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Scientific Articles - PTR-MS Bibliography

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2016
[1717] Klein, F., S. M. Platt, N. J. Farren, A. Detournay, E. A. Bruns, C. Bozzetti, K. R. Daellenbach, D. Kilic, N. K. Kumar, S. M. Pieber, et al., "Characterization of Gas-Phase Organics Using Proton Transfer Reaction Time-of-Flight Mass Spectrometry: Cooking Emissions.", Environ Sci Technol, vol. 50, pp. 1243–1250, Feb, 2016.
Link: http://dx.doi.org/10.1021/acs.est.5b04618
Abstract
<p>Cooking processes produce gaseous and particle emissions that are potentially deleterious to human health. Using a highly controlled experimental setup involving a proton-transfer-reaction time-of-flight mass spectrometer (PTR-ToF-MS), we investigate the emission factors and the detailed chemical composition of gas phase emissions from a broad variety of cooking styles and techniques. A total of 95 experiments were conducted to characterize nonmethane organic gas (NMOG) emissions from boiling, charbroiling, shallow frying, and deep frying of various vegetables and meats, as well as emissions from vegetable oils heated to different temperatures. Emissions from boiling vegetables are dominated by methanol. Significant amounts of dimethyl sulfide are emitted from cruciferous vegetables. Emissions from shallow frying, deep frying and charbroiling are dominated by aldehydes of differing relative composition depending on the oil used. We show that the emission factors of some aldehydes are particularly large which may result in considerable negative impacts on human health in indoor environments. The suitability of some of the aldehydes as tracers for the identification of cooking emissions in ambient air is discussed.</p>
[1735] Sukul, P., J. K. Schubert, P. Oertel, S. Kamysek, K. Taunk, P. Trefz, and W. Miekisch, "FEV manoeuvre induced changes in breath VOC compositions: an unconventional view on lung function tests", Scientific Reports, vol. 6, pp. 28029, Jun, 2016.
Link: http://dx.doi.org/10.1038/srep28029
Abstract
Breath volatile organic compound (VOC) analysis can open a non-invasive window onto pathological and metabolic processes in the body. Decades of clinical breath-gas analysis have revealed that changes in exhaled VOC concentrations are important rather than disease specific biomarkers. As physiological parameters, such as respiratory rate or cardiac output, have profound effects on exhaled VOCs, here we investigated VOC exhalation under respiratory manoeuvres. Breath VOCs were monitored by means of real-time mass-spectrometry during conventional FEV manoeuvres in 50 healthy humans. Simultaneously, we measured respiratory and hemodynamic parameters noninvasively. Tidal volume and minute ventilation increased by 292 and 171% during the manoeuvre. FEV manoeuvre induced substance specific changes in VOC concentrations. pET-CO2 and alveolar isoprene increased by 6 and 21% during maximum exhalation. Then they decreased by 18 and 37% at forced expiration mirroring cardiac output. Acetone concentrations rose by 4.5% despite increasing minute ventilation. Blood-borne furan and dimethyl-sulphide mimicked isoprene profile. Exogenous acetonitrile, sulphides, and most aliphatic and aromatic VOCs changed minimally. Reliable breath tests must avoid forced breathing. As isoprene exhalations mirrored FEV performances, endogenous VOCs might assure quality of lung function tests. Analysis of exhaled VOC concentrations can provide additional information on physiology of respiration and gas exchange.
2015
[1678] Colard, S., G. O'Connell, P. Sulzer, K. Breiev, X. Cahours, and S. S. Biel, "An Experimental Method to Determine the Concentration of Nicotine in Exhaled Breath and its Retention Rate Following Use of an Electronic Cigarette", J Environ Anal Chem, vol. 02, 2015.
Link: http://dx.doi.org/10.4172/2380-2391.1000161
Abstract
<p>An experimental method is presented for the first time to determine the concentration of nicotine in exhaled breath following e-cigarette use in experienced participants and the impact that vaping topography has on the retention rate of nicotine. Aerosols from e-cigarettes containing different concentrations of nicotine were first evaluated by GC-FID to determine the concentration of nicotine delivered per puff versus machine - vaping intensity. These e-cigarettes were then vaped by participants through a cigarette holder attached to a smoking topography analyzer which recorded puff volume and puff duration. This allowed the concentration of nicotine in the aerosol inhaled by the participant during each puff to be determined. A PTR-MS instrument was then used to determine the concentration of nicotine exhaled following each use of the e-cigarette. By dividing this figure by the nicotine concentration delivered enabled its retention rate to be calculated. The principal finding was over 99% of the nicotine was retained by the participants when the e-cigarette aerosol was inhaled and a reduced but still substantial quantity was retained (on average 86%) when the e-cigarette aerosol was held in the mouth only (i.e, no inhalation). In both cases, the nicotine concentrations detected in the exhaled breath were low (range 1.8 - 1786 ppb). The experimental method presented here may be used to determine the concentration of other e-cigarette aerosol constituents in exhaled breath and the retention rate of those constituents which is useful for the evaluation of e-cigarettes from a consumer and bystander perspective.</p>
[1715] Sukul, P., P. Trefz, S. Kamysek, J. K. Schubert, and W. Miekisch, "Instant effects of changing body positions on compositions of exhaled breath.", J Breath Res, vol. 9, pp. 047105, Dec, 2015.
