Diagnostic and Prognostic Value of Uric Acid in Patients with Acute Dyspnea

Background

Uric acid was shown to predict outcome in patients with stable chronic heart failure. Its impact in patients admitted in the Emergency Department with acute dyspnea, however, remains unknown.

Methods

We prospectively investigated the diagnostic and prognostic value of uric acid in 743 unselected patients presenting to the Emergency Department with acute dyspnea.

Results

Uric acid at admission was higher in patients with acute decompensated heart failure (51% of the cohort) as compared with patients with noncardiac causes of dyspnea (median, 447 μmol/L vs 340 μmol/L, P <.001). The area under the receiver operating characteristic curve for the accuracy to detect acute decompensated heart failure was inferior for uric acid (0.70) than for B-type natriuretic peptide (area under the receiver operating characteristic curve 0.91, P <.001). Patients in the highest uric acid tertile more often required admission to the hospital (92% vs 74% in the first tertile, P <.001) and had higher in-hospital mortality (13% vs 4% in the first tertile, P <.001). Cumulative 24-month mortality rates were 28% in the first, 31% in the second, and 50% in the third tertile (P <.001). After adjustment in multivariable Cox proportional hazard analysis, uric acid predicted 24-month mortality independently of B-type natriuretic peptide (P = .003).

Conclusions

Our study first shows that uric acid, measured at Emergency Department admission or hospital discharge, is a powerful predictor of long-term outcome in dyspneic patients.     

Cost-effectiveness of B-type natriuretic peptide testing in patients with acute dyspnea

BACKGROUND: B-type natriuretic peptide (BNP) is a quantitative marker of heart failure that seems to be helpful in its diagnosis. METHODS: We performed a prospective randomized study (B-Type Natriuretic Peptide for Acute Shortness of Breath Evaluation) including 452 patients who presented to the emergency department with acute dyspnea to estimate the long-term cost-effectiveness of BNP guidance. Participants were randomly assigned to a diagnostic strategy involving the measurement of BNP levels (n = 225) or assessment in a standard manner (n = 227). Nonparametric bootstrapping was used to estimate the distribution of incremental costs and effects on the cost-effectiveness plane during 180 days of follow-up. RESULTS: Testing of BNP induced several important changes in management of dyspnea, including a reduction in the initial hospital admission rate, the use of intensive care, and total days in the hospital at 180 days (median, 10 days [interquartile range, 2-24 days] in the BNP group vs 14 days [interquartile range, 6-27 days] in the control group; P = .005). At 180 days, all-cause mortality was 20% in the BNP group and 23% in the control group (P = .42). Total treatment cost was significantly reduced in the BNP group (7930 dollars vs 10,503 dollars in the control group; P = .004). Analysis of incremental 180-day cost-effectiveness showed that BNP guidance resulted in lower mortality and lower cost in 80.6%, in higher mortality and lower cost in 19.3%, and in higher or lower mortality and higher cost in less than 0.1% each. Results were robust to changes in most variables but sensitive to changes in rehospitalization with BNP guidance. CONCLUSION: Testing of BNP is cost-effective in patients with acute dyspnea.     

The bundling activity of vasodilator-stimulated phosphoprotein is required for filopodium formation

Filopodia are highly dynamic finger-like cell protrusions filled with parallel bundles of actin filaments. Previously we have shown that Diaphanous-related formin dDia2 is involved in the formation of filopodia. Another key player for the formation of filopodia across many species is vasodilator-stimulated phosphoprotein (VASP). It has been proposed that the essential role of VASP for formation of filopodia is its competition with capping proteins for filament barbed-end interaction. To better understand the function of VASP in filopodium formation, we analyzed the in vitro and in vivo properties of Dictyostelium VASP (DdVASP) and extended our findings to human VASP. Recombinant VASP from both species nucleated and bundled actin filaments, but did not compete with capping proteins or block depolymerization from barbed ends. Together with the finding that DdVASP binds to the FH2 domain of dDia2, these data indicate that the crucial role of VASP in filopodium formation is different from uncapping of actin filaments. To identify the activity of DdVASP required in this process, rescue experiments of DdVASP-null cells with mutant DdVASP constructs were performed. Only WT DdVASP, but not a mutant lacking the F-actin bundling activity, could rescue the ability of these cells to form WT-like filopodia. Our data suggest that DdVASP is complexed with dDia2 in filopodial tips and support formin-mediated filament elongation by bundling nascent actin filaments.     

Feasibility of clinical dendritic cell vaccination in acute myeloid leukemia

Dendritic cells (DC) are increasingly being utilized for anti-cancer therapy. Acute myeloid leukemia (AML) blasts are able to differentiate towards leukemia-derived DC enabling efficient presentation of known and unknown leukemic antigens. Advances in culture techniques and AML-DC characterization justify clinical application. However, clinical trials using AML-DC are hampered by patient inclusion criteria which allow selective entering of patients in second complete remission. Clinical relevant responses to DC-based immunotherapy are likely to only occur in non-end-stage patients. Application in early stage disease is mandatory to permit ultimate proof of clinical benefit of AML-DC vaccination strategy.     

