Endometrial and subendometrial blood flow measured by three-dimensional power Doppler ultrasound in patients with small intramural uterine fibroids during IVF treatment

Ernest Hung Yu Ng1,2, Carina Chi Wai Chan1, Oi Shan Tang1, William Shu Biu Yeung1 and Pak Chung Ho1

1 Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China

2 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, The University of Hong Kong, 6/F, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. Email: nghye{at}hkucc.hku.hk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: The impact of intramural fibroids on the success of IVF treatment is controversial and the mechanisms leading to poor treatment outcomes remain unknown. We compared endometrial and subendometrial blood flow between women with and without intramural fibroids during IVF treatment. METHODS: Three-dimensional (3D) ultrasound examination with power Doppler was performed on the day of oocyte retrieval in 50 patients with intramural fibroids not distorting the uterine cavity and in 50 matched controls to measure endometrial thickness, uterine pulsatility index (PI)/resistance index (RI), endometrial volume and vascularization index (VI)/flow index (FI)/vascularization flow index (VFI) of endometrial and subendometrial regions. Smokers, patients with serum estradiol concentrations ≥20 000 pmol/l on the day of HCG and previous history of myomectomy were excluded. RESULTS: Endometrial thickness and pattern, averaged uterine PI and RI and endometrial and subendometrial VI/FI/VFI were similar between the fibroid group and the control group. There was no correlation between the total volume of fibroids and endometrial and subendometrial 3D power Doppler flow indices in the fibroid group. CONCLUSION: Endometrial and subendometrial 3D power Doppler flow indices were similar in patients with and without small intramural fibroids.

Key words: endometrial and subendometrial blood flow/fibroids/three-dimensional power Doppler


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Uterine fibroids are the most common benign tumours found in women. They are present in 20–30% of reproductive age women, with an increasing frequency towards the end of their reproductive life (Novak and Woodruff, 1979Go). The role of fibroids as a possible cause of infertility is still a matter of considerable debate (Buttram and Reiter, 1981Go; Vollenhoven et al., 1990Go; Ubaldi et al., 1995Go; Vercellini et al., 1998Go). A submucous fibroid distorts the uterine cavity, and surgical removal is usually advised because of the adverse effects on implantation and the associated menorrhagia. However, the current data regarding the impact of intramural fibroids on the success of assisted reproductive technologies are still conflicting (Pritts, 2001Go; Surrey, 2003Go). The mechanisms leading to poor treatment outcomes remain unknown.

Kurjak et al. (1992)Go and Sladkevicius et al. (1996)Go reported significantly lower pulsatility index (PI) and resistance index (RI) of uterine vessels in patients with fibroids than in those of normal uteri during natural cycles. We previously found significantly lower uterine PI and RI in non-pregnant women with fibroids than their pregnant counterparts, although the presence of fibroids not distorting the uterine cavity did not adversely affect the outcomes of IVF/embryo transfer (IVF/ET) treatment (Ng and Ho, 2002Go). The blood flow to the endometrium was not measured as it was difficult to quantify the endometrial blood flow by two-dimensional (2D) colour Doppler ultrasound. Based on this result, we postulated that the presence of fibroids resulted in significantly reduced uterine PI and RI but the blood flow towards the endometrium might be compromised because of increased drainage of blood towards fibroids.

Angiogenesis plays a critical role in various female reproductive processes such as development of a dominant follicle, formation of a corpus lutuem, growth of the endometrium and implantation (Abulafia and Sherer, 2000Go; Smith, 2001Go). A good blood supply to the endometrium is usually considered to be an essential requirement for normal implantation. Endometrial microvascular blood flow determined by an intra-uterine laser Doppler technique in the early luteal phase of the cycle preceding an IVF cycle has been shown to be predictive of pregnancy and superior to other conventional parameters predicting endometrial receptivity (Jinno et al., 2001Go). Endometrial blood flow can be evaluated non-invasively by colour and power Doppler ultrasound. Power Doppler imaging is more sensitive than colour Doppler imaging at detecting low velocity flow and hence improves the visualization of small vessels (Guerriero et al., 1999Go). In combination with three-dimensional (3D) ultrasound, power Doppler provides a unique tool with which to examine the blood supply towards the whole endometrium and the subendometrial region (Schild et al., 2000Go; Kupesic et al., 2001Go; Wu et al., 2003Go; Ng et al., 2004Go; Raine-Fenning et al., 2004Go).

