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Right arrow Lung - transplantation

Ann Thorac Surg 2004;77:1944-1950
© 2004 The Society of Thoracic Surgeons

Original article: general thoracic

Alteration of cellular electrophysiologic properties in porcine pulmonary microcirculation after preservation with University of Wisconsin and Euro-Collins solutions

Rong-Zhen Zhang, MDa, Qin Yang, MD, PhDa, Anthony P. C. Yim, MDa, Guo-Wei He, MD, PhDa,b*

a Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
b Providence Heart Institute, Albert Starr Academic Center, Department of Surgery, Oregon Health and Science University, Portland, Oregon, and Wuhan Heart Institute, The Central Hospital, Wuhan, China

Accepted for publication November 7, 2003.

* Address reprint requests to Prof He, Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, China
e-mail: gwhe{at}cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The effect of cold storage of porcine pulmonary microvessels in University of Wisconsin (UW) and Euro-Collins (EC) solutions on the cellular electrophysiologic properties remains unknown.

METHODS: The pulmonary microarteries (PA, 381.6 ± 62.8 µm; n = 60) and microveins (PV, 360.8 ± 54.5 µm; n = 60) were incubated with Krebs (control), UW, or EC solution at 4°C for 4 hours in a myograph. The resting membrane potential and the endothelium-derived hyperpolarizing factor–mediated hyperpolarization to bradykinin (0.1 µmol/L) in the presence of inhibitors of nitric oxide and prostacyclin, N{omega}-nitro-l-arginine, hemoglobin, and indomethacin, in a single smooth muscle cell were directly measured.

RESULTS: The resting membrane potential (–60.8 ± 1.3 mV in PA and –48.1 ± 0.7 mV in PV, n = 6) was depolarized after exposure to UW solution (to –18.4 ± 0.7 mV in PA and –13.6 ± 0.8 mV in PV; n = 8; p < 0.001). The amplitude of endothelium-derived hyperpolarizing factor–mediated hyperpolarization to bradykinin was also decreased (from 7.4 ± 0.7 mV to 2.6 ± 0.7 mV in PA and from 4.6 ± 0.5 mV to 0.9 ± 0.4 mV in PV; p < 0.001). In comparison, EC depolarized the membrane potential to a lesser extent (to –28.3 ± 0.9 mV in PA and to –21.3 ± 0.8 mV in PV; n = 8; p < 0.001) and almost abolished the hyperpolarization to bradykinin. After washout, hyperpolarization was partially restored (UW, 4.9 ± 0.7 mV in PA and 2.0 ± 0.3 mV in PV. p < 0.01; EC, 2.3 ± 0.5 mV in PA and 1.0 ± 0.3 mV in PV. p < 0.01).

CONCLUSIONS: Cold storage of porcine PA and PV with UW or EC solution impairs the electrophysiologic properties (hyperpolarization) related to endothelium–smooth muscle interaction. The alteration is more profound with EC than UW solution and in veins than in arteries. The findings urge further studies on lung preservation solutions.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
In the past two decades, lung transplantation has become an effective therapy for end-stage pulmonary diseases. However, as a result of ischemia-reperfusion injury, the incidence of severe graft dysfunction is still as high as 10% to 20% [1], and reimplantation edema occurs in 48% of all patients [2]. University of Wisconsin (UW) and Euro-Collins (EC) solutions are intracellular type solutions (high potassium and low sodium) and have been commonly used clinically as pulmonary perfusate and lung storage solutions. In a survey in 1998, 77% (86 centers) continue to use EC solution and 13.5% (15 centers), UW solution [3]. These solutions are used to minimize the metabolic demands of the ischemic organ by induction of depolarization of membrane potential (MP) to create electromechanical arrest [4]. It has been demonstrated that hyperkalemia may promote intracellular calcium loading [5], induce sodium-calcium exchange outward current [6], and result in vasoconstriction and cell swelling. However, the cellular electrophysiologic effect of UW or EC solution on the pulmonary circulation remains unclear.

