Exercise-associated hyponatremia in marathon runners: a two-year experience.

This study was conducted to better define the pathophysiology, risk factors, and therapeutic approach to exercise-associated hyponatremia. Medical records from all participants in the 1998 Suzuki Rock 'N' Roll Marathon who presented to 14 Emergency Departments (EDs) were retrospectively reviewed to identify risk factors for the development of hyponatremia. Hyponatremic patients were compared to other runners with regard to race time and to other marathon participants seen in the ED with regard to gender, clinical signs of dehydration, and use of nonsteroidal anti-inflammatory drugs (NSAIDs). An original treatment algorithm incorporating the early use of hypertonic saline (HTS) was evaluated prospectively in our own ED for participants in the 1999 marathon to evaluate improvements in sodium correction rate and incidence of complications. A total of 26 patients from the 1998 and 1999 marathons were hyponatremic [serum sodium (SNa) < or =135 mEq/L] including 15 with severe hyponatremia (SNa < or = 125 mEq/L). Three developed seizures and required intubation and admission to an intensive care unit. Hyponatremic patients were more likely to be female, use NSAIDS, and have slower finishing times. Hyponatremic runners reported drinking "as much as possible" during and after the race and were less likely to have clinical signs of dehydration. An inverse relationship between initial SNa and time of presentation was observed, with late presentation predicting lower SNa values. The use of HTS in selected 1999 patients resulted in faster SNa correction times and fewer complications than observed for 1998 patients. It is concluded that the development of exercise-associated hyponatremia is associated with excessive fluid consumption during and after extreme athletic events. Additional risk factors include female gender, slower race times, and NSAID use. The use of HTS in selected patients seems to be safe and efficacious.

Chemical pathology in brain white matter of recently detoxified alcoholics: a 1H magnetic resonance spectroscopy investigation of alcohol-associated frontal lobe injury.

BACKGROUND: Investigations have suggested that frontal lobe abnormalities are a prominent feature of the alcoholic brain, indicated by impaired neuropsychological performance on tests of frontal lobe function and by reduced frontal lobe volume in neuroimaging and neuropathological examinations. White matter compartment volume loss may underlie observed brain shrinkage and cognitive deficits associated with the frontal lobes, although the nature of this change has not been well-characterized. METHOD: To investigate the susceptibility of frontal lobe white matter to alcohol-associated metabolic change and to understand the nature of alcohol-related white matter injury, 1H magnetic resonance spectroscopy (MRS) was used to measure concentrations of metabolites in frontal white matter (FWM) and parietal white matter (PWM) of recently detoxified alcoholics (RDA) and nonalcoholic controls (CON). Concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), myo-inositol (Ins), and creatine plus phosphocreatine (Cr) were measured in 37 RDA (mean age, 40.4 years; mean length of abstinence, 27.9 days) and 15 CON (mean age, 38.0 years). RESULTS: Analysis of variance (ANOVA) revealed a group by region of interest interaction for concentrations of NAA. Simple effects analysis revealed a significant 14.7% reduction in FWM NAA, while NAA levels in PWM were similar in RDA and CON. In addition, RDA had an 11.8% increase (averaged across both regions of interest) in brain white matter Ins relative to CON. Reductions in FWM NAA were associated with a longer drinking history in the RDA group, but this result was not found when both age and drinking history were used to predict the level of FWM NAA. CONCLUSIONS: Alcohol-associated reductions in FWM NAA may be the result of neuronal loss or dysfunction in the metabolism of NAA. While alcohol-induced oxidative stress may cause global brain impairments in the metabolism and subsequent reduction of NAA, the frontal lobes are particularly rich in excitatory amino acid pathways, and axonal damage or destruction secondary to glutamate-mediated excitotoxicity during alcohol withdrawal may cause frontal lobe-specific reductions in NAA. Elevations in brain white matter Ins may reflect astrocyte proliferation as well as an osmotic response to cell shrinkage.

Elevated myo-inositol in gray matter of recently detoxified but not long-term abstinent alcoholics: a preliminary MR spectroscopy study.

