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


     

Guest Access | Sign In via User Name/Password
First published online on September 21, 2007
Chest, doi:10.1378/chest.06-2975
doi:10.1378/chest.06-2975
(Chest. 2007; 132:1219-1226)
© 2007 American College of Chest Physicians
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
chest.06-2975v1
132/4/1219    most recent
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 Google Scholar
Google Scholar
Right arrow Articles by Yaakov, Y.
Right arrow Articles by Wilschanski, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yaakov, Y.
Right arrow Articles by Wilschanski, M.

Reproducibility of Nasal Potential Difference Measurements in Cystic Fibrosis*

Yasmin Yaakov, MSc; Eitan Kerem, MD; Yaakov Yahav, MD; Joseph Rivlin, MD; Hannah Blau, MD; Lea Bentur, MD; Micha Aviram, MD; Elie Picard, MD; Tali Bdolah-Abram, MSc and Michael Wilschanski, MBBS

* From the Cystic Fibrosis Center (Ms. Yaakov, Dr. Kerem, Ms. Bdolah-Abram, and Dr. Wilschanski), Hadassah University Hospital, Jerusalem, Israel; Cystic Fibrosis Center (Dr. Yahav), Sheba Medical Center, Tel Hashomer, Israel; Cystic Fibrosis Center (Dr. Rivlin), Carmel Medical Center, Haifa, Israel; Graub Cystic Fibrosis Center (Dr. Blau), Schneider Children’s Hospital, Petach Tiqva, Israel; Cystic Fibrosis Center (Dr. Bentur), Rambam Medical Center, Haifa, Israel; Cystic Fibrosis Center (Dr. Aviram), Soroka Medical Center, Beer Sheva, Israel; and Cystic Fibrosis Center (Dr. Picard), Shaare Zedek Medical Center, Jerusalem, Israel.

Correspondence to: Michael Wilschanski, MBBS, Director Pediatric Gastroenterology Unit and Electrophysiology Laboratory, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel 91240; e-mail: michaelwil{at}hadassah.org.il

Abstract

Background: Nasal potential difference (NPD) measurement has been advocated as a diagnostic tool for cystic fibrosis (CF) patients and as a method for assessing the response to new therapies. The purpose of this study was to examine the reproducibility of NPD measurements performed in a single center.

Methods: A total of 68 CF patients with a mean (± SD) age of 16 ± 8 years (age range, 6 to 52 years) underwent NPD measurements on at least two occasions.

Results: A total of 25 patients with classic CF (mean age, 21 ± 8 years) and 43 patients with nonclassic CF (mean age, 14 ± 8 years) underwent sweat tests and NPD measurements. The mean sweat chloride values were 102 ± 18 and 54 ± 14 mEq/L, respectively, for classic CF and nonclassic CF groups. All patients underwent repeat NPD measurements. The basal NPD and the response to amiloride ({Delta}Amil) and response to Cl– free and isoproterenol ({Delta}Cl– free + iso) were very similar in both measurements. In the classic CF group, the basal potential difference values were –40 ± 12 vs –39 ± 11 mV (p = 0.57), respectively, for the first and second measurements; 27 ± 9 vs 26 ± 10 mV (p = 0.55), respectively, for {Delta}Amil; and 2.1 ± 3.8 vs 0.4 ± 2.9 mV (p = 0.07), respectively, for {Delta}Cl– free + iso. In the nonclassic CF group, the values were –32 ± 13 vs –28 ± 10 mV (p = 0.008), respectively; 19 ± 10 vs 17 ± 8 mV (p = 0.388), respectively; and –3.2 ± 4.6 vs –3.3 ± 4.4 mV (p = 0.876), respectively.

Conclusion: When performed in a single center, NPD is a reproducible test for CF patients and thus may be a useful outcome measurement for assessment of the efficacy of new treatments.

Key Words: cystic fibrosis • nasal potential difference • nonclassic cystic fibrosis

Cystic fibrosis (CF) is characterized by abnormal epithelial sodium and chloride transport that reflects defects in the CF transmembrane conductance regulator (CFTR) gene. Measurements of transepithelial nasal potential difference (NPD) in patients with CF have a characteristic bioelectric pattern showing increased epithelial sodium channel (ENaC)-mediated sodium absorption and absent CFTR-mediated chloride secretion. These in vivo measurements define the ion transport abnormalities that are characteristic of CF. NPD measurements may be useful in assisting the diagnosis of CF in nonclassic cases when sweat test results are borderline or normal.1 The results of this test have been shown to be abnormal in cases of single-organ disease including congenital bilateral absence of the vas deferens,2 recurrent pancreatitis,3 and primary sclerosing cholangitis.4 This technique has been included in the diagnostic criteria for CF.5 The NPD may also serve as an outcome measure of new therapies directed at correcting CFTR function comparing values after intervention. It is therefore important to determine the reproducibility of this test. The purpose of this study was to examine the within-patient repeatability of NPD measurements, which has not been studied until now.