Endothelium plays an important role in maintaining vascular tone in the pulmonary circulation. It has been demonstrated that endothelium-derived nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF) released by vascular endothelial cells are important factors in regulation of the low-pressure pulmonary circulation [7–9]. The effect of EC, UW, or other solutions on pulmonary function has been studied but results are inconsistent [10–14]. However, it is clear that in ischemia-reperfusion injury, endothelial dysfunction plays a role [14]. Our previous studies suggested impairment of the EDHF-mediated endothelial function in coronary conduit [15] and resistant arteries [16] by UW solution. The mechanism of this effect of the depolarizing solution may be related to prolonged and partial membrane depolarization and to alteration of the potassium-channel function of the smooth muscle cell [16, 17]. Recently, we found that this impairing effect on EDHF-mediated relaxation also occurs in porcine pulmonary microarteries (PA) [10].

Because EDHF-mediated relaxation is coupled with electrophysiologic change (cellular MP change, ie, hyperpolarization), the electrophysiologic effect of EDHF on the smooth muscle cell may be changed after exposure to UW or EC solution. However, there are no reports regarding such electrophysiologic effect in the pulmonary microcirculation.

Further, the effect of UW or EC solution on the endothelial function in the pulmonary microveins (PV) remains unknown. It has been reported that cardiopulmonary bypass impairs pulmonary NO production [18]. Further, deep hypothermic circulatory arrest reduces the endothelium-dependent relaxation in the pulmonary vein but not in the pulmonary artery [19], suggesting a more vulnerable endothelial function in the pulmonary vein than that in the pulmonary artery during ischemia and reperfusion period.

The present study was therefore designed to evaluate the effect of UW and EC solutions on cellular electrophysiology in isolated PA and PV under conditions similar to the clinical setting.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Vessel preparation
Fresh porcine lungs collected from a local slaughterhouse were placed in a container filled with cold Krebs solution. The lungs were immediately transferred to the laboratory. The transportation time varied from 1 to 1.5 hours. The intralobular PA (381.6 ± 62.8 µm, n = 60) and PV (360.8 ± 54.5 µm, n = 60) were carefully dissected out and cleaned of fat and connective tissue under a microscope. The vessel was cut into cylindrical rings of 2-mm length. Krebs solution was aerated with a gas mixture of 95% O2 plus 5% CO2 and had the following components (in millimoles per liter): NaCl, 118.4; KCl, 4.7; MgSO4 · 7H2O, 1.2; KH2PO4, 1.2; NaHCO3, 25; (+)-glucose, 11.1; and CaCl2 · 2H2O, 2.5 (Table 1 for the final composition). A suitable length of two stainless steel wires (40 µm in diameter) was guided through the lumen of the ring. One wire was fixed tightly on a jaw of a dual-chamber myograph (model 500A; J. P. Trading, Aarhus, Denmark), and the other wire was passed lightly through the vascular lumen and then anchored to the other jaw of the same chamber. One of the two wires was attached to a force transducer that was used to measure the force. The output was shown on a computer screen, and the graphs were printed out. Data were digitized and stored in a computer.


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  		Table 1. Composition of Krebs, University of Wisconsin, and Euro-Collins Solutions

 
Normalization
After the ring was mounted in the myograph and equilibrated for 30 minutes, a previously described method [10, 20] was used to normalize the ring under a condition simulating the transmural pressure encountered in vivo in the pulmonary microcirculation. Briefly, the rings were progressively stretched every minute until the passive transmural pressure reached 40 mm Hg in arteries and 30 mm Hg in veins. The computerized program determines the length–tension exponential curve for each ring and gives the internal circumference and diameter at a pressure of 40 mm Hg in PA or 30 mm Hg in PV. The internal circumference was then set to a normalized value, estimated to be equivalent to 90% of the circumference at the above pressure. The vessels were then released to the normalized value. This degree of passive tension at this setting is the passive or resting situation in the absence of constricting tone and was maintained throughout the experiments.