Link: http://dx.doi.org/10.1088/1752-7155/9/4/047105
Abstract
<p>Concentrations of exhaled volatile organic compounds (VOCs) may depend not only on biochemical or pathologic processes but also on physiological parameters. As breath sampling may be done in different body positions, effects of the sampling position on exhaled VOC concentrations were investigated by means of real-time mass spectrometry. Breaths from 15 healthy volunteers were analyzed in real-time by PTR-ToF-MS-8000 during paced breathing (12/min) in a continuous side-stream mode. We applied two series of body positions (setup 1: sitting, standing, supine, and sitting; setup 2: supine, left lateral, right lateral, prone, and supine). Each position was held for 2&thinsp;min. Breath VOCs were quantified in inspired and alveolar air by means of a custom-made algorithm. Parallel monitoring of hemodynamics and capnometry was performed noninvasively. In setup 1, when compared to the initial sitting position, normalized mean concentrations of isoprene, furan, and acetonitrile decreased by 24%, 26%, and 9%, respectively, during standing and increased by 63%, 36%, and 10% during lying mirroring time profiles of stroke volume and pET-CO2. In contrast, acetone and H2S concentrations remained almost constant. In setup 2, when compared to the initial supine position, mean alveolar concentrations of isoprene and furan increased significantly up to 29% and 16%, respectively, when position was changed from lying on the right side to the prone position. As cardiac output and stroke volume decreased at that time, the reasons for the observed concentrations changes have to be linked to the ventilation/perfusion ratio or compartmental distribution rather than to perfusion alone. During final postures, all VOC concentrations, hemodynamics, and pET-CO2 returned to baseline. Exhaled blood-borne VOC profiles changed due to body postures. Changes depended on cardiac stroke volume, origin, compartmental distribution and physico-chemical properties of the substances. Patients&#39; positions and cardiac output have to be controlled when concentrations of breath VOCs are to be interpreted in terms of biomarkers.</p>
[1651] R. del Rio, F., M.E.. OHara, A.. Holt, P.. Pemberton, T.. Shah, T.. Whitehouse, and C.A.. Mayhew, "Volatile Biomarkers in Breath Associated With Liver Cirrhosis - Comparisons of Pre- and Post-liver Transplant Breath Samples", EBioMedicine, Jul, 2015.
Link: http://dx.doi.org/10.1016/j.ebiom.2015.07.027
Abstract
Background: The burden of liver disease in the UK has risen dramatically and there is a need for improved diagnostics. Aims: To determine which breath volatiles are associated with the cirrhotic liver and hence diagnostically useful. Methods: A two-stage biomarker discovery procedure was used. Alveolar breath samples of 31 patients with cirrhosis and 30 healthy controls were mass spectrometrically analysed and compared (stage 1). 12 of these patients had their breath analysed after liver transplant (stage 2). Five patients were followed longitudinally as in-patients in the posttransplant period. Results: Seven volatileswere elevated in the breath of patients versus controls. Of these, five showed statistically significant decrease post-transplant: limonene, methanol, 2-pentanone, 2-butanone and carbon disulfide. On an individual basis limonene has the best diagnostic capability (the area under a receiver operating characteristic curve (AUROC) is 0.91), but this is improved by combining methanol, 2-pentanone and limonene (AUROC curve 0.95). Following transplant, limonene shows wash-out characteristics. Conclusions: Limonene,methanol and 2-pentanone are breathmarkers for a cirrhotic liver. This study raises the potential to investigate these volatiles asmarkers for early-stage liver disease. Bymonitoring the wash-out of limonene following transplant, graft liver function can be non-invasively assessed.
2014
[1548] Aprea, E., L. Cappellin, F. Gasperi, F. Morisco, V. Lembo, A. Rispo, R. Tortora, P. Vitaglione, N. Caporaso, and F. Biasioli, "Application of PTR-TOF-{MS} to investigate metabolites in exhaled breath of patients affected by coeliac disease under gluten free diet", Journal of Chromatography B, vol. 966, pp. 208–213, Sep, 2014.
Link: http://dx.doi.org/10.1016/j.jchromb.2014.02.015
Abstract
<p>Coeliac disease (CD) is a common chronic inflammatory disorder of the small bowel induced in genetically susceptible people by the exposure to gliadin gluten. Even though several tests are available to assist the diagnosis, CD remains a biopsy-defined disorder, thus any non-invasive or less invasive diagnostic tool may be beneficial. The analysis of volatile metabolites in exhaled breath, given its non-invasive nature, is particularly promising as a screening tool of disease in symptomatic or non-symptomatic patients. In this preliminary study the proton transfer reaction time of flight mass spectrometry coupled to a buffered end-tidal on-line sampler to investigate metabolites in the exhaled breath of patients affected by coeliac disease under a gluten free diet was applied. Both H3O+ or NO+ were used as precursor ions. In our investigation no differences were found in the exhaled breath of CD patients compared to healthy controls. In this study, 33 subjects were enrolled: 16 patients with CD, all adhering a gluten free diet, and 17 healthy controls. CD patients did not show any symptom of the disease at the time of breath analysis; thus the absence of discrimination from healthy controls was not surprising.</p>
[1564] Smith, D., P. Spanel, J. Herbig, and J. Beauchamp, "Mass spectrometry for real-time quantitative breath analysis", Journal of Breath Research, vol. 8, pp. 027101, Mar, 2014.
