Chest ACCP Education Calendar
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Mayatepek, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Mayatepek, E.
(Chest. 2000;117:1393-1398.)
© 2000 American College of Chest Physicians

Urinary Leukotriene E4 Levels Are Not Increased Prior to High-Altitude Pulmonary Edema*

Peter Bärtsch, MD; Urs Eichenberger, MD; Peter E. Ballmer, MD, PD; J. Simon R. Gibbs, MD; Christian Schirlo, MD; Oswald Oelz, MD and Ertan Mayatepek, MD, PD

* From the Institute of Sportsmedicine (Drs. Bärtsch and Eichenberger) and Department of General Pediatrics (Dr. Mayatepek), University Hospital, Heidelberg, Germany; the Department of Medicine (Dr. Ballmer), Kantonsspital, Winterthur, Switzerland; the Department of Clinical Cardiology (Dr. Gibbs), National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, UK; the Institute of Physiology (Dr. Schirlo), University of Zürich, Switzerland; and the Department of Medicine (Dr. Oelz), Triemli Hospital, Zurich, Switzerland

Correspondence to: Peter Bärtsch, MD, Medizinische Klinik und Poliklinik, Abteilung für Sport und Leistungsmedizin, Hospitalstr. 3, Geb. 4100, D - 69115 Heidelberg, Germany; e-mail: peter_bartsch{at}med.uni-heidelberg.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To examine whether increased urinary cysteinyl-leukotriene E4 (LTE4) excretion, which has been found to be elevated in patients presenting with high-altitude pulmonary edema (HAPE), precedes edema formation.

Design: Prospective studies in a total of 12 subjects with susceptibility to HAPE.

Setting: In a chamber study, seven subjects susceptible to HAPE and five nonsusceptible control subjects were exposed for 24 h to an altitude of 450 m (control day), and exposed for 20 h to 4,000 m after slow decompression over 4 h. In a field study, prospective measurements at low and high altitude were performed in five subjects developing HAPE at 4,559 m.

Participants: Mountaineers with a radiographically documented history of HAPE and control subjects who did not develop HAPE with identical high-altitude exposure.

Interventions: 24-h urine collections.

Measurements and results: In the hypobaric chamber, none of the subjects developed HAPE. The 24-h urinary LTE4 did not differ between HAPE susceptible and control subjects, nor between hypoxia and normoxic control day. In the field study, urinary LTE4 was not increased in subjects with HAPE compared to values obtained prior to HAPE at high altitude and during 2 control days at low altitude.

Conclusions: These data do not provide evidence that cysteinyl–leukotriene-mediated inflammatory response is associated with HAPE susceptibility or the development of HAPE within the context of our studies.

Key Words: acute mountain sickness • eicosanoids • high altitude • high-altitude pulmonary edema • inflammation • leukotrienes • permeability


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
High -altitude pulmonary edema (HAPE) is a noncardiogenic pulmonary edema that may occur after rapid ascent to altitudes > 2,500 m1 or after re-ascent from low altitude in residents of altitudes > 3,000 m.2 An exaggerated pulmonary artery pressure appears to be a prerequisite for the development of HAPE.3 4 5 6 Heterogenous hypoxic pulmonary vasoconstriction leading to areas of under- and overperfusion, and thus increased capillary pressure in the latter areas has been postulated to explain edema formation on the downstream side of the resistance vessels.7 In about half of the HAPE-susceptible individuals, however, an abnormal increase of pulmonary artery pressure does not lead to pulmonary edema.6 These observations suggest that additional factors are necessary for the development of HAPE, such as increased vascular permeability due to an inflammatory process8 or decreased alveolar fluid clearance.9 10