Electrophysiologic study
The myograph was mounted within a metal-screened cage. A conventional glass microelectrode, filled with 3 mol/L KCl (tip resistance, 60 to 80 M{Omega}), was advanced using a pipette holder mounted on a three-dimensional vernier-type hydraulic micromanipulator and inserted into a single smooth muscle cell from the adventitial surface of the rings. The electrical signals were amplified by means of a battery-operated low-noise wide-band microelectrode amplifier electrometer (Electro 705; World Precision Instruments, Inc, Sarasota, FL). The output signals were monitored continuously on a dual-trace oscilloscope (model 2120 B; World Precision Instruments) and simultaneously recorded by a computer with the installed PicoScope program (Pico Technology Limited, Hardwick, UK). The following criteria were used to assess the validity of a successful impalement: (1) a sudden negative shift in voltage, followed by (2) a stable negative voltage for more than 2 minutes, and (3) an instantaneous return to the previous voltage level on dislodgement of the microelectrode, as previously reported [21].

Protocol
The rings mounted in the dual-chamber myograph were allocated to three main groups (groups 1 to 3) according to solutions used to bathe them: Krebs solution (control group), UW solution, or EC solution (Table 1 for composition of each). After equilibration for 30 minutes, the normalization procedure was performed and the pressure was completely released to 0. The rings were then incubated at 4°C (in a refrigerator) for 4 hours, a situation similar to the clinical setting. The rings were then taken from the refrigerator and equilibrated at 37° ± 0.1°C. The internal circumference of the ring was then set to the normalized value estimated by the previous normalization procedure. The rings were equilibrated for another 30 minutes with or without washout by Krebs solution (see below). This protocol was used for both PA and PV.

Group 1 (control group)
Group 1a (n = 6)
The resting MP of the smooth muscle cell in the vessel was recorded. Bradykinin (BK, 0.1 µmol/L) was added to induce repolarization (hyperpolarization). During this period, MP was continuously measured.

Group 1b (n = 6)
The protocol was the same as in group 1a, except that indomethacin (Indo, an inhibitor of cyclooxygenase [COX], 7 µmol/L) and N{omega}-nitro-L-arginine (L-NNA, an inhibitor of NO synthase, 300 µmol/L) plus oxyhemoglobin (HbO, a potent NO scavenger, 20 µmol/L) were added into the myograph chambers to completely inhibit the production of prostacyclin and NO. BK (0.1 µmol/L) was then added to induce hyperpolarization.

Group 2 (University of Wisconsin group)
Group 2a (n = 8)
After storage of the vessel in UW solution at 4°C for 4 hours, the vessel was taken from the refrigerator and rewarmed to 37°C in the myograph. The previously determined estimate of the normalization was applied to set the vessel at the optimal pressure. BK (0.1 µmol/L) was added to induce hyperpolarization, and MP was continuously measured.

Group 2b (n = 8)
The protocol was the same as in group 2a, except that Indo, L-NNA, and HbO were added into the myograph chamber. BK (0.1 µmol/L) was then added to induce hyperpolarization.

Group 2c (n = 8)
The protocol was the same as in group 2b, except that the UW solution in the myograph chamber was repeatedly washed out with Krebs solution before Indo, L-NNA, and HbO were added into the chamber. BK (0.1 µmol/L) was then added to induce hyperpolarization.

Group 3 (Euro-Collins group)
Group 3a (n = 8)
After storage of the vessel in EC solution at 4°C for 4 hours, the vessel was taken from the refrigerator and rewarmed to 37°C in the myograph and set at the optimal pressure. BK (0.1 µmol/L) was added to induce hyperpolarization, and MP was continuously measured.

Group 3b (n = 8)
The protocol was the same as in group 3a, except that Indo, L-NNA, and HbO were added into the myograph chamber. BK (0.1 µmol/L) was then added to induce hyperpolarization.

Group 3c (n = 8)
The protocol was the same as in group 3b, except that the EC solution in the myograph chamber was repeatedly washed out with Krebs solution before Indo, L-NNA, and HbO were added into the chamber. BK (0.1 µmol/L) was then added to induce hyperpolarization.

Data analysis
Results are expressed as mean ± the standard error of the mean for n observations, where n equals the number of pulmonary vessel rings. One-way analysis of variance followed by the Scheffé F test or unpaired Student's t test was used to calculate the difference. A p less than 0.05 was considered to be statistically significant.