Link: http://dx.doi.org/10.1088/1752-7155/8/2/027101
Abstract
<p>Breath analysis research is being successfully pursued using a variety of analytical methods, prominent amongst which are gas chromatography with mass spectrometry, GC-MS, ion mobility spectrometry, IMS, and the fast flow and flow-drift tube techniques called selected ion flow tube mass spectrometry, SIFT-MS, and proton transfer reaction mass spectrometry, PTR-MS. In this paper the case is made for real-time breath analysis by obviating sample collection into bags or onto traps that can suffer from partial degradation of breath metabolites or the introduction of impurities. Real-time analysis of a broad range of volatile chemical compounds can be best achieved using SIFT-MS and PTR-MS, which are sufficiently sensitive and rapid to allow the simultaneous analyses of several trace gas metabolites in single breath exhalations. The basic principles and the ion chemistry that underpin these two analytical techniques are briefly described and the differences between them, including their respective strengths and weaknesses, are revealed, especially with reference to the analysis of the complex matrix that is exhaled breath. A recent innovation is described that combines time-of-flight mass spectrometry with the proton transfer flow-drift tube reactor, PTR-TOFMS, which provides greater resolution in the analytical mass spectrometer and allows separation of protonated isobaric molecules. Examples are presented of some recent data that well illustrate the quality and real-time feature of SIFT-MS and PTR-MS for the analysis of exhaled breath for physiological/biochemical/pharmacokinetics studies and for the identification and quantification of biomarkers relating to specific disease states.</p>
[1602] Smith, D., P. Spanel, J. Herbig, and J. Beauchamp, "Mass spectrometry for real-time quantitative breath analysis.", J Breath Res, vol. 8, pp. 027101, Jun, 2014.
Link: http://dx.doi.org/10.1088/1752-7155/8/2/027101
Abstract
<p>Breath analysis research is being successfully pursued using a variety of analytical methods, prominent amongst which are gas chromatography with mass spectrometry, GC-MS, ion mobility spectrometry, IMS, and the fast flow and flow-drift tube techniques called selected ion flow tube mass spectrometry, SIFT-MS, and proton transfer reaction mass spectrometry, PTR-MS. In this paper the case is made for real-time breath analysis by obviating sample collection into bags or onto traps that can suffer from partial degradation of breath metabolites or the introduction of impurities. Real-time analysis of a broad range of volatile chemical compounds can be best achieved using SIFT-MS and PTR-MS, which are sufficiently sensitive and rapid to allow the simultaneous analyses of several trace gas metabolites in single breath exhalations. The basic principles and the ion chemistry that underpin these two analytical techniques are briefly described and the differences between them, including their respective strengths and weaknesses, are revealed, especially with reference to the analysis of the complex matrix that is exhaled breath. A recent innovation is described that combines time-of-flight mass spectrometry with the proton transfer flow-drift tube reactor, PTR-TOFMS, which provides greater resolution in the analytical mass spectrometer and allows separation of protonated isobaric molecules. Examples are presented of some recent data that well illustrate the quality and real-time feature of SIFT-MS and PTR-MS for the analysis of exhaled breath for physiological/biochemical/pharmacokinetics studies and for the identification and quantification of biomarkers relating to specific disease states.</p>
[1606] Denzer, M. Y., S. Gailer, D. W. Kern, P. L Schumm, N. Thuerauf, J. Kornhuber, A. Buettner, and J. Beauchamp, "Quantitative Validation of the n-Butanol Sniffin' Sticks Threshold Pens.", Chemosens Percept, vol. 7, pp. 91–101, 2014.
Link: http://dx.doi.org/10.1007/s12078-014-9168-1
Abstract
<p>Odorant pens are used by medical practitioners and researchers to assess olfactory dysfunction. Despite their routine use, there are currently no data on the gas-phase odorant concentrations released from the pen tips or whether these concentrations scale linearly with the aqueous-phase concentrations inside the pens. The commercially available Sniffin&#39; Sticks odor threshold test containing n-butanol was chosen for evaluation. The gas-phase concentration of n-butanol at the tip of each pen was measured directly in a new set of pens via proton-transfer-reaction mass spectrometry (PTR-MS). Measurements were additionally made on the same pens after 6&nbsp;months and two older pen sets, namely a 3-year-old (used) and 4-year-old (new) set. Furthermore, application-related tests were made to determine the performance of the pens during routine use and under stress. These data demonstrate that the gas-phase n-butanol concentrations of the threshold pens are linear over the entire set, both for brand-new pens and 6&nbsp;months later; this reflects the expected performance that was previously only assumed. Furthermore, the application-simulation tests demonstrated a good performance of the pens when used according to their intended protocol. Measurements of the older pen sets suggest that storage conditions are more critical than usage for pen stability. The present findings confirm that the n-butanol odorant pens are an appropriate tool for threshold testing, provided they are stored and handled correctly.</p>
2013
[Kohl2013] Kohl, I., J. Herbig, J. Dunkl, A. Hansel, M. Daniaux, and M. Hubalek, "Chapter 6 - Smokers Breath as Seen by Proton-Transfer-Reaction Time-of-Flight Mass Spectrometry (PTR-TOF-MS)", Volatile Biomarkers, Boston, Elsevier, pp. 89 - 116, 2013.