BACKGROUND: Individuals in short-term abstinence from chronic alcohol consumption commonly have neuropsychological impairments with parallel abnormalities in brain structure. Stable, long-term sobriety often results in improvements in both brain structure and function, although the mechanisms underlying these changes are currently not well understood. METHODS: To investigate further the neurobiological underpinnings of alcohol-associated brain abnormalities in short-term and long-term abstinence from alcohol, proton magnetic resonance spectroscopy (echo time, 35 msec; repetition time, 1.5 sec) was used to assay metabolites in the anterior centrum semiovale, anterior cingulate gyrus, and right thalamus of two groups of non-Korsakoff alcoholic men, at different stages of abstinence, compared with a control group of alcohol-nonabusing men. Absolute concentrations of N-acetylaspartate, choline, myo-inositol, and creatine were measured in four recently detoxified alcoholics (mean age, 48.7 years; median abstinence, 41.5 days), five long-term abstinent alcoholics (mean age, 45.1 years; median abstinence, 1.7 years), and five nonalcoholic controls (mean age, 45.0 years). RESULTS: Although there were no between-group differences in concentrations of N-acetylaspartate, choline, or creatine, recently detoxified alcoholics had significantly higher myo-inositol in the thalamus, compared with controls and long-term abstinent alcoholics, and significantly higher myo-inositol in the anterior cingulate gyrus, compared with the controls. CONCLUSIONS: Elevations in myo-inositol in recently detoxified alcoholics are compatible with an acute alcohol cytotoxicity model. myo-Inositol is elevated in hyperosmolar states such as hypernatremia, renal failure, and diabetes; alcohol-induced hyperosmolarity may trigger accumulation of myo-inositol to stabilize the intracellular environment. Increases in myo-inositol may also reflect proliferation or activation of glia. The reduction of myo-inositol to control group levels in long-term abstinent alcoholics may reflect osmolar stability in abstinent alcoholics and/or a reduction in glial cell activation.

Noninvasive evaluation of adult onset myopathy from carnitine palmitoyl transferase II deficiency using proton magnetic resonance spectroscopy.

OBJECTIVE: The adult onset metabolic myopathy of carnitine palmitoyl transferase II (CPT II) deficiency is under-recognized, in part due to variable degrees of enzyme deficiency and symptomatology, as well as limitations in means for noninvasive evaluation. We describe a proton magnetic resonance spectroscopy (MRS) technique, using a standard clinical magnetic resonance imaging scanner, to diagnose and help monitor the response to therapy in adult CPT II deficiency. METHODS: A 53-year-old woman presented with a long standing history of diffuse aching and fatigue provoked by high fat intake, fasting, or prolonged exertion. Muscle biopsy revealed myopathic features and a deficiency (33% of control) of CPT II activity with elevated palmitoyl carnitine. Proton MRS of the soleus muscle was performed using a 1.5 Tesla scanner before and during dietary therapy. RESULTS: Proton MRS revealed shortening of the transverse relaxation time (T2), consistent with increased acetylation of the carnitine pool. The symptoms resolved completely by treatment with frequent feedings of a high carbohydrate diet low in long chain fatty acids supplemented with medium chain triglycerides and L-carnitine. Recovery of normal muscle MRS and carnitine T2 relaxation was documented by the third month of therapy. CONCLUSION: Proton MRS is a novel, potentially useful, and readily available adjunct in the diagnosis and therapeutic monitoring of muscle CPT II deficiency.

Phosphocreatine hydrolysis during submaximal exercise: the effect of FIO2.

There is evidence that the concentration of the high-energy phosphate metabolites may be altered during steady-state submaximal exercise by the breathing of different fractions of inspired O2 (FIO2). Whereas it has been suggested that these changes may be the result of differences in time taken to achieve steady-state O2 uptake (V(O2)) at different FIO2 values, we postulated that they are due to a direct effect of O2 tension. We used 31P-magnetic resonance spectroscopy during constant-load, steady-state submaximal exercise to determine 1) whether changes in high-energy phosphates do occur at the same V(O2) with varied FIO2 and 2) that these changes are not due to differences in V(O2) onset kinetics. Six male subjects performed steady-state submaximal plantar flexion exercise [7.2 +/- 0.6 (SE) W] for 10 min while lying supine in a 1.5-T clinical scanner. Magnetic resonance spectroscopy data were collected continuously for 2 min before exercise, 10 min during exercise, and 6 min during recovery. Subjects performed three different exercise bouts at constant load with the FIO2 switched after 5 min of the 10-min exercise bout. The three exercise treatments were 1) FIO2 of 0.1 switched to 0.21, 2) FIO2 of 0.1 switched to 1.00, and 3) FIO2 of 1.00 switched to 0.1. For all three treatments, the FIO2 switch significantly (P

Light-scattering intensity fluctuations in microdroplets containing inclusions.