Drugs
The drugs used and their sources were as follows: BK, L-NNA, Indo, and hemoglobin were from Sigma Chemical Co (St. Louis, MO). Solutions of L-NNA (dissolved in distilled water) and Indo (dissolved in ethanol) were stored at 4°C. Commercial bovine hemoglobin was dissolved in 0.9% saline solution to make up a 3-mL stock solution. The stock solution was subsequently reduced to HbO by addition of a small amount (<0.3 g) of sodium dithionite. Excessive sodium dithionite was extracted by running the solution through an Econo-Pac 10DG column (Bio-Rad, Hercules, CA) equilibrated with 0.9% saline solution. The HbO solutions were frozen in aliquots at –20°C and stored for up to 14 days. University of Wisconsin solution was purchased from DuPont Pharma (Bad Homburg, Germany) and Euro-Collins solution, from Fresenius AG (Bad Homburg, Germany).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Resting force
There were no statistical differences in the normalized resting force of both PA and PV among the three groups (UW, EC, and control group; Table 2).


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  		Table 2. Resting Force of Porcine Pulmonary Microarteries and Microveins in the Three Groups

 
Resting membrane potential
In group 1a (control group), after storage in Krebs solution at 4°C for 4 hours, the resting MP of the smooth muscle cells of PV was –48.1 ± 0.7 mV, higher than that in PA (–60.8 ± 1.3 mV, p < 0.01). Addition of Indo and L-NNA plus HbO (group 1b) did not significantly change the resting MP of smooth muscle cells of either PA (–60.6 ± 1.3 mV) or PV (–49.4 ± 1.0 mV; Fig 1).



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  		Fig 1. Resting membrane potential of smooth muscle cells from pulmonary arteries (PA) and pulmonary veins (PV) after exposure to University of Wisconsin (UW) or Euro-Collins (E-C) solutions in the presence of indomethacin, N{omega}-nitro-L-arginine, and hemoglobin with (top) or without (bottom) washout by Krebs solution. **p < 0.01 or ##p < 0.01 versus Krebs group. Data are mean ± standard error of the mean.

 
Endothelium-derived hyperpolarizing factor–mediated hyperpolarization during exposure to University of Wisconsin or Euro-Collins solution
The resting MP was greatly elevated during exposure to UW solution (to –18.4 ± 0.7 mV in PA, p < 0.001; and –13.6 ± 0.8 mV in PV, p < 0.001; group 2a). In comparison, EC depolarized the resting MP to a lesser extent (–28.3 ± 0.9 mV in PA and –21.3 ± 0.8 mV in PV, p < 0.001; group 3a; Fig 1). Similar to that in the control group, the combination of Indo and L-NNA plus HbO did not further change the MP of pulmonary microvessels in all groups.

In the control group (group 1a), the maximal amplitude of hyperpolarization (repolarization) by BK (0.1 µmol/L) was 9.5 ± 1.7 mV in PA and 7.5 ± 1.3 mV in PV (p = 0.019) in the absence of inhibitors. In the presence of inhibitors (group 1b), this hyperpolarization (repolarization) was reduced to 7.4 ± 0.7 mV (p < 0.01) in PA and to 4.6 ± 0.5 mV (p < 0.01) in PV.

In the UW group (group 2), in the absence of inhibitors (group 2a), the BK-induced hyperpolarization was significantly decreased (compared with control group 1a) to 3.7 ± 0.9 mV in PA (p < 0.001) and 2.0 ± 0.3 mV in PV (p < 0.001; Fig 2). In the presence of Indo and L-NNA plus HbO (group 2b), the EDHF-mediated hyperpolarization was further reduced to 2.6 ± 0.7 mV (p = 0.016) in PA and to 0.9 ± 0.4 mV (p < 0.001) in PV.



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  		Fig 2. Bradykinin (0.1 µmol/L)-induced hyperpolarization of smooth muscle cells from pulmonary microarteries (top) and pulmonary microveins (bottom) preserved by Krebs, University of Wisconsin (UW), or Euro-Collins (E-C) solutions in the absence (control group) or presence of N{omega}-nitro-L-arginine, indomethacin, and hemoglobin (L-NNA+Indo+HbO group). **p < 0.01 or ##p <0.01 versus Krebs group. Data are mean ± standard error of the mean.