Link: http://www.sciencedirect.com/science/article/pii/B9780444626134000064
Abstract
Abstract Proton-transfer-reaction time-of-flight mass spectrometry has been employed in a 12&#xa0;months breath gas analysis study to describe the breath composition of 19 cigarette smoking and 53 non-smoking women. The most prevalent constituents were acetone (1.8&#xa0;ppmv), methanol (310&#xa0;ppbv), isoprene (280&#xa0;ppbv), ethanol (130&#xa0;ppbv), acetaldehyde (90&#xa0;ppbv) and acetic acid (70&#xa0;ppbv). Smokers showed the largest signal increase in acetonitrile (ratio smoker/non-smoker 29), benzene (ratio 11), 2-methylfuran (ratio 8) and 2,5-dimethylfuran (ratio 7). Calibration gas measurements allowed the instruments performance regarding precision and accuracy of ion mass-to-charge, m/z, and concentration accuracy measurement to be assessed. The standard deviation of the concentration measurements was 14% or smaller (with the exception of ethanol) with no trend in this variation of sensitivity. The limit of detection (LOD) lay in the sub ppbv range, based on an integration time of 2&#xa0;s. The m/z accuracy was better than 0.0016 (or less than 29&#xa0;ppm of the ion mass) throughout the study. The standard deviation of the measured m/z was less than 0.0025 and the coefficient of variation was less than 29&#xa0;ppm. Keywords PTR-TOF-MS, Smokers’ breath, Breath volatile organic compounds, \{VOCs\}
[1699] Trefz, P., M. Schmidt, P. Oertel, J. Obermeier, B. Brock, S. Kamysek, J. Dunkl, R. Zimmermann, J. K. Schubert, and W. Miekisch, "Continuous real time breath gas monitoring in the clinical environment by proton-transfer-reaction-time-of-flight-mass spectrometry.", Anal Chem, vol. 85, pp. 10321–10329, Nov, 2013.
Link: http://dx.doi.org/10.1021/ac402298v
Abstract
<p>Analysis of volatile organic compounds (VOCs) in breath holds great promise for noninvasive diagnostic applications. However, concentrations of VOCs in breath may change quickly, and actual and previous uptakes of exogenous substances, especially in the clinical environment, represent crucial issues. We therefore adapted proton-transfer-reaction-time-of-flight-mass spectrometry for real time breath analysis in the clinical environment. For reasons of medical safety, a 6 m long heated silcosteel transfer line connected to a sterile mouth piece was used for breath sampling from spontaneously breathing volunteers and mechanically ventilated patients. A time resolution of 200 ms was applied. Breath from mechanically ventilated patients was analyzed immediately after cardiac surgery. Breath from 32 members of staff was analyzed in the post anesthetic care unit (PACU). In parallel, room air was measured continuously over 7 days. Detection limits for breath-resolved real time measurements were in the high pptV/low ppbV range. Assignment of signals to alveolar or inspiratory phases was done automatically by a matlab-based algorithm. Quickly and abruptly occurring changes of patients&#39; clinical status could be monitored in terms of breath-to-breath variations of VOC (e.g. isoprene) concentrations. In the PACU, room air concentrations mirrored occupancy. Exhaled concentrations of sevoflurane strongly depended on background concentrations in all participants. In combination with an optimized inlet system, the high time and mass resolution of PTR-ToF-MS provides optimal conditions to trace quick changes of breath VOC profiles and to assess effects from the clinical environment.</p>
[Kohl2013b] Kohl, I., J. Beauchamp, F. Cakar-Beck, J. Herbig, J.. Dunkl, O. Tietje, M. Tiefenthaler, C. Boesmueller, A. Wisthaler, M. Breitenlechner, et al., "First observation of a potential non-invasive breath gas biomarker for kidney function.", J Breath Res, vol. 7, no. 1: Ionimed Analytik GmbH, Eduard Bodem Gasse 3, A-6020 Innsbruck, Austria., pp. 017110, Mar, 2013.
Link: http://dx.doi.org/10.1088/1752-7155/7/1/017110
Abstract
We report on the search for low molecular weight molecules-possibly accumulated in the bloodstream and body-in the exhaled breath of uremic patients with kidney malfunction. We performed non-invasive analysis of the breath gas of 96 patients shortly before and several times after kidney transplantation using proton-transfer-reaction mass spectrometry (PTR-MS), a very sensitive technique for detecting trace amounts of volatile organic compounds. A total of 642 individual breath analyses which included at least 41 different chemical components were carried out. Correlation analysis revealed one particular breath component with a molecular mass of 114 u (unified atomic mass units) that clearly correlated with blood serum creatinine, which is the currently accepted marker for assessing the function of the kidney. In particular, daily urine production showed good correlation with the identified breath marker. An independent set of seven samples taken from three patients at the onset of dialysis and three controls with normal kidney function confirmed a significant difference in concentration between patients and controls for a compound with a molecular mass of 114.1035 u using high mass resolving proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS). A chemical composition of CHO was derived for the respective component. Fragmentation experiments on the same samples using proton-transfer-reaction triple-quadrupole tandem mass spectrometry (PTR-QqQ-MS) suggested that this breath marker is a C-ketone or a branched C-aldehyde. Non-invasive real-time monitoring of the kidney function via this breath marker could be a possible future procedure in the clinical setting.
[1598] Ruzsanyi, V.., "Ion mobility spectrometry for pharmacokinetic studies–exemplary application.", J Breath Res, vol. 7, pp. 046008, Dec, 2013.