Examinations of fluid obtained by BAL from individuals with HAPE have demonstrated the presence of various cytokines, eicosanoids, and highly increased concentrations of large proteins indicating an inflammatory vascular leak.8 11 Furthermore, increased urinary leukotriene E4 (LTE4) levels were found in tourists presenting with HAPE to clinics in the Rocky Mountains.12 All of these investigations were carried out in individuals who had suffered from HAPE for some time. To establish a cause-and-effect relation between inflammatory processes and the development of HAPE, it is necessary to perform such investigations prior to the development of HAPE. Therefore, we measured urinary LTE4 levels in subjects before and during early HAPE at 4,559 m. To examine whether susceptibility to HAPE is associated with a hypoxia-induced increase of cysteinyl-leukotrienes, we also investigated such individuals during a 24-h exposure to a simulated altitude of 4,000 m.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chamber Study
This study was performed on mountaineers whose tolerance to high altitude was known because they had all participated in previous field studies with rapid ascent to 4,559 m. The protocol of this study was approved by the ethics committee of the University of Zürich, and all subjects provided written informed consent. Seven HAPE-susceptible mountaineers with one to four previous episodes of HAPE (Table 1 ) and five control subjects shown not to be susceptible to HAPE spent 2 days in a low-pressure chamber located at an altitude of 450 m. Exposure consisted of 24 h at ambient pressure followed by an ascent within 4 h to a simulated altitude of 4,000 m, where they spent the remaining 20 h. Urine was collected during the 24 h in normoxia and during the subsequent 24 h in hypoxia. Chest radiographs were obtained prior to entering the chamber and within 1 h after recompression. arterial oxygen saturation (SaO2) was measured by pulse oximetry (Nellcor N-2OOE, Nellcor; Hayward, CA), and acute mountain sickness (AMS) was assessed by the Lake Louise Score13 at the end of the normoxic and hypoxic study period. Further details of this study will be published elsewhere (J.S.R. Gibbs, MD; unpublished data; July 1996).


View this table:
[in this window]
[in a new window]

  		Table 1. Chamber Study*

 
Field Study
LTE4 was measured in the urine of five male subjects (age, 21 to 54 years; mean age, 43 years) who developed HAPE during a study performed at an altitude of 4,559 m. The diagnosis of HAPE was confirmed by chest radiographs. Details of this study have been reported previously.6 The protocol of the study was approved by the ethics committee of the University of Bern, and all subjects provided written informed consent. In these five individuals, 24-h urine samples were collected on 2 days at low altitude (approximately 500 m) prior to ascent, and over the first and second 24-h period at 4,559 m. Radiographic evidence of HAPE was found in two subjects at the end of the first collection period and in all subjects at the end of the second collection period at 4,559 m. Subjects were treated with nifedipine when clinical signs confirmed by chest radiograph indicated HAPE. This was the case in one subject after the first collection period, and in the other four subjects after the second collection period for urine at high altitude.

Measurement of LTE4
All urine samples were frozen immediately after sampling at - 80°C or in liquid nitrogen and stored at - 80°C until analysis. An aliquot of each urine sample was screened (Combure9 test; Boehringer Mannheim; Mannheim, Germany) to exclude the presence of pathologic amounts of leukocytes, erythrocytes, and protein. None of the samples investigated contained any pathologic constituents.

Urinary LTE4 was measured essentially as described in detail.14 Briefly, 3H-labeled LTE4 (Du Pont-New England Nuclear; Boston, MA) was added to each urine example as an internal standard. Samples were then acidified to pH 4.5 by addition of 0.1 hydrochloric acid, homogenized, and pumped through activated Sep-Pak C18 cartridges (Waters Associates, Millipore; Milford, MA). Fractions having the same elution time as synthetic LTE4 were separated by reverse-phase high-performance liquid chromatography using a mixture of methanol/water (65:35, vol/vol), the aqueous part containing 0.1% acetic acid, 1 mM ethylenediaminetetraacetic acid, and adjusted to pH 5.6 by ammonium hydroxide. The immunoreactive LTE4 content was determined by enzyme immunoassay using a specific antibody (Cayman Chemicals; Ann Arbor, MI). Radioactivity was measured by scintillation counting, and each LTE4 value was corrected for (3H)LTE4 recovery for that sample. Calculation of the standard curve regression and LTE4 concentrations were carried out after a linear log-logit transformation.

The identity of urinary LTE4 was demonstrated by gas chromatography mass spectrometry as described previously.15 Briefly, synthetic and isolated urinary LTE4 were catalytically reduced and desulphurized to 5-hydroxyeicosanoic acid and derivatized to their pentafluorobenzyl ester trimethylsilyl ether derivatives.

Statistical Analysis
Student’s t test for unpaired data was used for comparison between HAPE-susceptible and control subjects of the chamber study. Repeated measurements of the field study were analyzed by nonparametric analysis of variance (ANOVA) according to Friedmann. Values are reported as mean ± SD unless otherwise stated. The p values < 0.05 were considered to indicate statistical significance.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In the chamber study, urinary LTE4 excretion (Table 1 and Fig 1 ) was not significantly different between HAPE-susceptible and control subjects at low or high altitude, and did not significantly change between normoxia and hypoxia within each group. Exclusion of the control subject with very high urinary LTE4 excretion revealed significantly lower values for the control group at baseline, while differences between groups at high altitude remained not significant (NS). Furthermore, there was no significant correlation between urinary LTE4 excretion and maximum AMS scores (r = 0.01) or mean SaO2 (r = 0.01) during hypoxia. Mean SaO2 was significantly lower, and AMS scores were significantly higher in HAPE compared to control subjects (Table 1) . There were no clinical or radiographic signs of pulmonary edema in any subjects after 24 h of hypoxia.