 
In comparison, in the EC group (group 3), in the absence of inhibitors (group 3a), BK-induced hyperpolarization was greatly reduced (0.7 ± 0.2 mV, p < 0.001 in PA; and 0.4 ± 0.1 mV, p < 0.001 in PV) compared with the control group and the UW group. In the presence of inhibitors (group 3b), the EDHF-mediated hyperpolarization was essentially abolished (PA, 0.2 ± 0.2 mV, p < 0.001 compared with the control group and the UW group; PV, 0.1 ± 0.1 mV, p < 0.001 compared with the control group and p = 0.079 compared with UW group; Fig 2).

Endothelium-derived hyperpolarizing factor–mediated hyperpolarization after exposure to University of Wisconsin or Euro-Colllins solution
After repeated washing with Krebs solution, the resting MP was completely restored in the UW group (group 2c, –60.9 ± 1.1 mV in PA, p > 0.05; and –50.8 ± 1.0 mV in PV, p > 0.05, respectively, compared with the control group; Fig 1) and in the EC group (group 3c, –50.7 ± 1.9 mV in PV, p > 0.05; and –59.4 ± 0.7 mV in PA, p > 0.05, respectively, compared with the control group; Fig 1). The mean washout time before the electrophysiologic study was 56.7 ± 13.3 minutes (n = 32).

After storage of vessels in UW solution for 4 hours followed by repeated washing with Krebs solution (group 2c), the EDHF-mediated hyperpolarization in response to BK was only partially restored (to 4.9 ± 0.7 mV in PA, 66.2% recovery of the control group 1b, p < 0.01; and to 2.0 ± 0.3 mV in PV, 43.5% recovery of the control group 1b, p < 0.01; Fig 3).



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  		Fig 3. Endothelium-derived hyperpolarizing factor (EDHF)–mediated hyperpolarization to bradykinin (0.1 µmol/L) in porcine pulmonary microarteries and pulmonary microveins after exposure to Krebs solution, University of Wisconsin (UW) solution, or Euro-Collins (E-C) solution in the presence of N{omega}-nitro-L-arginine, indomethacin, and hemoglobin. **p < 0.01 or ##p < 0.01 versus Krebs group. Data are mean ± standard error of the mean.

 
In comparison, in the EC group (group 3c), the recovery was even less (2.3 ± 0.5 mV in PA, 31.1% recovery of control group 1b, p < 0.01 compared with control group 1b and UW group 2c; and 1.0 ± 0.3 mV in PV, 21.7% recovery of control group 1b, p < 0.01 compared with control group 1b and UW group 2c; Fig 3).

Regarding the comparison between the PA and PV, alternation of the MP was more profound in PV than in PA after exposure to either UW or EC solution (p < 0.001), as shown above.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
The present cellular electrophysiologic study has demonstrated in PA and PV that (1) NO and EDHF play a crucial role in both porcine PA and PV; (2) storage of lungs with UW or EC solutions at 4°C for 4 hours impairs the electrophysiologic properties related to EDHF-mediated endothelial function and the impairment is more profound in EC than UW solution; (3) the influence of such impairment lasts for more than 1 hour in the early reperfusion period with more profound changes in EC solution; and (4) the above alteration was more profound in veins than in arteries, revealing the more vulnerable nature of the EDHF-mediated function in the pulmonary vein than in the artery.

As mentioned before, high incidence of primary graft failure in lung transplantation has stimulated studies on lung preservation solutions clinically and experimentally. Recently, we have shown that after cold storage with EC or UW solution EDHF-mediated relaxation is also reduced in porcine PA [10]. However, the electrophysiologic mechanism remains unknown.

Further, preservation of the lung predisposes both PA and PV to preservation solution, ischemia, and reperfusion. The PVs, like other systemic veins, are thin walled and have relatively little smooth muscle compared with pulmonary arteries [22]. The tone of PV has been demonstrated to contribute significantly to the total pulmonary vascular resistance [23]. Pulmonary vein constriction has also been implicated in the pathogenesis of pulmonary edema caused by congestive heart failure [24] and open heart operation under deep hypothermic circulatory arrest [19]. However, the influence of preservation solutions on the PV has not been reported.