Link: http://dx.doi.org/10.1088/1752-7155/7/4/046008
Abstract
<p>Breath analysis is an attractive non-invasive method for diagnosis and therapeutic monitoring. It uses endogenously produced compounds and metabolites of isotopically labeled precursors. In order to make such tests clinically useful, it is important to have relatively small portable instruments detecting volatile compounds within short time. A particularly promising analytical technique is ion mobility spectrometry (IMS) coupled to a multi capillary column (MCC). This paper focuses on demonstrating the suitability of breath analysis for pharmacokinetic applications using MCC-IMS with respect to practicability and reproducibility testing the model substrate eucalyptol. Validation of the MCC-IMS measurements were performed using proton transfer reaction mass spectrometry (PTR-MS) and resulted in an excellent correspondence of the time-dependent concentrations presented by the two different analytical techniques. Moreover, the good accordance in variance of kinetic parameters with repeated measures, and the determined inter-subject differences indicate the eligibility of the analysis method.</p>
[1445] Ruzsanyi, V., L. Fischer, J. Herbig, C. Ager, and A. Amann, "Multi-capillary-column proton-transfer-reaction time-of-flight mass spectrometry.", J Chromatogr A, vol. 1316, pp. 112–118, Nov, 2013.
Link: http://dx.doi.org/10.1016/j.chroma.2013.09.072
Abstract
<p>Proton-transfer-reaction time-of-flight mass-spectrometry (PTR-TOFMS) exhibits high selectivity with a resolution of around 5000m/Δm. While isobars can be separated with this resolution, discrimination of isomeric compounds is usually not possible. The coupling of a multi-capillary column (MCC) with a PTR-TOFMS overcomes these problems as demonstrated in this paper for the ketone isomers 3-heptanone and 2-methyl-3-hexanone and for different aldehydes. Moreover, fragmentation of compounds can be studied in detail which might even improve the identification. LODs for compounds tested are in the range of low ppbv and peak positions of the respective separated substances show good repeatability (RSD of the peak positions &lt;3.2%). Due to its special characteristics, such as isothermal operation, compact size, the MCC setup is suitable to be installed inside the instrument and the overall retention time for a complete spectrum is only a few minutes: this allows near real-time measurements in the optional MCC mode. In contrast to other methods that yield additional separation, such as the use of pre-cursor ions other than H3O(+), this method yields additional information without increasing complexity.</p>
[Morisco2013] Morisco, F., E. Aprea, V. Lembo, V. Fogliano, P. Vitaglione, G. Mazzone, L. Cappellin, F. Gasperi, S. Masone, G. Domenico { De Palma}, et al., "Rapid "breath-print" of liver cirrhosis by proton transfer reaction time-of-flight mass spectrometry. A pilot study.", PLoS One, vol. 8, no. 4: Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. filomena.morisco@unina.it, pp. e59658, 2013.
Link: http://dx.doi.org/10.1371/journal.pone.0059658
Abstract
The aim of the present work was to test the potential of Proton Transfer Reaction Time-of-Flight Mass Spectrometry (PTR-ToF-MS) in the diagnosis of liver cirrhosis and the assessment of disease severity by direct analysis of exhaled breath. Twenty-six volunteers have been enrolled in this study: 12 patients (M/F 8/4, mean age 70.5 years, min-max 42-80 years) with liver cirrhosis of different etiologies and at different severity of disease and 14 healthy subjects (M/F 5/9, mean age 52.3 years, min-max 35-77 years). Real time breath analysis was performed on fasting subjects using a buffered end-tidal on-line sampler directly coupled to a PTR-ToF-MS. Twelve volatile organic compounds (VOCs) resulted significantly differently in cirrhotic patients (CP) compared to healthy controls (CTRL): four ketones (2-butanone, 2- or 3- pentanone, C8-ketone, C9-ketone), two terpenes (monoterpene, monoterpene related), four sulphur or nitrogen compounds (sulfoxide-compound, S-compound, NS-compound, N-compound) and two alcohols (heptadienol, methanol). Seven VOCs (2-butanone, C8-ketone, a monoterpene, 2,4-heptadienol and three compounds containing N, S or NS) resulted significantly differently in compensate cirrhotic patients (Child-Pugh A; CP-A) and decompensated cirrhotic subjects (Child-Pugh B+C; CP-B+C). ROC (Receiver Operating Characteristic) analysis was performed considering three contrast groups: CP vs CTRL, CP-A vs CTRL and CP-A vs CP-B+C. In these comparisons monoterpene and N-compound showed the best diagnostic performance.Breath analysis by PTR-ToF-MS was able to distinguish cirrhotic patients from healthy subjects and to discriminate those with well compensated liver disease from those at more advanced severity stage. A breath-print of liver cirrhosis was assessed for the first time.
[Winkler2013] Winkler, K., J. Herbig, and I. Kohl, "Real-time metabolic monitoring with proton transfer reaction mass spectrometry", Journal of breath research, vol. 7, no. 3: IOP Publishing, pp. 036006, 2013.