Principles of dendritic cell-based immunotherapy in myeloid leukemia

Persistent presence of minimal residual disease in myeloid leukemia carries the risk of a relapse of the disease. In the setting of allogeneic transplants, leukemic cells have been proven to be susceptible to the action of immunocompetent T cells. Thus, an immunotherapeutic approach might hold promise in the attempt to eradicate or control residual leukemia cells. Dendritic cells (DCs) are very potent stimulators of immune responses and these cells have been widely used to target other types of malignancies. This review discusses the function and the applicability of leukemia-derived DCs for active specific immunotherapy in myeloid leukemia including possible pitfalls, and describes options to optimize DC-based vaccines.     

Downregulation of multiple stress defense mechanisms during differentiation of human embryonic stem cells

Evolutionary theory predicts that cellular maintenance, stress defense, and DNA repair mechanisms should be most active in germ line cells, including embryonic stem cells that can differentiate into germ line cells, whereas it would be energetically unfavorable to keep these up in mortal somatic cells. We tested this hypothesis by examining telomere maintenance, oxidative stress generation, and genes involved in antioxidant defense and DNA repair during spontaneous differentiation of two human embryonic stem cell lines. Telomerase activity was quickly downregulated during differentiation, probably due to deacetylation of histones H3 and H4 at the hTERT promoter and deacetylation of histone H3 at hTR promoter. Telomere length decreased accordingly. Mitochondrial superoxide production and cellular levels of reactive oxygen species increased as result of increased mitochondrial biogenesis. The expression of major antioxidant genes was downregulated despite this increased oxidative stress. DNA damage levels increased during differentiation, whereas expression of genes involved in different types of DNA repair decreased. These results confirm earlier data obtained during mouse embryonic stem cell differentiation and are in accordance with evolutionary predictions.     

Stability and uniqueness of clonal immunoglobulin CDR3 sequences for MRD tracking in multiple myeloma

Minimal residual disease (MRD) tracking, by next generation sequencing of immunoglobulin sequences, is moving towards clinical implementation in multiple myeloma. However, there is only sparse information available to address whether clonal sequences remain stable for tracking over time, and to what extent light chain sequences are sufficiently unique for tracking. Here, we analyzed immunoglobulin repertoires from 905 plasma cell myeloma and healthy control samples, focusing on the third complementarity determining region (CDR3). Clonal heavy and/or light chain expression was identified in all patients at baseline, with one or more subclones related to the main clone in 3.2%. In 45 patients with 101 sequential samples, the dominant clonal CDR3 sequences remained identical over time, despite differential clonal evolution by whole exome sequencing in 49% of patients. The low frequency of subclonal CDR3 variants, and absence of evolution over time in active multiple myeloma, indicates that tumor cells at this stage are not under selective pressure to undergo antibody affinity maturation. Next, we establish somatic hypermutation and non-templated insertions as the most important determinants of light chain clonal uniqueness, identifying a potentially trackable sequence in the majority of patients. Taken together, we show that dominant clonal sequences identified at baseline are reliable biomarkers for long-term tracking of the malignant clone, including both IGH and the majority of light chain clones.     

Pandemic influenza A H1N1 vaccine in recipients of solid organ transplants: immunogenicity and tolerability outcomes after vero cell derived, non-adjuvanted, whole-virion vaccination

During the 2009/10 pandemic of influenza A (H1N1), the American Society of Transplantation and other health organizations recommended that immunocompromised patients should be vaccinated as the key preventive measure. Since there are no data available for the immunogenicity of the unadjuvanted pandemic influenza vaccine in immunocompromised patients - as opposed to the adjuvanted preparation - the objective of this study was to evaluate the immunogenicity of an adjuvant-free H1N1 vaccine in recipients of solid organ transplants. Patients were recruited at the Vienna General Hospital, Austria. The vaccination schedule consisted of 2 doses of a whole-virion, vero cell derived, inactivated, non-adjuvanted influenza A/California/07/2009 (H1N1) vaccine given with an interval of 3 weeks. A hemagglutination inhibition (HI) assay on blood samples obtained prior to the first and after each vaccination was used for serologic analysis. The primary immunologic endpoint was the seroconversion rate, defined as the proportion of subjects with an individual 4-fold increase in HI titer of at least 1:40. In addition, virus-specific IgG antibodies to the pandemic H1N1 strain were measured using a commercially available ELISA.Twenty-five organ transplant patients (16 males, 9 females) aged 25-79 years were vaccinated and provided blood samples for serologic analysis. The time elapsed since transplantation was 10 months to 25 years (mean: 9 years; 95% CI 6-13 years). The vaccine was well tolerated and no local adverse events were noticed. After two vaccinations 37% of the patients demonstrated seroconversion in the HI assay as defined above and 70% had virus-specific IgG antibodies. Among the HI vaccine responders were 6 of 14 heart transplant recipients and 1 of 4 liver transplant recipients. The number and type of immunosuppressive agents did not significantly differ in their effect on the immune response.Our results show that the novel vero cell derived and adjuvant-free pandemic A/California/07/2009 (H1N1) influenza vaccine induced limited but measurable immune responses in adult recipients of solid organ transplants.