The hypothesis was that endometrial and subendometrial blood flow was significantly lower in patients with fibroids than those without fibroids. The aim of this study was to compare endometrial and subendometrial blood flow measured by 3D power Doppler ultrasound between patients with and without fibroids during the IVF treatment.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Consecutive patients attending the Assisted Reproduction Unit at the Department of Obstetrics and Gynaecology, The University of Hong Kong between November 2002 and July 2003 for IVF/ET treatment were recruited when the following criteria were met: (i) presence of fibroids; (ii) no distortion of the endometrial lining confirmed in the multi-planar view on the day of transvaginal ultrasound-guided oocyte retrieval (TUGOR); (iii) non-smokers; and (iv) serum estradiol (E2) concentration <20 000 pmol/l on the day of HCG. Exclusion criteria were: (i) history of myomectomy; (ii) the presence of pedunculated subserosal fibroids only; and (iii) the endometrial lining could not be clearly visualized because of the presence of fibroids during ultrasound examination on the day of TUGOR. The patients next to the recruited subjects and with normal uterus and no history of myomectomy served as controls when they were matched with the study subjects with respect to age (±2 years), type of infertility (primary or secondary) and serum E2 concentrations (±1000 pmol/l). Every patient gave a written informed consent prior to participating in the study, which was approved by the Ethics Committee, Faculty of Medicine, The University of Hong Kong. Each patient was evaluated only once during the study period and did not receive any monetary compensation for participation in this study.

Patients had serum basal FSH concentrations checked on day 2–3 of the cycle within 2–3 months of commencing treatment. All received a long protocol of pituitary downregulation as previously described (Ng et al., 2000Go). In short, they were pre-treated with buserelin (Suprecur, Hoechst, Frankfurt, Germany) nasal spray 150 µg four times a day from the mid-luteal phase of the cycle preceding the treatment cycle and received HMG (Pergonal, Serono, Geneva, Switzerland) for ovarian stimulation. HCG (Profasi, Serono, Geneva, Switzerland) was given i.m. when the leading follicle reached 18 mm in diameter and there were at least three follicles of ≥16 mm in diameter. Serum E2 concentration was measured on the day of HCG administration. TUGOR was scheduled 36 h after the HCG injection. A maximum of three normally cleaving embryos were replaced into the uterine cavity 48 h after TUGOR. Excess good quality embryos were frozen for subsequent transfer.

Measurement of uterine, endometrial and subendometrial blood flow, and volume of fibroids
All ultrasound measurements were performed by E.H.Y.N. on the day of TUGOR prior to the procedure using Voluson 730® (Kretz, Zipf, Austria) at ~8–10 a.m. after they had emptied their bladder. The results of this ultrasound assessment did not affect subsequent clinical management. The maximum thickness of the endometrium on both sides of the midline was measured in a longitudinal plane. The endometrial pattern visualized was designated as a multilayered or a non-multilayered endometrium (Sher et al., 1991Go). A multilayered endometrium presented as a triple-line pattern in which hyperechogenic outer lines and a well-defined central echogenic line were seen, with hypoechogenic or black areas seen between these lines. A non-multilayered endometrium consisted of homogenous endometrial patterns characterized by either hyperechogenic or isoechogenic endometrium.

Using colour Doppler in the 2D mode, flow velocity waveforms were obtained from the ascending main branch of the uterine artery on the right and left side of the cervix in a longitudinal plane before it entered the uterus. The ‘gate’ of the Doppler was positioned when the vessel with good colour signals was identified on the screen. PI and RI of the uterine arteries were calculated electronically when similar consecutive waveforms of good quality were obtained (Ng and Ho, 2002Go). As there were no differences in uterine PI and RI between the left side and the right side, the averaged uterine PI and RI were given.

The details of 3D ultrasound and data analysis were as previously described (Ng et al., 2004Go; Raine-Fenning et al., 2004Go). The ultrasound machine was switched to the 3D mode with power Doppler. The setting condition for this study was: frequency, mid; dynamic set, 2; balance, G >140; smooth, 5/5; ensemble, 12; line density, 7; power Doppler map, 5; and the setting condition for the subpower Doppler mode was: gain, –6.0; balance, 140; quality, normal; wall motion filter, low1; velocity range, 0.9 kHz. The resultant truncated sector covering the endometrial cavity in a longitudinal plane of the uterus was adjusted and moved and the sweep angle set to 90° to ensure that a complete uterine volume encompassing the entire subendometrium was obtained. The patient and the 3D transvaginal probe remained as still as possible during the volume acquisition. A three-dimensional data set was then acquired using the medium speed sweep mode. The resultant multi-planar display was examined to ensure that the area of interest had been captured in its entirety. If the volume measurement was complete without power Doppler artefact, the data set was stored for later analysis by E.H.Y.N. The uterus was visualized in both sagittal and coronal planes to determine the number and position of fibroids, if present. A three-dimensional data set of the fibroid was acquired.

The built-in VOCAL® (virtual organ computer-aided analysis) Imaging Program for the 3D power Doppler histogram analysis was used with computer algorithms to form the endometrial volume and indices of blood flow within the endometrium. The vascularization index (VI) measuring the ratio of the number of colour voxels to the number of all the voxels is thought to represent the presence of blood vessels (vascularity) in the endometrium and is expressed as a percentage (%) of the endometrial volume. Flow index (FI), the mean power Doppler signal intensity inside the endometrium, is thought to express the average intensity of flow. The vascularization flow index (VFI) made by multiplying VI and FI is a combination of vascularity and flow intensity (Pairleitner et al., 1999Go). During the analysis and calculation, the manual mode of the VOCAL® Contour Editor was used to cover the whole 3D volume of the endometrium with a 15° rotation step. Hence, 12 contour planes were analysed for the endometrium of each patient to cover 180°. Following assessment of the endometrium itself, the subendometrium was examined through the application of ‘shell-imaging’, which allows the user to generate a variable contour that parallels the originally defined surface contour. In the present study, the subendometrial region was considered to be within 1 mm of the originally defined myometrial–endometrial contour (Ng et al., 2004Go). VI, FI and VFI of the subendometrial region were obtained accordingly. The volume of a fibroid was determined using VOCAL® as above, and the volume of individual fibroids was added to give the total volume when multiple fibroids were seen.