Link: http://iopscience.iop.org/1752-7163/7/3/036006
Abstract
<p><span style="color: rgb(0, 0, 0); font-family: Arial, Helvetica, Verdana, sans-serif; font-size: 12px; line-height: 16.1875px; background-color: rgb(255, 255, 255);">We analysed the time evolution of several volatile organic compounds formed by the catabolism of ingested isotope-labelled ethanol using real-time breath gas analysis with proton-transfer-reaction mass spectrometry. Isotope labelling allowed distinguishing the emerging volatile metabolites from their naturally occurring, highly abundant counterparts in the human breath. Due to an extremely low detection limit of the employed technologies in the parts per trillion per volume range, it was possible to detect the emerging metabolic products in exhaled breath within ~10&nbsp;min after oral ingestion of isotope-labelled ethanol. We observed that ethanol was in part transformed into deuterated acetone and isoprene, reflecting the different fates of activated acetic acid (acetyl-coenzyme A), formed in ethanol metabolism. Using ethanol as a model clearly demonstrated the value of the here presented technique for the search for volatile markers for metabolic disorders in the exhaled breath and its potential usefulness in the diagnosis and monitoring of such diseases.</span></p>
2012
[Aprea2012] Aprea, E., F. Morisco, F. Biasioli, P. Vitaglione, L. Cappellin, C. Soukoulis, V. Lembo, F. Gasperi, G. D'Argenio, V. Fogliano, et al., "Analysis of breath by proton transfer reaction time of flight mass spectrometry in rats with steatohepatitis induced by high-fat diet.", J Mass Spectrom, vol. 47, no. 9: IASMA Research and Innovation Centre, Fondazione Edmund Mach, Food Quality and Nutrition Department, Via E. Mach, 1, 38010, S. Michele a/A, Italy. eugenio.aprea@iasma.it, pp. 1098–1103, Sep, 2012.
Link: http://dx.doi.org/10.1002/jms.3009
Abstract
Breath testing has been largely used as a diagnostic tool, but the difficulties in data interpretation and sample collection have limited its application. We developed a fast (< 20?s), on-line, non-invasive method for the collection and analysis of exhaled breath in awake rats based on proton transfer reaction time of flight mass spectrometry (PTR-ToF-MS) and applied it to investigate possible relationships between pathologies induced by dietary regime and breath composition. As a case study, we investigated rats with dietary induced non-alcoholic steatohepatitis (NASH) and modifications induced by coffee addition to the diet. We considered two different diets (standard and high fat) complemented with two different drinking possibilities (water or decaffeinated coffee) for a total of four groups with four rats each. Several spectrometric peaks were reliable markers for both dietary fat content and coffee supplementation. The high resolution and accuracy of PTR-ToF-MS allowed the identification of related compounds such as methanol, dimethyl sulphide, dimethyl sulphone and ammonia. In conclusion, the rapid and minimally invasive breath analysis of awake rats permitted the identification of markers related to diet and specific pathologic conditions and provided a useful tool for broader metabolic investigations.
[Zehm2012] Zehm, S., S. Schweinitz, R. Wuerzner, H. Peter Colvin, and J. Rieder, "Detection of Candida albicans by mass spectrometric fingerprinting.", Curr Microbiol, vol. 64, no. 3: Department of Vascular Surgery, Innsbruck University Hospital, Anichstrasse 35, Innsbruck, Austria. sarah.zehm@gmail.com, pp. 271–275, Mar, 2012.
Link: http://dx.doi.org/10.1007/s00284-011-0064-5
Abstract
<p>Candida albicans is one of the most frequent causes of fungal infections in humans. Significant correlation between candiduria and invasive candidiasis has previously been described. The existing diagnostic methods are often time-consuming, cost-intensive and lack in sensitivity and specificity. In this study, the profile of low-molecular weight volatile compounds in the headspace of C. albicans-urine suspensions of four different fungal cell concentrations compared to nutrient media and urine without C. albicans was determined using proton-transfer reaction mass spectrometry (PTR-MS). At fungal counts of 1.5 x 10(5) colony forming units (CFU)/ml signals at 45, 47 and 73 atomic mass units (amu) highly significantly increased. At fungal counts of &lt;1.5 x 10(5) CFU/ml signals at 47 and 73 amu also increased, but only at 45 amu a statistically significant increase was seen. Time course alterations of signal intensities dependent on different cell concentrations and after addition of Sabouraud nutrient solution were analysed. Recommendations for measurement conditions are given. Our study is the first to describe headspace profiling of C. albicans-urine suspensions of different fungal cell concentrations. PTR-MS represents a promising approach to rapid, highly sensitive and non-invasive clinical diagnostics allowing qualitative and quantitative analysis.</p>
2011
[Singer2011] Singer, W., J. Herbig, R. Gutmann, K. Winkler, I. Kohl, and A. Hansel, "Applications of PTR-MS in medicine and biotechnology", American Laboratory, vol. 43, no. 7: AMER LABORATORY-LABCOMPARE 30 CONTROLS DRIVE, SHELTON, CT 06484 USA, pp. 34–37, 2011.
Link: http://www.americanlaboratory.com/913-Technical-Articles/19001-Applications-of-PTR-MS-in-Medicine-and-Biotechnology/
Abstract
Proton transfer reaction-mass spectrometry (PTR-MS) is a well-established analytical tool for the measurement of volatile organic compounds (VOCs), and offers real-time detection and quantification of VOCs at trace concentrations. This paper focuses on the measurement of VOCs in biological systems. Both microorganisms and cells, e.g., in the human body, constantly produce a large variety of volatile organic metabolites. Analyzing VOCs in exhaled human breath reveals information about the status of the body. In a similar manner, monitoring the off-gas of fermentations in the biopharmaceutical industry allows microbial activity to be gauged. Undesired compounds (those that are harmful to the human body or impurities in biotechnical processes) can also be tracked in real time using the technique.