A prominent characteristic of the light scattered from a microparticle containing inclusions is a fluctuation in the intensity that is due to the changing positions of the inclusions with respect to each other and the host droplet. We calculate the magnitude of these fluctuations for a host sphere containing a single eccentrically located spherical inclusion and experimentally measure the fluctuation amplitudes for host spheres containing multiple inclusions. We find that, for sufficiently small single inclusions, the amplitude of the scattering fluctuations increases approximately linearly with the area of the inclusion. For multiple inclusions, the fluctuation amplitude increases with concentration with an approximate power-law dependence.

Dialysis and transplantation affect cerebral abnormalities of end-stage renal disease.

Localized short echo time proton magnetic resonance spectroscopy was performed to determine whether chronic and end-stage renal failure, hemodialysis, continuous ambulatory peritoneal dialysis, or renal transplantation result in alterations of cerebral water and metabolites in humans. Hemodialysis patients show an increased cerebral concentration of myo-inositol (+ 14%; P < .05). Increased metabolite ratios are found for myo-inositol/creatine (+14%; P <.01) and choline containing compounds choline/creatine (+10%; P < .01) and are more marked in gray than in white matter. N-acetylaspartate and total creatine concentrations are unaffected. Compared to hemodialysis, continuous ambulatory peritoneal dialysis patients show a larger increase in choline and less elevated myo-inositol. Acutely, hemodialysis significantly decreases the cerebrospinal fluid content of the examined brain regions, but metabolite changes are small compared to the persistent alterations in patients receiving hemodialysis or continuous ambulatory peritoneal dialysis. Undialyzed patients with chronic renal failure do not differ from patients on hemodialysis, but cerebral metabolite changes are completely reversed by transplantation. Cerebral metabolic effects of end-stage renal disease differ from Alzheimer's disease, which is associated with markedly reduced N-acetylaspartate, increased myo-inositol, and normal choline concentrations. The small but significant cerebral metabolic disorders associated with renal failure and dialysis may be a consequence of osmotic dysregulation.

Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study.

The pathogenesis of morbidity associated with hyponatremia is postulated to be determined by the state of intracellular cerebral osmolytes. Previously inaccessible, these metabolites can now be quantitated by proton magnetic resonance spectroscopy. An in vivo quantitative assay of osmolytes was performed in 12 chronic hyponatremic patients (mean serum sodium 120 meq/liter) and 10 normal controls. Short echo time proton magnetic resonance spectroscopy of occipital gray and parietal white matter locations revealed dramatic reduction in the concentrations of several metabolites. In gray matter, myo-inositol was most profoundly reduced at 49% of control value. Choline containing compounds were reduced 36%, creatine/phosphocreatine 19%, and N-acetylaspartate 11% from controls. Similar changes were found in white matter. Recovery of osmolyte concentrations was demonstrated in four patients studied 8-14 wk later. These results are consistent with a reversible osmolyte reduction under hypoosmolar stress in the intact human brain and offer novel suggestions for treatment and monitoring of this common clinical event.

Hormone storage vesicle proteins. Transcriptional basis of the widespread neuroendocrine expression of chromogranin A, and evidence of its diverse biological actions, intracellular and extracellular.

Chromogranin A (CgA) is an acidic soluble protein found in the core of secretory vesicles throughout the neuroendocrine system, from which it is coreleased by exocytosis with a variety of amine and peptide hormones and neurotransmitters. Much has now been learned about the structure of CgA, and there is emerging evidence that it plays several biological roles, both within secretory granules and after release from neuroendocrine cells. Factors governing its gene's widespread yet restricted (neuroendocrine) pattern of expression are only now being explored. In an attempt to understand how cells throughout the neuroendocrine system (but not exocrine or other nonendocrine cells) turn on and control the expression of CgA, we have isolated and begun to characterize functional 5' promoter elements from the rodent CgA genes. Within the sympathoadrenal system, interest focuses on a recently proposed (though as yet incompletely investigated) function of CgA: its ability to suppress catecholamine release from adrenal chromaffin cells when such cells are stimulated by their usual physiologic secretagogue. We anticipate that such studies will contribute to an understanding of this abundant, yet previously mysterious protein's role in neuroendocrine function.

Thermodynamics of cyclophilin catalyzed peptidyl-prolyl isomerization by NMR spectroscopy.

One-dimensional nmr exchange spectroscopy was carried out to determine thermodynamic parameters of cyclophilin-induced cis-trans isomerization of succinyl-Ala-Phe-Pro-Phe-p-nitroanilide. Rate measurements were possible at physiological temperatures. The kc/Km of rat cyclophilin was found to be 12.8 (+/- 0.5) s-1 microM-1 at 37 degrees C, intermediate to previously reported values that used a coupled enzyme assay extrapolated to this temperature. Activation energies (delta G not equal to) for the uncatalyzed and catalyzed reaction at 37 degrees C were found to be 19.7 and 17.1 kcal/mol, respectively, and were primarily due to an enthalpic barrier.

Calcium and catecholamine interactions with adrenal chromogranins. Comparison of driving forces in binding and aggregation.

The soluble core of catecholamine storage vesicles in the adrenal medulla contains high concentrations of the cations calcium (20 mM) and catecholamine (600 mM). Do these cations interact with the abundant vesicle core anionic proteins, the chromogranins? We investigated the binding of calcium and norepinephrine (NE) to bovine adrenal chromogranins by equilibrium dialysis. Both calcium and NE were bound saturably by chromogranins, with low affinity (Kd values of 1.3 x 10(-4) M and 2.1 x 10(-3) M), but high capacity (17 and 32 mol of ligand/mol of chromogranin A). Both ligands bound maximally at a pH greater than 5.5 and were displaced by competing cations in a pattern (trivalent greater than divalent greater than monovalent) consistent with electrostatic components to the interactions. Binding of calcium and NE was not impaired by prior heat denaturation of the chromogranins, and chromogranin A was involved in both binding reactions. Calcium but not NE binding was enhanced by nonpolar solvents. Temperature dependence studies indicated that calcium binding to chromogranins was largely entropy-driven, while NE binding was driven by a significantly negative (favorable) change in enthalpy (5760 cal/mol), even in the face of an unfavorable entropy. Exposure of chromogranins to calcium or NE resulted in precipitation (aggregation) as analyzed by centrifugation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. NE was a more effective chromogranin precipitant than calcium, and in combination, the NE effect was antagonized by calcium. Precipitation of chromogranins by both calcium and NE was inhibited by NaCl at ionic strengths comparable with those of the ligands. These data suggest that chromogranins bind and are precipitated by calcium and NE at affinities compatible with their in situ concentrations, but that the interactions exhibit different thermodynamic driving forces. Furthermore, NE may trigger an enthalpy-driven conformational change in chromogranins, resulting in aggregation.

Hemodynamic comparison of ventricular pacing, atrioventricular sequential pacing, and atrial synchronous ventricular pacing using radionuclide ventriculography.

To assess the hemodynamic effects of physiologic pacing, 13 patients with DDD pacemakers who had varying degrees of atrioventricular (AV) block were studied with radionuclide ventriculography during VVI, DVI and VDD modes. Radionuclide ventriculography was performed with patient in the supine position at rest 5 to 10 minutes after the pacing mode and AV delay were changed. The AV delays selected were short (mean 147 +/- 4.8 ms) and long (mean 197 +/- 4.8 ms), with a constant difference of 50 ms. During VVI, 6 patients (group 1) had a left ventricular ejection fraction of 40% or less (mean 22 +/- 11) and 7 patients (group 2) had an ejection fraction of more than 40% (mean 59 +/- 11). Comparisons of ejection fraction, end-diastolic volume and cardiac index between VVI and both modes of AV pacing (VDD and DVI) and between long and short AV delays led to the following conclusions: DVI or VDD pacing produces more beneficial hemodynamic effects than VVI, and these effects are more pronounced in patients with low ejection fraction if longer AV delay is used. The VDD mode significantly improves ventricular function over the DVI mode in patients with an ejection fraction of more than 40% independent of heart rate. Longer AV delay is essential in patients with an ejection fraction of 40% or less to improve ventricular function with physiologic pacing.