Materials and Methods

Patients
We analyzed retrospectively repeated NPD measurements in 68 CF patients (mean [± SD] age, 16 ± 8 years; age range, 6 to 52 years) who had at least two NPD measurements. The patients were divided into the following two groups:

  1. A group of 25 CF patients (mean age, 21 ± 8 years; 12 men) with classic disease. CF was diagnosed by typical respiratory and GI presentation together with elevated sweat chloride levels. All patients had genetic analysis for all known CFTR mutations in Israel (W1282X/3849 + 10 kb C -> T [n = 3]; W1282X/G542X [n = 2]; W1282X/W1282X [n = 7]; 3849 + 10 kb C -> T/405 + 1 G -> A [n = 2]; W1282X/{Delta}F508 [n = 6]; W1282X/G85E [n = 1]; and {Delta}F508/{Delta}F508 [n = 4]). Mutations were classified according to Zielenski.6
  2. A group of 43 patients with nonclassic CF (mean age, 14 ± 8 years; 24 men). We defined as nonclassic CF designates individuals with a CF phenotype in at least one organ system and a normal sweat chloride value (< 40 mmol/L) or borderline sweat chloride value (40 to 60 mmol/L) in whom confirmation of the diagnosis of CF requires the detection of one disease-causing mutation on each CFTR gene or the direct measurement of CFTR dysfunction by NPD measurement.278 The term nonclassic CF includes patients with milder disease with multiorgan involvement as well as patients with single-organ system involvement only. These patients had partial symptoms of CF and older age at diagnosis compared to the CF patient group. All patients had pancreatic sufficiency. The patients were tested for the presence of all known CFTR mutations in Israel,9 including the 5T allele10 (W1282X/5T [n = 2], {Delta}F508/5T [n = 2], D1152H/5T [n = 1], 5T/–[n = 2], W1282X/–[n = 2], {Delta}F508/–[n = 2], G85E/–[n = 1], and –/– [n = 31]). All patients from both groups underwent NPD measurements on two occasions. These results were compared to those from 50 non-CF patients who underwent NPD measurement on one occasion.

NPD Measurements
The NPD is measured between a fluid-filled exploring bridge on the nasal mucosa and a reference bridge (21-gauge or 23-gauge needle filled with Ringers solution in 4% agar) inserted subcutaneously into the forearm. Both bridges were linked by calomel electrodes (Fisher Scientific; Waltham, MA) to a high-impedance, low-resistance buffer amplifier. Using direct vision with an otoscope, the exploring catheter was advanced through the inferior meatus of both nostrils, and NPD was recorded at various sites.11 After consistent baseline NPD measurements have been obtained (basal NPD, which is defined as the most stable value), the response to amiloride ({Delta}Amil) superfusion through a second tube overriding the exploring catheter is evaluated. To study nasal chloride permeability and cyclic adenosine monophosphate (cAMP) activation of chloride permeability, a large chloride chemical gradient is generated across the apical membrane by superfusion of the nasal mucosa for 3 min with a chloride-free solution containing 10–4 mmol/L amiloride in Ringers solution with gluconate substituted for chloride, at a rate of 5 mL/min. The same solution to which 10–5 mmol/L isoproterenol has been added is perfused for a further 3 min. The change in voltage response over the final 6 min (ie, the response to Cl– free and isoproterenol [{Delta}Cl– free + iso]) serves as an index of cAMP activation of the epithelial chloride permeability.12 NPD was performed in one nostril only. The Human Ethics Committee of The Israeli Ministry of Health approved the study, and informed written consent was obtained from all of the patients or parents.