Role of endothelium-derived hyperpolarizing factor–mediated endothelial function in the pulmonary microcirculation
The present study demonstrates that EDHF plays a role in both PA and PV. This is shown by the changes of cellular MP of smooth muscle in both PA and PV in response to BK even in the presence of NO synthase and COX inhibitors (l-NNA and Indo) plus the NO scavenger HbO. Because the production of NO and prostacyclin was completely inhibited, this electrophysiologic change is clearly related to EDHF.

Effects of University of Wisconsin or Euro-Collins solution on cellular electrophysiologic changes in the pulmonary microcirculation
In the present study the PA and PV were stored in UW or EC solution at 4°C for 4 hours, a situation mimicking the clinical setting. In the protocol in which UW or EC solution was washed out, the MP was measured at approximately 1 hour to mimic the clinical reperfusion period.

Our data show that the resting MP was greatly elevated (depolarization) during incubation with UW solution. The magnitude of the depolarization was less in the EC group. The significant depolarization of the MP of the vascular smooth muscle is obviously related to the high concentrations of potassium in these solutions, and the difference of depolarization caused by these two solutions may be related to the even higher concentration of potassium in UW (125 mmol/L) than that in EC (115 mmol/L) solution. However, this remains to be further studied. Despite such different levels of MP, the recovery of EDHF-mediated hyperpolarization remained greater in the UW group than that in the EC group. In fact, the hyperpolarization in the EC group was almost abolished. The components of UW [25] other than potassium, such as lactobionate and raffinose (cell membrane–impermeable molecules to control cold-induced cellular swelling), allopurinol and glutathione (to minimize free radical damage), adenosine (to aid with adenosine triphosphate synthesis), phosphate buffer (to maintain the pH stability), and the normal osmolarity (Table 1), may be responsible for the better protective effect of UW solution. Further, as we recently reported [26], magnesium provides protective effect on the EDHF-mediated endothelial function during cardioplegic arrest. Clearly, the addition of magnesium (5 mmol/L) to UW solution (or, the absence of magnesium in EC solution) is one of many differences between the two solutions.

In addition, after repeated washout by Krebs solution, the EDHF-mediated hyperpolarization was only partially recovered when the vessel was stored in either UW or EC solution. These results clearly demonstrate that the impairing effect of UW or EC solution on cellular membrane hyperpolarization lasts during the reperfusion period because the MP was measured at approximately 1 hour after the procedure of washout was started. These findings, transferred to the clinical setting, may suggest that the unfavorable effect of UW or EC solution on endothelial function lasts for at least 1 hour during the reperfusion period and may be longer.

Comparison between pulmonary microarteries and pulmonary microveins
The present study also demonstrates that the EDHF-mediated hyperpolarization is more significant in PA than in PV in physiologic conditions (in the control group). During and after incubation of the vessels in UW or EC solution, the alternation of the MP was more profound in PV than in PA, suggesting the more vulnerable nature of EDHF-mediated hyperpolarization in PV than in PA.

The tone of PV has been demonstrated to contribute significantly to total pulmonary vascular resistance under physiologic [23] and certain pathophysiologic conditions [19, 24]. The more vulnerable nature of PV in response to organ preservation solutions should be taken into account in future development of preservation solutions.

Limitation of the study
The present study is an in vitro experimental investigation at the cellular level. The observed effect on the function of the lung as a whole remains to be further defined. Further, the study was performed in normal porcine tissue, and differences between this tissue and diseased human tissue should not be ignored.

Clinical implications
The present study demonstrates that the pulmonary endothelium–smooth muscle interaction through the EDHF pathway in the microcirculation is impaired during cold storage of the lung in UW and EC solutions. Alteration of the electrophysiologic properties (hyperpolarization) of the vascular smooth muscle of PA and PV is only partially recovered after reperfusion for 1 hour. The alteration is more significant when the lung is preserved with EC solution. These facts should be taken into account in lung transplantation. This comparative study promotes further investigations on preservation solutions for lung transplantation.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The work described in this paper was fully supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region (Project no. CUHK4127/01M and CUHK4383/03M), China, and the Providence St. Vincent Medical Foundation, Portland, OR.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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