[Cappellin2011a] Cappellin, L., F. Biasioli, P. M. Granitto, E. Schuhfried, C. Soukoulis, F. Costa, T. D. Maerk, and F. Gasperi, "On data analysis in PTR-TOF-MS: From raw spectra to data mining", Sensors and actuators B: Chemical, vol. 155, no. 1: Elsevier, pp. 183–190, 2011.
Link: http://www.sciencedirect.com/science/article/pii/S0925400510009135
Abstract
Recently the coupling of proton transfer reaction ionization with a time-of-flight mass analyser (PTR-TOF-MS) has been proposed to realise a volatile organic compound (VOC) detector that overcomes the limitations in terms of time and mass resolution of the previous instrument based on a quadrupole mass analysers (PTR-Quad-MS). This opens new horizons for research and allows for new applications in fields where the rapid and sensitive monitoring and quantification of volatile organic compounds (VOCs) is crucial as, for instance, environmental sciences, food sciences and medicine. In particular, if coupled with appropriate data mining methods, it can provide a fast MS-nose system with rich analytical information. The main, perhaps even the only, drawback of this new technique in comparison to its precursor is related to the increased size and complexity of the data sets obtained. It appears that this is the main limitation to its full use and widespread application. Here we present and discuss a complete computer-based strategy for the data analysis of PTR-TOF-MS data from basic mass spectra handling, to the application of up-to date data mining methods. As a case study we apply the whole procedure to the classification of apple cultivars and clones, which was based on the distinctive profiles of volatile organic compound emissions.
[Brunner2011] Brunner, C.., W.. Szymczak, W.. Li, C. Hoeschen, S.. Moertl, F.. Eckardt-Schupp, and U. Oeh, "Headspace measurements of irradiated in vitro cultured cells using PTR-MS.", Radiat Environ Biophys, vol. 50, no. 1: Department of Medical Radiation Physics and Diagnostics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany. claudia.brunner@helmholtz-muenchen.de, pp. 209–217, Mar, 2011.
Link: http://dx.doi.org/10.1007/s00411-010-0327-8
Abstract
A pilot study was performed to evaluate a new concept for a radiation biodosimetry method. Proton transfer reaction-mass spectrometry (PTR-MS) was used to find out whether radiation induces changes in the composition of volatile organic compounds (VOCs) in the headspace of in vitro cultured cells. Two different cell lines, retinal pigment epithelium cells hTERT-RPE1 and lung epithelium cells A-549, were irradiated with gamma radiation at doses of 4 Gy and 8 Gy. For measuring the cell-specific effects, the VOC concentrations in the headspace of flasks containing cells plus medium, as well as of flasks containing pure medium were analyzed for changes before and after irradiation. No significant radiation-induced alterations in VOC concentrations in the headspace could be observed after irradiation.
[Boshier2011] Boshier, P. R., O. H. Priest, G. B. Hanna, and N. Marczin, "Influence of respiratory variables on the on-line detection of exhaled trace gases by PTR-MS", Thorax, vol. 66, no. 10: BMJ Publishing Group Ltd and British Thoracic Society, pp. 919–920, 2011.
Link: http://thorax.bmj.com/content/66/10/919.short
Abstract
{Background Modern gas analysis techniques permit real time and on-line quantification of multiple volatile trace gases within a single exhalation. However, the influence of various respiratory manoeuvres affecting exhalation flow and the kinetics of metabolite release to the gas-phase remain largely unknown. Methods We examined variation in the concentrations of selected trace gases over a range of expiratory flows (50; 100; 250 ml/s) and after 30 second periods of breathold and paced hyperventilation. On-line measurement of breath samples from healthy volunteers (n=10) was performed by proton transfer mass spectrometry. Results Exhaled acetone increased with higher expiratory flow rate (805, 838, 898 ppb
[Schwoebel2011] Schwoebel, H., R. Schubert, M. Sklorz, S. Kischkel, R. Zimmermann, J. K. Schubert, and W. Miekisch, "Phase-resolved real-time breath analysis during exercise by means of smart processing of PTR-MS data.", Anal Bioanal Chem, vol. 401, no. 7: Department of Anaesthesia and Intensive Care Medicine, University of Rostock, Schillingallee 70, 18057 Rostock, Germany., pp. 2079–2091, Oct, 2011.
Link: http://dx.doi.org/10.1007/s00216-011-5173-2
Abstract
Separation of inspiratory, mixed expired and alveolar air is indispensable for reliable analysis of VOC breath biomarkers. Time resolution of direct mass spectrometers often is not sufficient to reliably resolve the phases of a breathing cycle. To realise fast on-line breath monitoring by means of direct MS utilising low-fragmentation soft ionisation, a data processing algorithm was developed to identify inspiratory and alveolar phases from MS data without any additional equipment. To test the algorithm selected breath biomarkers (acetone, isoprene, acetaldehyde and hexanal) were determined by means of quadrupole proton transfer reaction mass spectrometry (PTR-MS) in seven healthy volunteers during exercise on a stationary bicycle. The results were compared to an off-line reference method consisting of controlled alveolar breath sampling in Tedlar(R) bags, preconcentration by solid-phase micro extraction (SPME), separation and identification by GC-MS. Based on the data processing method, quantitative attribution of biomarkers to inspiratory, alveolar and mixed expiratory phases was possible at any time during the experiment, even under respiratory rates up to 60/min. Alveolar concentrations of the breath markers, measured by PTR-MS ranged from 130 to 2,600 ppb (acetone), 10 to 540 ppb (isoprene), 2 to 31 ppb (acetaldehyde), whereas the concentrations of hexanal were always below the limit of detection (LOD) of 3 ppb. There was good correlation between on-line PTR-MS and SPME-GC-MS measurements during phases with stable physiological parameters but results diverged during rapid changes of heart rate and minute ventilation. This clearly demonstrates the benefits of breath-resolved MS for fast on-line monitoring of exhaled VOCs.