View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Urinary LTE4 excretion over 24 h of normoxia (450 m) and 24 h of hypoxia (4,000 m) in seven HAPE-susceptible subjects and five control subjects of the chamber study.

 
At high altitude, mean values (± SD) of urinary LTE4 excretion expressed in nanomoles per mole of creatinine in subjects with HAPE were not significantly increased compared to control values obtained at low altitude (Table 2 ). The individual values expressed in nanograms per 24 h (Fig 2 ) are also in the same range as those measured during the chamber study. The 1.6-fold increase of urinary LTE4 excretion expressed in nanomoles per 24 h in one subject from the first to the second sampling period at high altitude was due to a 1.7-fold increase in diuresis (from 700 to 1,920 mL with a 0.4-fold increase of creatinine excretion from 1,547 to 2,150 mg) associated with treatment of HAPE with nifedipine. This is demonstrated by virtually unchanged values between the two sampling periods at high altitude when urinary LTE4 excretion is related to creatinine excretion in this subject: 62 mmol/mol creatinine on day 1 and 65 mmol/mol creatinine on day 2. Thus, urinary LTE4 excretion in these five subjects before and during HAPE was not different from levels and daily variations observed at low altitude.


View this table:
[in this window]
[in a new window]

  		Table 2. Field Study*

 


View larger version (20K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Urinary LTE4 excretion on 2 control days at low altitude and on the first and second day at 4,559 m in five subjects developing HAPE. ANOVA according to Friedmann revealed no significant differences between days. * denotes radiographic evidence of HAPE present at the end of the collection period.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
These investigations demonstrate that urinary LTE4 levels are not increased in HAPE-susceptible subjects during an acute exposure over 24 h to a simulated altitude of 4,000 m, as well as prior to and during early stages of HAPE at an altitude of 4,559 m. It indicates that a cysteinyl–leukotriene-mediated inflammatory process is not likely a primary cause of HAPE in our subjects.

Our findings are in agreement with other investigations showing absence of inflammatory markers in subjects developing HAPE after a rapid ascent to an altitude of 4,559 m.16 17 18 19 There was no significant increase in the transcapillary escape rate of labeled albumin and in plasma levels of interleukin-1, interleukin-2, and tumor necrosis factor {alpha} in four mountaineers with evidence of HAPE.16 Plasma levels of the adhesion molecules E-selectin, L-selectin, and intracellular adhesion molecule-1 were not different between HAPE and control subjects.17 In two studies carried out at 4,559 m, C-reactive protein was normal during the 18 to 42 h preceding HAPE, and increased when pulmonary edema was detectable by radiography.16 18 In a most recent study, pulmonary leak index was not increased in beginning HAPE at 4,559 m.19 These observations indicate that markers of inflammation cannot be detected in plasma prior to HAPE and that an inflammatory capillary leak cannot be demonstrated in early HAPE.

Our findings are at variance with the recent report of Kaminsky et al,12 who found a significant increase in urinary LTE4 excretion in patients reporting with HAPE to practitioners in the Colorado Rocky Mountains. Although there is a large variability of urinary LTE4 excretion in the study of Kaminsky et al,12 we consider it unlikely that the relatively small number of subjects in our investigation can account for the different findings. Exclusion of the control subject with very high urinary LTE4 values from analysis does not change the results of statistical analysis regarding the effects of hypoxia. Furthermore, in the five subjects developing HAPE during the field study, we had repeated measurements on 2 separate days at low altitude and on 2 consecutive days at high altitude that revealed reproducibly stable values demonstrating clearly that urinary LTE4 did not increase with early HAPE in these five individuals.

It is more likely that the apparent discrepancy may be attributed to the fact that the patients of Kaminsky et al12 who sought medical advice because of established HAPE had a more advanced disease than our subjects. At the time of urine collection, the mean duration of the illness of these patients was 3 days. The discrepancies between the two studies looking at urinary LTE4 excretion could be explained by the assumption that an increase of urinary LTE4 excretion is a consequence rather than a cause of HAPE. The findings reported from Mount McKinley8 and Japan11 are also compatible with this notion, as these investigators performed BAL mostly in mountaineers with advanced disease.

