Renal function including fluid and electrolyte balance was studied during recovery in eight subjects who developed symptomatic hyponatremia (HN; plasma sodium concentration less than 130 mM) during an 88-km ultramarathon footrace and compared with results for normonatremic runners [NN; n = 18, mean postrace plasma sodium concentration, 138.2 +/- 1.2 (SE) mM]. Estimated fluid intake during the race for HN was 12.5 +/- 1.6 (SE) liters over 9 h 41 min (+/- 28 min). HN excreted a net fluid excess of 2.95 +/- 0.56 (range 1.2-5.9) liters compared with a fluid deficit of 2.7 +/- 0.3% body weight in NN. The sodium deficit was 153 +/- 35 mmol in HN and 187 +/- 37 mmol in NN. Despite the fluid overload, plasma volume was decreased by 24.1 +/- 5.0% in HN compared with 8.2 +/- 2.6% in NN. Serum renin activity (5.1 +/- 2.0 ng.ml-1.h-1), aldosterone concentrations (410 +/- 34 ng/l), creatinine clearances (174.8 +/- 28.2 ml/min), and urine output (6.4 +/- 1.0 ml/min) were markedly elevated in HN during recovery. Thus the hyponatremia of exercise results from fluid retention in subjects who ingest abnormally large fluid volumes during prolonged exercise.
The Ig new antigen receptors (IgNARs) are single-domain antibodies found in the serum of sharks. Here, we report 2.2-and 2.8-Å structures of the type 2 IgNAR variable domains 12Y-1 and 12Y-2. Structural features include, first, an Ig superfamily topology transitional between cell adhesion molecules, antibodies, and T cell receptors; and, second, a vestigial complementarity-determining region 2 at the ''bottom'' of the molecule, apparently discontinuous from the antigen-binding paratope and similar to that observed in cell adhesion molecules. Thus, we suggest that IgNARs originated as cell-surface adhesion molecules coopted to the immune repertoire and represent an evolutionary lineage independent of variable heavy chain͞variable light chain type antibodies. Additionally, both 12Y-1 and 12Y-2 form unique crystallographic dimers, predominantly mediated by main-chain framework interactions, which represent a possible model for primordial cell-based interactions. Unusually, the 12Y-2 complementarity-determining region 3 also adopts an extended -hairpin structure, suggesting a distinct selective advantage in accessing cryptic antigenic epitopes.
The new antigen receptor (IgNAR) is an antibody unique to sharks and consists of a disulphide-bonded dimer of two protein chains, each containing a single variable and five constant domains. The individual variable (V(NAR)) domains bind antigen independently, and are candidates for the smallest antibody-based immune recognition units. We have previously produced a library of V(NAR) domains with extensive variability in the CDR1 and CDR3 loops displayed on the surface of bacteriophage. Now, to test the efficacy of this library, and further explore the dynamics of V(NAR) antigen binding we have performed selection experiments against an infectious disease target, the malarial Apical Membrane Antigen-1 (AMA1) from Plasmodium falciparum. Two related V(NAR) clones were selected, characterized by long (16- and 18-residue) CDR3 loops. These recombinant V(NAR)s could be harvested at yields approaching 5mg/L of monomeric protein from the E. coli periplasm, and bound AMA1 with nanomolar affinities (K(D)= approximately 2 x 10(-7) M). One clone, designated 12Y-2, was affinity-matured by error prone PCR, resulting in several variants with mutations mapping to the CDR1 and CDR3 loops. The best of these variants showed approximately 10-fold enhanced affinity over 12Y-2 and was Plasmodium falciparum strain-specific. Importantly, we demonstrated that this monovalent V(NAR) co-localized with rabbit anti-AMA1 antisera on the surface of malarial parasites and thus may have utility in diagnostic applications.
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