Statistical Analysis
NPD variables, as well as measurements derived from them, are presented as the mean ± SD. A few approaches were applied in order to assess the repeatability of the two measurements for each variable. First, the difference between the two repeated measurements for each variable was tested using the paired t test and the nonparametric Wilcoxon paired signed rank test. In addition, for each variable (in each of the groups separately), a clinically significant difference between the two repeated measurements was defined as a difference exceeding one SD (the SD chosen was approximately the average of the SDs of the first and second measurement for each variable). The one-sample t test (one-tailed) was used to test whether the mean absolute difference between the repeated measurements was statistically significantly larger than the clinically defined difference at the group level; at the individual patient level, each patient was "tagged" for each of the NPD variables as either having clinically similar measurements or not. For each variable, in each group, the percentage of patients with clinically similar pairs of measurements was reported. Second, the coefficient of variation (CV) was calculated for each pair of measurements for each of the NPD variables.

An additional approach that was applied was the graphic method suggested by Bland and Altman.13 In this method, we calculated the mean of the differences between the two measurements and their SD. The differences between the two measurements were then plotted against the average of the two measurements, and measurements outside the range of average ± 2 SDs (of the difference) were considered to be outside "the limits of agreement." The Pearson correlation coefficient was calculated in order to estimate the linear association between the time that elapsed between the two repeated measurements and the difference between them.

Results

Table 1 shows the clinical characteristics of CF patients with classic and nonclassic disease. All patients underwent standard sweat testing, the results of which were borderline (54 ± 14 mEq/L) for the nonclassic CF group and pathologic (102 ± 19 mEq/L) for the classic CF group. The time period between the measurements was within 1 year for 80% of the patients. NPD in the control group was significantly different in all parameters (basal NPD, –16 ± 5 mV; {Delta}Amil, 10 ± 4 mV; and {Delta}Cl– free + iso, –12 ± 7 mV). Three parameters of NPD measurement were obtained at each measurement for each group (Table 1, Fig 1 ).


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

  		Table 1.. Clinical, Genetic, and Electrophysiologic Data of Study Groups*

 

Figure 1
View larger version (12K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1.. Top: the difference between the first and second measurements of basal NPD, {Delta}Amil, and {Delta}Cl– free + iso in the classic CF group (n = 25). Bottom: the difference between the first and second measurements of basal NPD, {Delta}Amil, and {Delta}Cl– free + iso in the nonclassic CF group (n = 43).

 
We defined significant change as ± 1 SD for classic CF and nonclassic CF groups for basal potential difference (PD) (12 and 10 mV, respectively), {Delta}Amil (10 and 10 mV, respectively), and {Delta}Cl– free + iso (4 and 4.5 mV, respectively). The mean difference between the repeated measurements (Table 2 ) was significantly lower than the clinically significant difference for the basal PD measurement in the classic CF group (p < 0.001) but was not significantly different in the nonclassic CF group (p = 0.252). For {Delta}Amil, the mean difference was statistically significantly lower than the clinical significant difference (p < 0.001 and p = 0.043, respectively, for the classic CF and nonclassic CF groups). For {Delta}Cl– free + iso, comparing the mean differences between the repeated measurements to the clinically significant difference yielded no significant difference for either group (p = 0.438 and p = 0.476 respectively, for the classic CF and nonclassic CF groups). Individual differences between the measurements are shown in Figure 2 .


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

  		Table 2.. Difference Between the Two NPD Measurements*

 

Figure 2
View larger version (13K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2.. Top: individual differences between the first and second measurements of {Delta}Cl– free + iso in the classic CF group (n = 25). Change in the positive range (0 to 12 mV) is of no clinical significance. Bottom: individual differences between the first and second measurements of {Delta}Cl– free + iso in the nonclassic CF group (n = 43). Change in the positive range (0 to 10 mV) is of no clinical significance.

 
For basal PD, {Delta}Amil, and {Delta}Cl– free + iso, the percentage of patients with clinically similar pairs of measurements in the classic CF group was 80%, 88%, and 64%, respectively, and in the nonclassic CF group it was 63%, 70%, and 60.5% respectively. The CV was relatively small for the basal PD and {Delta}Amil variables in both groups (mean CV was between 14% and 33%), but was quite high for {Delta}Cl– free + iso (mean CV was 157% in the nonclassic CF group and 193% in the classic CF group), as presented in Table 3 .


