulfide formation, metal-binding and redox catalysis. Since sulfur occurs in various oxidation states, it exhibits interesting chemistry and reactivity. In this Dissertation computational modeling techniques have been used to investigate several aspects of sulfur\u27s unique chemistry. Particularly, previously proposed mechanisms for sulfenic acids formation and reduction/overoxidation pathways have been examined In detail. A holistic picture of sulfur/sulfenic acid chemistry in biochemistry has been portrayed. For instance, the importance of non-covalent interaction in stabilizing the unstable sulfenic acid intermediates has been highlighted. Furthermore, the mechanism of Thiol activation in several active sites as well as the factors affecting thiolate stabilization has been determined in several enzymes. The role of protein dynamics and possible effects on catalysis has been emphasized. Moreover, a novel antioxidant pathway has been proposed. Computationally, the effect of choosing starting structure for modelling was also stressed

Randomized controlled trial of influenza vaccine in patients with heart failure to reduce adverse vascular events (IVVE): Rationale and design

Background: Influenza is associated with an increase in the risk of cardiac and other vascular events. Observational data and small randomized trials suggest that influenza vaccination may reduce such adverse vascular events. Research Design and Methods: In a randomized controlled trial patients with heart failure are randomized to receive either inactivated influenza vaccine or placebo annually for 3 years. Patients aged ≥18 years with a clinical diagnosis of heart failure and NYHA functional class II, III and IV are eligible. Five thousand patients from 10 countries where influenza vaccination is not common (Asia, the Middle East, and Africa) have been enrolled. The primary outcome is a composite of the following: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalizations for heart failure using standardized criteria. Analyses will be based on comparing event rates between influenza vaccine and control groups and will include time to event, rate comparisons using Poisson methods, and logistic regression. The analysis will be conducted by intention to treat i.e. patients will be analyzed in the group in which they were assigned. Multivariable secondary analyses to assess whether variables such as age, sex, seasonality modify the benefits of vaccination are also planned for the primary outcome. Conclusion: This is the largest randomized trial to test if influenza vaccine compared to control reduces adverse vascular events in high risk individuals

Global mortality variations in patients with heart failure: results from the International Congestive Heart Failure (INTER-CHF) prospective cohort study

Background Most data on mortality and prognostic factors in patients with heart failure come from North America and Europe, with little information from other regions. Here, in the International Congestive Heart Failure (INTERCHF) study, we aimed to measure mortality at 1 year in patients with heart failure in Africa, China, India, the Middle East, southeast Asia and South America; we also explored demographic, clinical, and socioeconomic variables associated with mortality. Methods We enrolled consecutive patients with heart failure (3695 [66%] clinic outpatients, 2105 [34%] hospital in patients) from 108 centres in six geographical regions. We recorded baseline demographic and clinical characteristics and followed up patients at 6 months and 1 year from enrolment to record symptoms, medications, and outcomes. Time to death was studied with Cox proportional hazards models adjusted for demographic and clinical variables, medications, socioeconomic variables, and region. We used the explained risk statistic to calculate the relative contribution of each level of adjustment to the risk of death. Findings We enrolled 5823 patients within 1 year (with 98% follow-up). Overall mortality was 16·5%: highest in Africa (34%) and India (23%), intermediate in southeast Asia (15%), and lowest in China (7%), South America (9%), and the Middle East (9%). Regional differences persisted after multivariable adjustment. Independent predictors of mortality included cardiac variables (New York Heart Association Functional Class III or IV, previous admission for heart failure, and valve disease) and non-cardiac variables (body-mass index, chronic kidney disease, and chronic obstructive pulmonary disease). 46% of mortality risk was explained by multivariable modelling with these variables; however, the remainder was unexplained. Interpretation Marked regional differences in mortality in patients with heart failure persisted after multivariable adjustment for cardiac and non-cardiac factors. Therefore, variations in mortality between regions could be the result of health-care infrastructure, quality and access, or environmental and genetic factors. Further studies in large, global cohorts are needed

Computational Approach Choice in Modeling Flexible Enzyme Active Sites

The last step in the reductase step of the catalytic mechanism of MsrB was re-investigated using several computational approaches. Our previous QM-cluster paper showed that two possible mechanisms could occur, however the direct formation of disulfide from sulfonium cation was favored over sulfenic acid formation. In contrary, experimental studies suggest sulfenic acid formation. Therefore, first, we investigated the effect of level of theory, which confirmed previous conclusion. In addition, the effect of model choice was also investigated using ONIOM including a large QM layer around Cys440. Interestingly, deprotonating Cys440 leads to direct nucleophilic attack on Cys495 forming disulfide. Second, to eliminate the possibility that all previous results are an artifact of the used crystal structure in which the S...S distance is 3.29 Å, we ran a 5 ns MD simulation on the sulfonium cation intermediate. Surprisingly, our results show that the distance between the two sulfur is significantly increased to 4.88 Å. More importantly a water molecule is located in a proper position for nucleophilic attack. QM/MM calculations shows that sulfenic acid is formed via low barrier of 16.7 kJ mol-1. Finally, the effect of substrate binding on the two Cys\u27s distance were investigated via running several MD simulations of possible intermediates, showing that substrate binding induces conformational changes increasing the sulfur\u27s distance which is decreased upon substrate removal upon sulfenic acid formation. These results question the applicability of QM cluster approach in systems including flexible turns. It also emphasizes the importance of proper preparation of the starting structure.</div

Quantum Mechanical/Molecular Mechanical investigation of the reduction mechanism of Cysteine Sulfinic acid of Peroxiredoxin via Sulfiredoxin

The formation of the overoxidized cysteine sulfinic acid in proteins has been connected to be associated with various diseases including cancer and age-related diseases. This post-transitional modification of proteins under oxi- dative stress has been known to be irreversible. However, in eukaryotic, the overoxidation of typical 2-Cys perxoiredoxins (Prxs) to sulfinic acid is reversible via a repair enzyme known as sulfiredoxin (Srx) leading to the regulation of both per- oxide signaling and Prxs chaperon activity. In this study, the molecular modeling techniques including molecular dynam- ics simulations (MD) and the hybrid quantum mechanical/molecular mechanical (QM/MM) approach were used to eluci- date the atomistic details of this unique reaction in sulfur chemistry. Our results support the previous experimentally pro- posed mechanism in which the sulfinic acid oxygen perform an in line direct nucleophilic attack on the γ-phosphate of ATP forming sulfinic acid phosphoryl ester intermediate and ADP, via a low barrier of 16.3 kJ mol-1. Subsequently, the formed intermediate is directly reduced via an SN2 mechanism by the Srx-Cys99 forming thiosulfinate. Our results suggest that the rate-limiting step of the reduction mechanism is associated with the reduction step of the thiosulfinate intermedi- ate. This work significantly improves the current knowledge of this unique reaction, which could contribute to the discov- ery of new groups of antioxidants capable of reducing this irreversible overoxidized state in other proteins.</div