2010
[1586] Brunner, C.., W.. Szymczak, V.. Höllriegl, S.. Mörtl, H.. Oelmez, A.. Bergner, R.. M. Huber, C. Hoeschen, and U. Oeh, "Discrimination of cancerous and non-cancerous cell lines by headspace-analysis with PTR-MS.", Anal Bioanal Chem, vol. 397, pp. 2315–2324, Jul, 2010.
Link: http://dx.doi.org/10.1007/s00216-010-3838-x
Abstract
<p>Proton transfer reaction mass spectrometry (PTR-MS) has been used to analyze the volatile organic compounds (VOCs) emitted by in-vitro cultured human cells. For this purpose, two pairs of cancerous and non-cancerous human cell lines were selected:1. lung epithelium cells A-549 and retinal pigment epithelium cells hTERT-RPE1, cultured in different growth media; and 2. squamous lung carcinoma cells EPLC and immortalized human bronchial epithelial cells BEAS2B, cultured in identical growth medium. The VOCs in the headspace of the cell cultures were sampled: 1. online by drawing off the gas directly from the culture flask; and 2. by accumulation of the VOCs in PTFE bags connected to the flask for at least 12 h. The pure media were analyzed in the same way as the corresponding cells in order to provide a reference. Direct comparison of headspace VOCs from flasks with cells plus medium and from flasks with pure medium enabled the characterization of cell-line-specific production or consumption of VOCs. Among all identified VOCs in this respect, the most outstanding compound was m/z = 45 (acetaldehyde) revealing significant consumption by the cancerous cell lines but not by the non-cancerous cells. By applying multivariate statistical analysis using 42 selected marker VOCs, it was possible to clearly separate the cancerous and non-cancerous cell lines from each other.</p>
[Riess2010] Riess, U., U. Tegtbur, C. Fauck, F. Fuhrmann, D. Markewitz, and T. Salthammer, "Experimental setup and analytical methods for the non-invasive determination of volatile organic compounds, formaldehyde and NOx in exhaled human breath.", Anal Chim Acta, vol. 669, no. 1-2: Hannover Medical School, Sports Physiology and Sports Medicine, Carl-Neuberg-Str. 1, 30625 Hannover, Germany., pp. 53–62, Jun, 2010.
Link: http://dx.doi.org/10.1016/j.aca.2010.04.049
Abstract
Different analytical devices were tested and evaluated for their suitability of breath gas analysis by examining the physiological parameters and chemical substances in the exhaled breath of ten healthy probands during light cycling in dependence of methanol-rich nutrition. The probands exercised under normal breathing conditions on a bicycle ergometer. Breath air was exhaled into a glass cylinder and collected under steady-state conditions. Non-invasively measured parameters were pulse rate, breath frequency, temperature, relative humidity, NO(x), total volatile organic compounds (TVOC(PAS)), carbon dioxide (CO(2)), formaldehyde, methanol, acetaldehyde, acetone, isoprene and volatile organic compounds (VOCs). Methanol rich food and beverages strongly influenced the concentration of methanol and other organic substances in human breath. On the other hand, nutrition and smoking had no clear effect on the physical conditions of the probands. The proton transfer reaction mass spectrometry (PTR-MS) method was found to be very suitable for the analysis of breath gas but the m/z 31, if assigned to formaldehyde, is sensitive to interferences. The time vs. concentration curves of nitric oxide showed sudden peaks up to 120ppb in most of the measurements. In one case a strong interference of the NO(x) signal was observed. The time resolved analysis of exhaled breath gas is of high capability and significance for different applications if reliable analytical techniques are used. Some compounds like nitric oxide (NO), methanol, different VOCs as well as sum parameters like TVOC(PAS) are especially suitable as markers. Formaldehyde, which is rapidly metabolized in the human body, could be measured reliably as a trace component by the acetylacetone (acac) method but not by PTR-MS.

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Selected PTR-MS related Reviews

F. Biasioli, C. Yeretzian, F. Gasperi, T. D. Märk: PTR-MS monitoring of VOCs and BVOCs in food science and technology, Trends in Analytical Chemistry 30 (7) (2011).
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J. de Gouw, C. Warneke, T. Karl, G. Eerdekens, C. van der Veen, R. Fall: Measurement of Volatile Organic Compounds in the Earth's Atmosphere using Proton-Transfer-Reaction Mass Spectrometry. Mass Spectrometry Reviews, 26 (2007), 223-257.
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W. Lindinger, A. Hansel, A. Jordan: Proton-transfer-reaction mass spectrometry (PTR–MS): on-line monitoring of volatile organic compounds at pptv levels, Chem. Soc. Rev. 27 (1998), 347-375.
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Lists with PTR-MS relevant publications of the University of Innsbruck can be found here: Atmospheric and indoor air chemistry, IMR, Environmental Physics and Nano-Bio-Physics

 

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