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

  		Table 3.. CV Between the Two Repeated Measurements*

 
From the graphs assessing the reproducibility13 (Fig 3 ), we counted the number of measurements that were outside the "limits of agreement" (average, ± 2 SDs). When the differences are normally distributed (normality was confirmed in our data), not > 5% of the measurements should lie outside the "limits of agreement." In the classic CF group, 4%, 12%, and 0%, respectively, are outside the limits of the average ± 2 SDs for basal PD, {Delta}Amil, and {Delta}Cl– free + iso. In the nonclassic CF group, 2.3%, 4.6%, and 4.6%, respectively, are outside the limits of the average ± 2 SDs for basal PD, {Delta}Amil, and {Delta}Cl– free + iso. The median time that elapsed between the two measurements was 2 weeks (range, 10 days to 4.5 years) in the classic CF group and 4 months (range, 1 month to 7.5 years) in the nonclassic CF group. There was no association of the time lag between the two repeated measurements and the difference between them in any of the variables. The Pearson correlation coefficients were –0.02 (p = 0.87), –0.1 (p = 0.40), and 0.19 (p = 0.11) , respectively, between the time lag and the difference between the two measurements, for {Delta}Cl– free + iso, {Delta}Amil, and basal PD.


Figure 3
View larger version (19K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3.. Top: {Delta}Cl– free + iso (in millivolts) in classic CF group (n = 25) according to Bland and Altman.13 Bottom: {Delta}Cl– free + iso (in millivolts) in nonclassic CF group (n = 43) according to Bland and Altman.13

 
To verify the results in the nonclassic CF group, a high-stringency subgroup of patients with sweat chloride levels of > 40 mEq/L and chronic lung disease was studied. The results were very similar. The mean basal PD was –31 ± 12 vs –28 ± 2mV, respectively, the mean {Delta}Amil was 16 ± 10 vs 18 ± 10 mV, respectively, and the {Delta}Cl– free + iso was –2.8 ± 2 vs –2.8 ± 4 mV, respectively.

Discussion

In this study, we have shown for the first time in a heterogeneous group of patients with CF that NPD is reproducible with variability in the acceptable range. For most parameters, there was no significant change between the two measurements (p > 0.05) except for the basal PD values in the nonclassic CF group (p = 0.008). These results were confirmed by all the different statistical approaches we applied to the data.

NPD is made up of the following three important parameters: basal PD; {Delta}Amil; and {Delta}Cl– free + iso. The first is the most variable because it is affected by nasal pathology, for example, polyps and recent history of upper respiratory tract infection. It should be noted that sweat test values may also vary in nonclassic CF patients perhaps due to the interaction between a partially functional CFTR and ENaC. Our values for basal PD in classic CF patients (–40 ± 12 vs –39 ± 11 mV, respectively) was very similar to those from a previously published study (–45 ± 12 mV).14

The second parameter, {Delta}Amil, is an indication for the inhibition of ENaC, which seems to be larger for the classic CF group. The interaction between ENaC and CFTR is poorly understood. Some studies1516171819 have suggested that CFTR acts as cAMP-dependent regulator of ENaC and that enhanced Na+ absorption in CF airways may be explained by lack of down-regulation by mutant CFTR. In contrast, Nagel et al20 reported a lack of evidence for the regulation of ENaC by CFTR and concluded that the coexpression of CFTR and ENaC results in nonspecific activation of ENaC due to electrochemical coupling rather then specific inhibition. Mall and Kunzelmann21 suggested that the interaction between the CFTR and the ENaC may not be direct, but rather mediated by a third, as yet unidentified, factor. ENaC may be also regulated by proteases, as described by Myerburg et al,22 and renal ENaC is regulated by aldosterone.

The most important parameter is the third stage of the NPD measurement, chloride transport. The {Delta}Cl– free + iso solutions reflect the activity of the CFTR Cl– channel. Dysfunction of the channel leads to CF disease. According to our results, there was no significant change in this parameter for both groups. We contend that this is the most important end point variable for clinical studies, as have others.23 In the classic CF group, the mean {Delta}Cl– free + iso in the first test was + 2.1 ± 3.8 mV; in the second it was + 0.4 ± 2.9 mV. This shows a trend toward zero and polarization. As both results are positive, they are of no clinical or electrophysiologic significance. The variability observed, particularly in the basal PD, in patients with nonclassic CF is concomitant with the known variability of the sweat chloride measurement, particularly in patients with nonclassic CF.124 In addition, each of the three parameters may be affected by other factors like physical exercise25 and cigarette smoking.26

The standard procedure in our laboratory is to calculate the exponent of the ratio of response to {Delta}Cl– free + iso/{Delta}Amil, which takes into account both sodium and chloride transport. If the value is > 0.7, the NPD is abnormal; if it is < 0.7, the NPD is normal.1 As shown in our previous study,1 this exponent value is the best discriminative model in our laboratory between nonclassic CF and healthy patients. This parameter showed no significant difference between the first and second NPD test in the nonclassic CF group (data not shown).