An alternative explanation is that the increased levels of urinary LTE4 in the patients of Kaminsky et al12 may reflect a primary inflammatory response preceding and facilitating the development of HAPE. The relatively lower altitude of the resorts in the Rocky Mountains at about 2,800 m presumably leads to a smaller rise in pulmonary artery pressure than at altitudes around 4,500 m. Additional precipitating factors such as heavy exercise leading to considerable increase in pulmonary artery pressure20 and/or upper respiratory tract infection possibly enhancing permeability of lung blood vessels may play an important role in triggering HAPE at intermediate altitude. Increased susceptibility to HAPE during viral infections has been suggested in a recent retrospective analysis from Colorado.21 This observation is supported by evidence from animal experiments.22 The same considerations may apply to the Japan Alps, where HAPE also occurs at moderate altitudes between 2,500 m and 3,000 m. The association between susceptibility to HAPE with certain human leukocyte antigen in Japanese mountaineers23 is compatible with a primary role of an inflammatory response in the pathophysiology of HAPE occurring at moderate altitudes. Statistically significant lower baseline levels of LTE4 in control vs HAPE susceptible subjects after exclusion of one outlier in our study (Fig 1) may point to the possibility that HAPE susceptibility could be associated with higher baseline leukotriene production.

We were not able to confirm the association of greater AMS scores with higher urinary LTE4 levels reported by Roach et al24 in a small group of subjects after staged ascent to 4,300 m. We consider it very unlikely that the difference of sampling periods (analysis of only one urine sample vs 24-h collection) accounts for the discrepancies between the studies of Kaminsky et al12 or Roach et al24 and the present study, since inflammation and activation of the lipoxygenase pathway evoked by hypoxia, if present, is likely to be a continuous process. The significant correlation in the study of Roach et al24 was mainly due to the value of one individual. This fact and the lack of confirmation in the present investigation may point to a statistical type-I error in the previous investigation.

In conclusion, our study does not provide evidence that a cysteinyl–leukotriene-mediated inflammatory response is associated with HAPE susceptibility or the development of HAPE in alpine mountaineers. Interventional trials with leukotriene receptor blockers or synthesis inhibitors may help to determine the significance of cysteinyl-leukotrienes in the pathophysiology of high-altitude illness.


   Acknowledgements
 
The authors thank V. Pavlicek, J. Kohl and E. A. Koller from the Department of Physiology Zürich and P. Vock and F. Keller from the Department of Radiology, Inselspital Bern and G. R. Kleger, Kantonsspital Chur for their contributions to the organization of these studies, and V. Swonke and I. Slater for the secretarial work. We also thank the Club Alpino Italiano for providing the locations at the Capanna Regina Margherita.


   Footnotes
 
Abbreviations: AMS = acute mountain sickness; ANOVA = analysis of variance; HAPE = high-altitude pulmonary edema; LTE4 = leukotriene E4; NS = not significant; SaO2 = arterial oxygen saturation

Supported by Schweizerischer Nationalfonds Grant 32–33729.92 and Deutsche Forschungsgemeinschaft Grant-Ma 1314/2–3.

