Background: There is considerable disagreement regarding the concentration of glucose in tears and its relationship to the concentration in blood. Improved sampling and analysis methods may resolve these discrepancies and possibly provide a basis for in situ tear glucose sensors. Methods: We used liquid chromatography (LC) with electrospray ionization mass spectrometry (ESI-MS) to determine glucose in 1-L tear fluid samples obtained from 25 fasting study participants. Tear fluid was collected with microcapillaries and a slitlamp microscope. Results: The median (range) of fasting tear glucose concentrations was 28 (7-161) mol/L or 0.50 (0.13-2.90) mg/dL. The SD of tear glucose measurements for individuals varied linearly with the mean tear glucose concentration and was approximately half of the mean. We found no significant difference in tear glucose concentrations between contact lens users and nonusers (P ؍ 0.715). We observed significant correlations between fasting blood and tear glucose concentrations (R ؍ 0.50, P ؍ 0.01). Conclusions: Our tear fluid collection and analysis method enables reliable measurement of equilibrium, fasting tear glucose concentrations. These concentrations are lower than those previously reported for nondiabetic persons. Larger population studies are required to determine correlations between blood and tear glucose concentrations and to determine the utility of contact lens-based sensors for the monitoring of diabetes. Our methods are applicable for study of other tear fluid analytes and may prove useful for monitoring other disease states. © 2007 American Association for Clinical ChemistryGlucose has been a recognized component of tear fluid since the early 1900s, but disagreement continues regarding its concentration in tear fluid and its correlation with blood glucose concentration (1)(2)(3)(4)(5)(6). Literature reports of normal tear glucose concentrations range between 0 and 9.1 mmol/L (164 mg/dL), with median values of 110 -280 mol/L (1.98 and 5.04 mg/dL) (1, 7 ). In a recent study of 121 persons, tear glucose concentrations ranged from below the limit of detection to 9.1 mmol/L (164 mg/dL) (7 ). Much of the difference in reported tear glucose concentrations is likely from the use of different tear collection techniques (8 ). Collection techniques causing severe eye irritation [such as filter paper collection (6 )] are associated with the highest tear glucose concentrations, whereas less irritating techniques (such as glass capillary collection) are associated with the lowest (2, 3 ). Chemically stimulated tears have increased tear glucose (8, 9 ). Reliable tear sampling may also be confounded by individual differences in tolerance to real or expected eye stimulation during sampling. (See the Data Supplement that accompanies the online version of this Technical Brief at http://www.clinchem.org/content/vol53/issue7 for an extensive review of the tear glucose literature.)Improved tear fluid collection, and the ability to analyze very low volumes of tear fluid, may dramatic...
We have developed a mass spectrometry-based method that allows one to accurately determine the glucose concentration of tear fluid. We used a 1 L micro-capillary to collect tear fluid from the tear meniscus with minimal irritation of the eye. We analyzed the 1 L volume of collected tear fluid with liquid-chromatography electrospray ionization mass spectrometry with the use of D-glucose-6,6-d 2 as an internal standard. Repeated measurements and a recovery experiment on pooled, onion-induced tears showed that the analysis of the glucose in tears was precise (4% relative standard deviation) and provided 100% recovery. We found the tear glucose concentration of one fasting nondiabetic subject to be 13 to 51 M while the onion-induced tear glucose concentration of a different nondiabetic subject to be 211 to 256 M. . Current self-monitoring methods rely on invasive finger sticks to directly measure blood glucose levels to provide the critical information required to achieve glycemic control. A number of noninvasive approaches to monitoring blood glucose concentrations are being pursued; however, none have been successfully developed to the point where they have gained widespread clinical acceptance [3]. There has been significant recent activity in exploring noninvasive monitoring by using tear fluid glucose as an indicator for blood glucose [4 -6]. Such an approach will be effective only if the glucose concentrations in tear fluid are a reliable surrogate for blood glucose concentrations.A survey of the literature over the last 70 years on tear glucose determinations indicates significant disagreement in measured tear glucose concentrations and on the relationship of tear fluid glucose to blood glucose concentrations. Daum and Hill [7] The differences in tear glucose concentrations between these reports are likely due to the use of different tear fluid collection methods. Van Haeringen and Glasius specifically addressed the dependence of tear fluid glucose on the method of collection [9]. They used a glucose dehydrogenase method to analyze chemically stimulated tears collected with a capillary and mechanically stimulated tear fluid collected by filter paper. Van Haeringen and Glasius found higher glucose concentrations in the tear fluid collected by filter paper and concluded that the increase is due to the mechanical stimulation of the corneal and conjunctival epithelium [9]. Other studies reported similar findings in experiments on rabbits [10] and in subjects who were tested immediately after swimming [7]. Therefore, it is apparent that to determine a physiologically relevant, baseline tear glucose concentration, tear fluid must be acquired with minimal tear stimulation and eye irritation.
Abstract. The Loeb-Eiber mass filter is best operated at relatively high pressures-such as 1 Torr-where collisional dampening of ions up to the mass filter thermalizes the ions' kinetic energy, which is a requirement for effective filtering. The inter-electrode gaps of~8 μm require rf amplitudes on the order of 0-5 V p-p at approximately 50 MHz to achieve mass filtering up to m/z 40. Mass filtering between the 25-μm diameter wires, therefore, takes place on time frames less than the collision frequency at~1 Torr. The low power and high pressure capabilities of the Loeb-Eiber mass filter make it ideally suited for miniaturization, where power and space are a premium. In the present work, a Loeb-Eiber mass filter was constructed using commercial silicon-on-insulator (SOI) microfabrication techniques. Ions transmitting through the chip-based Loeb-Eiber mass filter were characterized in real time using a traditional linear quadrupole mass analyzer in series with the Loeb-Eiber mass filter. The new hybrid instrument has enabled us to verify several important claims regarding the operation of the Loeb-Eiber mass filter: (1) that ions can be effectively filtered at~1 Torr, (2) that for ions of a fixed mass-to-charge ratio, the ion transmission current decreases linearly with increasing rf amplitude on the Loeb-Eiber mass filter, (3) that the cutoff voltage at which all ions of a particular m/z value are effectively blocked is linearly related to mass-to-charge, and (4) that square waveforms can filter ions more effectively than sinusoidal waveforms for a given peak-to-peak rf amplitude.
A new ion source region has been constructed and attached to a variable temperature selected ion flow tube. The source features the capabilities of electron impact, chemical ionization, a solids probe, and electrospray ionization. The performance of the instrument is demonstrated through a series of reactions from ions created in each of the new source regions. The chemical ionization source is able to create H3O(+), but not as efficiently as similar sources with larger apertures. The ability of this source to support a solids probe, however, greatly expands our capabilities. A variety of rhenium cations and dications are created from the solids probe in sufficient abundance to study in the flow tube. The reaction of Re(+) with O2 proceeds with a rate constant that agrees with the literature measurements, while the reaction of Re2(2+) is found to charge transfer with O2 at about 60% of the collision rate; we have also performed calculations that support the charge transfer pathway. The electrospray source is used to create Ba(+), which is reacted with N2O to create BaO(+), and we find a rate constant that agrees with the literature.
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