We have shown the low variability of measurements performed in one center using the standard protocol. NPD in this center is performed in one nostril only. The introduction of testing a second nostril may introduce more variability. However, higher variability was found in NPD measurements performed in several laboratories. Standaert et al14 performed a multicenter study of NPD measurements. The results from healthy subjects and CF patients from eight academic CF research centers were analyzed, using standardized NPD measurements. There were a few differences in conditions between the centers, as follows: methods for visualizing placement of the exploring electrode (direct vision with nasal speculum vs endoscope); the approach to securing the exploring catheter in place (hand-held vs taped in place); the type of electrode (silver-silver chloride vs calomel); and the type of recording device (strip chart recorder vs computer). Their solutions were perfused at room temperature, while ours perfused at 37°C in order to obtain a larger activated chloride conductance.27 In our single-center study, the conditions were identical for all patients. It is important to emphasize that they did not repeat NPD measurements for each patient, as we did.

In addition to its important role in CF diagnosis, NPD may also used as an outcome measurement for the treatment of the electrophysiologic abnormalities of CF in the nose.28 The results of this study compare favorably with those of Clancy et al,29 who reported repeat NPD measurements in a treatment study.

For some patients, the repeated measurements were performed within 2 to 4 weeks as part of a clinical research project and for the others due to a routine diagnostic procedure. It is important to clarify that the repeated measurements in the clinical research project were not performed in the time any drug was given. As a routine laboratory practice, any suspected CF patient whose first NPD measurement was abnormal, is repeated.

The time period between the measurements was variable. This fact can support the hypothesis that the NPD measurement is repeatable regardless of the time between the measurements. In conclusion, NPD is a repeatable electrophysiologic tool that may be increasingly useful as a diagnostic tool and biophysical end point for studying treatment effects.

Footnotes

Abbreviations: {Delta}Amil = response to amiloride; cAMP = cyclic adenosine monophosphate; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; {Delta}Cl– free + iso = response to Cl– free and isoproterenol; CV = coefficient of variation; ENaC = epithelial sodium channel; NPD = nasal potential difference; PD = potential difference

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication December 11, 2006. Accepted for publication June 21, 2007.