Received for publication August 11, 1999. Accepted for publication November 5, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Houston, CS (1960) Acute pulmonary edema of high altitude. N Engl J Med 263,478-480
  2. Hultgren, HN, Marticorena, EA (1978) High altitude pulmonary edema: epidemiologic observations in Peru. Chest 74,372-376[Abstract/Free Full Text]
  3. Penaloza, D, Sime, F (1969) Circulatory dynamics during high altitude pulmonary edema. Am J Cardiol 23,369-378[CrossRef][ISI][Medline]
  4. Hultgren, HN, Lopez, CE, Lundberg, E, Miller, H (1964) Physiologic studies of pulmonary edema at high altitude. Circulation 29,393-408[Abstract/Free Full Text]
  5. Bärtsch, P, Maggiorini, M, Ritter, M, et al (1991) Prevention of high-altitude pulmonary edema by nifedipine. N Engl J Med 325,1284-1289[Abstract]
  6. Scherrer, U, Vollenweider, L, Delabays, A, et al (1996) Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med 334,624-629[Abstract/Free Full Text]
  7. Hultgren, HN (1978) High altitude pulmonary edema. Staub, NC eds. Lung water and solute exchange ,237-269 Marcel Dekker New York, NY.
  8. Schoene, RB, Swenson, ER, Pizzo, CJ, et al (1988) The lung at high altitude: bronchoalveolar lavage in acute mountain sickness and pulmonary edema. J Appl Physiol 64,2605-2613[Abstract/Free Full Text]
  9. Planes, C, Friedlander, G, Loiseau, A, et al (1996) Inhibition of Na-K-ATPase activity after prolonged hypoxia in an alveolar epithelial cell line. Am J Physiol 271,L70-L78[Abstract/Free Full Text]
  10. Mairbäurl, H, Wodopia, R, Eckes, S, et al (1997) Impairment of cation transport in A549 cells and rat alveolar epithelial cells by hypoxia. Am J Physiol (Lung Cell Mol Physiol) 273,L797-L806[Abstract/Free Full Text]
  11. Kubo, K, Hanaoka, M, Yamaguchi, S, et al (1996) Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan. Thorax 51,739-742[Abstract]
  12. Kaminsky, DA, Jones, K, Schoene, RB, et al (1996) Urinary leukotriene E (4) levels in high-altitude pulmonary edema: a possible role for inflammation. Chest 110,939-945[Abstract/Free Full Text]
  13. Anonymous. The Lake Louise Consensus on the Definition and Quantification of Altitude Illness. 7th International Hypoxia Symposium. In: Sutton JR, Coates G, Houston CS, eds. Hypoxia and mountain medicine. Lake Louise, Canada: Pergamon Press, 1991; 327–330
  14. Mayatepek, E, Pecher, G (1993) Increased excretion of endogenous urinary leukotriene E4 in extrahepatic cholestasis. Clin Chim Acta 218,185-192[CrossRef][ISI][Medline]
  15. Mayatepek, E, Lehmann, WD (1995) Increased generation of cysteinyl leukotrienes in Kawasaki disease. Arch Dis Child 72,526-527[Abstract]
  16. Kleger, G-R, Bärtsch, P, Vock, P, et al (1996) Evidence against an increase of capillary permeability in subjects exposed to high altitude. J Appl Physiol 81,1917-1923[Abstract/Free Full Text]
  17. Eldridge, MW, Johnson, DH, Hill, HR (1995) Cytokines and adhesion molecules in high altitude pulmonary edema. Sutton, JR Houston, CS Coates, G eds. Hypoxia and the brain ,243-550 Queen City Printers Burlington, VT.
  18. Bärtsch, P, Haeberli, A, Franciolli, M, et al (1989) Coagulation and fibrinolysis in acute mountain sickness and beginning pulmonary edema. J Appl Physiol 66,2136-2144[Abstract/Free Full Text]
  19. Maggiorini, M, Mélot, C, Pierre, S, et al (1999) High altitude pulmonary edema is an hydrostatic and not high permeability type of edema [abstract]. Am J Respir Crit Care Med 159,A355
  20. Eldridge, MW, Podolsky, A, Richardson, RS, et al (1996) Pulmonary hemodynamic response to exercise in subjects with prior high-altitude pulmonary edema. J Appl Physiol 81,911-921[Abstract/Free Full Text]
  21. Durmowicz, AG, Nooordeweir, E, Nicholas, R, et al (1997) Inflammatory processes may predispose children to develop high altitude pulmonary edema. J Pediatr 130,838-840[ISI][Medline]
  22. Carpenter, TD, Reeves, JT, Durmowicz, AG (1998) Viral respiratory infection increases susceptibility of young rats to hypoxia-induced pulmonary edema. J Appl Physiol 84,1048-1054[Abstract/Free Full Text]
  23. Hanaoka, M, Kubo, K, Yamazaki, Y, et al (1998) Association of high-altitude pulmonary edema with the major histocompatibility complex. Circulation 97,1124-1128[Abstract/Free Full Text]
  24. Roach, JM, Muza, SR, Rock, PB, et al (1996) Urinary leukotriene E4 levels increase upon exposure to hypobaric hypoxia. Chest 110,946-951[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 ChestHome page
C. K. Grissom, L. D. Richer, and M. R. Elstad
The Effects of a 5-Lipoxygenase Inhibitor on Acute Mountain Sickness and Urinary Leukotriene E4 After Ascent to High Altitude
Chest, February 1, 2005; 127(2): 565 - 570.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
L. W. Raymond
Altitude Pulmonary Edema Below 8,000 Feet: What Are We Missing?
Chest, January 1, 2003; 123(1): 5 - 7.
[Full Text] [PDF]

Home page
 JAMAHome page
E. R. Swenson, M. Maggiorini, S. Mongovin, J. S. R. Gibbs, I. Greve, H. Mairbaurl, and P. Bartsch
Pathogenesis of High-Altitude Pulmonary Edema: Inflammation Is Not an Etiologic Factor
JAMA, May 1, 2002; 287(17): 2228 - 2235.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Mayatepek, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bärtsch, P.
Right arrow Articles by Mayatepek, E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS