N-terminal-pro-brain natriuretic peptide, a surrogate biomarker of combined clinical and hemodynamic outcomes following percutaneous transvenous mitral commissurotomy.

AIM: To examine the relationship between plasma levels of N-terminal-proB type natriuretic peptide (NT-proBNP) and various echocardiographic and hemodynamic parameters in patients with mitral stenosis undergoing percutaneous transvenous mitral commissurotomy (PTMC). MATERIALS AND METHODS: The study population consisted of 100 patients with rheumatic mitral stenosis who underwent PTMC. NT-proBNP levels in these patients were measured before PTMC and 48 hours after PTMC. These levels were then correlated with various echocardiographic and hemodynamic parameters measured before and after PTMC. RESULTS: Eighty-one percent of the study population were women, and the most common presenting symptom was dyspnea which was present in 94% of the patients. Dyspnea New York Heart Association class correlated significantly with baseline NT-proBNP levels (r = 0.63; p < 0.01). The plasma NT-proBNP levels in these patients increased as echocardiogram signs of left atrial enlargement and right ventricular hypertrophy developed (r = 0.59, p < 0.01). Patients in atrial fibrillation had significantly higher NT-proBNP levels than patients in sinus rhythm. Baseline NT-proBNP levels correlated significantly with left atrial volume (r = 0.38; p < 0.01), left atrial volume index (r = 0.45; p < 0.01), systolic pulmonary artery pressures (r = 0.42; p < 0.01), and mean pulmonary artery pressures (r = 0.41; p < 0.01). All patients who underwent successful PTMC showed a significant decrease in NT-proBNP (decreased from a mean 763.8 pg/mL to 348.6 pg/mL) along with a significant improvement in all echocardiographic and hemodynamic parameters (p < 0.01). The percent change in NT-proBNP correlated significantly with the percent improvement noted with left atrial volume (r = 0.39; p < 0.01), left atrial volume index (r = 0.41; p < 0.01), systolic (r = 0.32, p < 0.01), and mean pulmonary artery pressures (r = 0.31, p < 0.01). CONCLUSIONS: The decrease in NT-proBNP levels following PTMC reflects an improvement in clinical and hemodynamic status; hence, it is reasonable to suggest that NT-proBNP is helpful in evaluating the response to PTMC.

HIV evolution: CTL escape mutation and reversion after transmission.

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

Essential role of the conformational flexibility of helices 1 and 5 on the lipid binding activity of apolipophorin-III.

It has been recently postulated that the conformational flexibility of helices 1 and 5 of Locusta migratoria apoLp-III could play an important role in early steps of binding of this apolipoprotein to a lipid surface (Soulages, J. L., and Arrese, E. L. (2000) J. Biol. Chem. 275, 17501-17509). To test this model, we have designed a double Cys mutant in which a disulfide bond linking helices 1 and 5 could be formed, resulting in an apolipoprotein with reduced conformational flexibility of its N- and C-terminal helices. Substitution of Thr(18) and Ala(147) by Cys residues provided a protein that under nonreducing conditions was fully oxidized. The far-UV CD spectra of this mutant in the reduced and oxidized states indicated that their secondary structures were identical to the structure of the wild type recombinant apoLp-III, which contains no Cys residues. Near-UV CD studies confirmed the formation of a disulfide bond and the absence of structural perturbations. The lipid binding activity of the reduced mutant, as determined by its ability to form discoidal lipoproteins, was nearly identical to that of the wild type protein. Contrarily, the disulfide form of the mutant was not able to form discoidal lipoproteins with liposomes of either dimirystoylphosphatidylcholine or dimyristoylphosphatidylglycerol. It is concluded that the separation of the helices 1 and 5 constitutes one of the key steps along the complex pathway for the formation of the final apolipoprotein lipid-bound state. It is inferred that the conformational flexibility of helices 1 and 5 is a key property of apoLp-III, allowing the exposure of hydrophobic protein regions and the interaction of the hydrophobic faces of the amphipathic alpha-helices with the lipoprotein lipid surface.