References

  1. Wilschanski, M, Famini, H, Strauss-Liviatan, N, et al (2001) Nasal potential difference measurements in patients with atypical cystic fibrosis. Eur Respir J 17,1208-1215[Abstract/Free Full Text]
  2. Pradal, U, Castellani, C, Delmarco, A, et al Nasal potential difference in congenital bilateral absence of the vas deference. Am J Respir Crit Care Med 1998;158,896-901[Abstract/Free Full Text]
  3. Bishop, MD, Freedman, SD, Zielenski, J, et al The cystic fibrosis transmembrane conductance regulator gene and ion channel function in patients with idiopathic pancreatitis. Hum Genet 2005;118,372-381[CrossRef][ISI][Medline]
  4. Sheth, S, Shea, JC, Bishop, MD, et al Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum Genet 2003;113,286-292[CrossRef][ISI][Medline]
  5. Rosenstein, BJ, Cutting, GR The diagnosis of cystic fibrosis: a consensus statement: Cystic Fibrosis Foundation Consensus Panel. J Pediatr 1998;132,589-595[CrossRef][ISI][Medline]
  6. Zielenski, J Genotype and phenotype in cystis fibrosis. Respiration 2000;67,117-133[CrossRef][ISI][Medline]
  7. Boyle, MP Nonclassic cystic fibrosis and CFTR-related diseases. Curr Opin Pulm Med 2003;9,498-503[CrossRef][ISI][Medline]
  8. De Boeck, K, Wilshanski, M, Castellani, C, et al Cystic fibrosis: terminology and diagnostic algorithms. Thorax 2006;61,627-635[Abstract/Free Full Text]
  9. Kerem, E, Kalman, YM, Yahav, Y, et al Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel. Hum Genet 1995;96,193-197[CrossRef][ISI][Medline]
  10. Kerem, E, Rave-Harel, N, Augarten, A, et al A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations. Am J Respir Crit Care Med 1997;155,1914-1920[Abstract]
  11. Knowles, MR, Paradiso, AM, Boucher, RC In vivo nasal potential techniques and protocols for the assessment of the efficiency of gene transfer in cystic fibrosis. Hum Gene Ther 1995;6,445-455[ISI][Medline]
  12. Schuler, D, Sermet-Gaudelus, I, Wilschanski, M, et al Basic protocol for transepithelial potential difference measurements. J Cyst Fibros 2004;3,151-156[Medline]
  13. Bland, JM, Altman, DG Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1,307-310[CrossRef][ISI][Medline]
  14. Standaert, TA, Boitano, L, Emerson, J, et al Standardized procedure for measurement of nasal potential: an outcome measure in multicenter cystic fibrosis clinical trials. Pediatr Pulmonol 2004;37,385-392[CrossRef][ISI][Medline]
  15. Chabot, H, Vives, MF, Dagenais, A, et al Down regulation of epithelial sodium channel (ENaC) by CFTR coexpressed in Xenopus oocytes is independent of Cl– conductance. J Membr Biol 1999;169,175-188[CrossRef][ISI][Medline]
  16. Ji, HL, Chalfant, ML, Jovov, B, et al The cytosolic termini of the beta- and gamma-ENaC subunits are involved in the functional interactions between cystic fibrosis transmembrane conductance regulator and epithelial sodium channel. J Biol Chem 2000;275,27947-27956[Abstract/Free Full Text]
  17. Jiang, Q, Li, J, Dubroff, R, et al Epithelial sodium channels regulate cystic fibrosis transmembrane conductance regulator chloride channels in Xenopus oocyte. J Biol Chem 2000;275,13266-13274[Abstract/Free Full Text]
  18. Mall, M, Hipper, A, Greger, R, et al Wild type but not F508 CFTR inhibits Na+ conductance when coexpressed in Xenopus oocyte. FEBS Lett 1996;381,47-52[CrossRef][ISI][Medline]
  19. Stutts, MJ, Canessa, CM, Olsen, JC, et al CFTR as a cAMP-dependent regulator of sodium channels. Science 1995;269,847-850[Abstract/Free Full Text]
  20. Nagel, G, Szellas, T, Riordan, JR, et al Non-specific activation of the epithelial sodium channel by the CFTR chloride channel. EMBO Rep 2001;2,249-254[CrossRef][ISI][Medline]
  21. Mall M, Kunzelmann K. CFTR: a regulator of the amiloride-sensitive epithelial Na+ channel, ENaC. Available at: http://pen2.igc.gulbenkian.pt/cftr/vr/e/mall_kunzelmann_cftr_a_regulator_of_the_amiloride_sensitive.pdf. Accessed September 20, 2007
  22. Myerburg, MM, Butterworth, MB, McKenna, EE, et al Airway surface liquid volume regulates ENaC by altering the serine protease-protease inhibitor balance: a mechanism for sodium hyperabsorption in cystic fibrosis. J Biol Chem 2006;281,27942-27949[Abstract/Free Full Text]
  23. Zeitlin, PL, Diener-West, M, Rubenstein, RC, et al Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate. Mol Ther 2002;6,119-126[CrossRef][ISI][Medline]
  24. Stewart, B, Zabner, J, Shuber, AP, et al Normal sweat chloride values do not exclude the diagnosis of cystic fibrosis. Am J Respir Crit Care Med 1995;151,899-903[Abstract]
  25. Hebestreit, A, Kersting, U, Basler, B, et al Exercise inhibits epithelial sodium channels in patients with cystic fibrosis. Am J Respir Crit Care Med 2001;164,443-446[Abstract/Free Full Text]
  26. Cantin, AM, Hanrahan, JM, Bilodeau, G, et al Cystic fibrosis transmembrane conductace regulator function is suppressed in cigarette smokers. Am J Respir Crit Care Med 2006;173,1139-1144[Abstract/Free Full Text]
  27. Boyle, MP, Diener-West, M, Milgram, L, et al A multicenter study of the effect of solution temperature on nasal potential difference. Chest 2003;124,482-489[Abstract/Free Full Text]
  28. Wilschanski, M, Yahav, Y, Yaacov, Y, et al Gentamicin-induced correction of CFTR function in patient with cystic fibrosis and CFTR stop mutations. N Engl J Med 2003;349,1433-1441[Abstract/Free Full Text]
  29. Clancy, JP, Rowe, SM, Bebok, Z, et al No detectable improvements in CFTR by nasal aminoglycosides in CF patients with stop mutations. Am J Respir Cell Mol Biol 2007;37,57-66[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
chest.06-2975v1
132/4/1219    most recent
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 Google Scholar
Google Scholar
Right arrow Articles by Yaakov, Y.
Right arrow Articles by Wilschanski, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yaakov, Y.
Right arrow Articles by Wilschanski, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS