Urinary total globotriaosylceramide and isoforms to identify women with Fabry disease: a diagnostic test study.

BACKGROUND: Fabry disease is a treatable X-linked lysosomal storage disorder caused by alterations in the structural gene (GLA) of α-galactosidase A (AGAL), manifesting with cardiovascular and/or kidney disease and decreased life span. Although males as well as females can be affected, females cannot be identified using AGAL activity. We evaluated urinary total globotriaosylceramide (Gb3) and single N-acyl isoforms for the detection of Fabry disease in female patients with and without chronic kidney disease (CKD). STUDY DESIGN: Diagnostic accuracy study. SETTING & PARTICIPANTS: 28 untreated women with Fabry disease and 335 female outpatients without Fabry disease with (n = 213) and without CKD (n = 122). INDEX TEST: Assessment of urinary Gb3 using electrospray ionization tandem mass spectrometry, including 6 N-acyl isoforms, total Gb3 related to urinary creatinine, and ratios of Gb3-24 to Gb3-18 and Gb3-24 to urinary AGAL. REFERENCE TEST: Fabry disease, diagnosed by identification of known pathogenic GLA mutations in patients or their male relatives. RESULTS: 6 parameters (ratio of Gb3-24 to urinary AGAL activity; Gb3-24; ratio of Gb3-24 to Gb3-18; Gb3-22; Gb3-16; and total Gb3) were highly informative for the diagnosis of Fabry disease independent of the presence or absence of CKD (area under the receiver operating characteristic curve, 0.876-0.927; all P < 0.001). LIMITATIONS: Because of low signal-to-noise ratios, 15.8% of samples had to be excluded. CONCLUSION: Total urinary Gb3 and Gb3 isoforms can be used for the diagnosis of Fabry disease in women.

Hemodynamic and autonomic changes induced by Ironman: prediction of competition time by blood pressure variability.

We hypothesized that the extreme endurance exercise of an Ironman competition would lead to long-standing hemodynamic and autonomic changes. We investigated also the possibility of predicting competition performance from baseline hemodynamic and autonomic parameters. We have investigated 27 male athletes before competition, 1 h after, and then for the following week after the competition. The Task Force monitor was used to measure beat-to-beat hemodynamic and autonomic parameters during supine rest and active standing. Heart rate (P < 0.001) was increased, and stroke index (P = 0.011), systolic blood pressure (P = 0.004), diastolic blood pressure (P < 0.001), total peripheral resistance index (P < 0.001), and baroreceptor reflex sensitivity (P < 0.001) were decreased after the competition. The 0.05- to 0.17-Hz band of heart rate and blood pressure variability was increased (P < 0.001 and P < 0.001, respectively), the 0.17- to 0.40-Hz band of heart rate interval variability was decreased after the competition (P < 0.001). All parameters returned to baseline values 3 days after the competition. After the competition, the autonomic response to orthostasis was significantly impaired. The 0.05- to 0.17-Hz band of diastolic blood pressure variability before competition and weekly net exercise training, but not the other hemodynamic and autonomic parameters, were related to competition time in multivariate regression analysis (multiple r = 0.70, P < 0.001). The marked hemodynamic and autonomic changes after an ultraendurance race, which are compatible with myocardial depression in the face of sympathetic activation and reduction of afterload, return to baseline after only 1-3 days. Because the 0.05- to 0.17-Hz band of diastolic blood pressure variability contributes to the prediction of competition time, the analysis of blood pressure variability in the frequency domain deserves further study for the prediction of endurance capacity.

Temporal nitric oxide dynamics in the paranasal sinuses during humming.

In this study, the temporal shape of voice-induced nitric oxide (NO) signals in exhaled air has been investigated in eight healthy individuals by means of laser magnetic resonance spectroscopy. The results of the experimental part have been compared with calculated signals obtained by using a simple one-compartment model of the paranasal sinuses. In the experimental part, a rapidly increasing NO concentration has been found when the subjects started humming. After reaching a maximum, the emission starts to decrease with the shape of an exponential decay and finally reaches a constant level. The time constant of this decay (NO washout) is 3.0 +/- 1.2 s. The peak height of the NO emission during humming increases when the time between two humming processes increases. When no voice-induced NO emission takes place, the NO concentration in the paranasal sinuses rebuilds again to a maximum concentration. The typical time constant for the NO recovery is 4.5 +/- 3.2 min. A three-compartment model defining exactly the geometry and anatomy of the paranasal sinuses has been developed that is based on three main assumptions of the NO dynamics: 1) constant NO production of the epithelium in the sinuses; 2) the rate of the chemical reaction of NO with the epithelium of the paranasal sinuses is proportional to the NO concentration; and 3) the emission of NO from the sinuses (volume/s) is proportional to the NO concentration. It is shown that the three-compartment model under the experimental conditions can be reduced to a one-compartment model, which describes the complete temporal behavior of the NO exchange.

Release of nitric oxide from novel diazeniumdiolates monitored by laser magnetic resonance spectroscopy.

We describe a technique in which for the first time laser magnetic resonance spectroscopy (LMRS) is used online to monitor the release of nitric oxide from synthetic NO donors. LMRS is a spectroscopic method for selective, sensitive (to 1 ppb), and time-resolved NO gas detection in the far-infrared and midinfrared spectral regions. We used two partly novel sets of diazeniumdiolates, the first set derived from N,N-diethylamine (-->DEA-NO), piperidine ((-->PIPE-NO), 2-methylpiperidine (-->MEPIPE-NO), and 2-ethylpiperidine (-->EPIPE-NO) and the second set derived from 2-, 3-, and 4-piperidine carboxylic acids (-->PIPECO-NO, NIPECO-NO, ISONIPECO-NO). We monitored the acid-catalyzed NO liberation from these compounds as influenced by parameters such as pH, temperature, concentration, and molecular structure. PIPECO-NO turned out to be the fastest donor of the group. The 3- and 4-substituted isomer derivatives were only negligibly faster releasers than unsubstituted PIPE-NO, which on the other hand showed to be faster than the higher homologues MEPIPE-NO and EPIPE-NO. The results demonstrate that varying neighboring groups affect the functional diazeniumdiolate group differently. A vicinal carboxyl group increases and alkyl groups decrease the rate of NO release.