To assess the reliability of 3D scanning and data acquisition of endometrial volume and blood flow, 15 patients without fibroids involving stimulated IVF and frozen embryo transfer (FET) cycles were scanned twice and each 3D data set was analysed twice using VOCAL®. The mean intra-class correlation coefficient (ICC) with 95% confidence interval (CI) was calculated by the one-way random effects model (Järvelä et al., 2003Go; Raine-Fenning et al., 2003Go). The mean ICC for 3D scanning of endometrial volume, VI, FI and VFI were 0.9509 [95% confidence interval (CI) 0.8591–0.9838], 0.9896 (95% CI 0.9689–0.9966), 0.8957 (95% CI 0.7157–0.9649) and 0.9916 (95% CI 0.9750–0.9973), respectively. The mean ICC for data acquisition of endometrial volume, VI, FI and VFI were 0.9923 (95% CI 0.9746–0.9917), 0.9827 (95% CI 0.9437–0.9949), 0.9884 (95% CI 0.9619–0.9966) and 0.9852 (95% CI 0.9517–0.9957), respectively. The mean ICC for 3D scanning and data acquisition of the fibroid volume in another 10 IVF patients with fibroids were 0.978 (95% CI 0.943–0.991) and 0.956 (95% CI 0.893–0.982), respectively.

Statistical analysis
Kurjak et al. (1992)Go reported a 14% reduction in uterine PI in patients with fibroids, when compared with those with a normal uterus. Our pilot study of 54 patients without fibroids showed that mean endometrial FI was 21.095 with an SD of 5.500. Assuming that a 15% reduction of endometrial FI in patients with fibroids is significant, the sample size required would be 49 in each arm to give a test of significance of 0.05 and a power of 0.8 (Sigmastat, Jandel Scientific, San Rafael, CA). Therefore, 100 patients were recruited in this study. The clinical significance of a 15% reduction in FI was undetermined as there was very limited information regarding the impact of the endometrial blood flow on implantation and pregnancy rates.

Only clinical pregnancies were considered and are defined by the presence of one or more gestation sacs or the histological confirmation of gestational products in miscarriages. Ongoing pregnancies were those pregnancies beyond 10–12 weeks of gestation, at which stage the patients were referred for antenatal care. Implantation rate was the proportion of embryos transferred resulting in an intra-uterine gestational sac. Patients with fibroids were classified in the fibroid group whereas those without fibroids were the control group. The primary outcome measures were VI, FI and VFI of endometrial and subendometrial regions. Continuous variables were not normally distributed and were given as median (range), unless indicated. Statistical comparison was carried out by Mann–Whitney, {chi}2 and Fisher's exact tests, where appropriate. Correlation was assessed by the Spearman rank method. A P-value (two-tailed) of <0.05 was taken as significant.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Two hundred and twenty-seven patients underwent IVF treatment during the study period. Fibroids were present in 57 patients, and seven patients having fibroids were not recruited because their serum E2 concentration on the day of HCG was ≥20 000 pmol/l. No patients with fibroids were excluded during the study period because of poor image clarity. A single fibroid was found in 31 (68.0%) patients and 19 (38.0%) had multiple fibroids, ranging from two to six in number. The median total volume of fibroids was 6.8 cm3 (range 2.9–120.0 cm3). Eleven (22.0%) patients had anterior wall fibroids only, 26 (52.0%) patients had posterior wall fibroids only and the remaining 13 (26.0%) patients had fibroids in mixed positions.

Table I summarizes the demographic data and ovarian responses. There were no differences in age of women, primary/secondary infertility, cause of infertility, duration of infertility, body mass index, basal serum FSH concentration, HMG dosage and duration, serum E2 concentration and number of eggs aspirated between the fibroid group and the control group. Patients in the fibroid group had significantly higher endometrial volume than those in the control group (median 5.77 versus 4.72 cm3, respectively, P=0.027, Mann–Whitney test). Endometrial thickness and pattern, averaged uterine PI and RI and endometrial and subendometrial VI/FI/VFI were similar between the fibroid group and the control group (Table II). No differences were observed in endometrial and subendometrial 3D power Doppler flow indices between women in the control group and those with posterior fibroids only and between those with anterior and posterior wall fibroids (data not shown). There was no correlation between the total volume of fibroids and endometrial and subendometrial VI/FI/VFI in the fibroid group.


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Table I. Comparison of demographic data and ovarian responses between patients with and without uterine fibroids

 

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Table II. Comparison of uterine PI and RI and endometrial and subendometrial three-dimensional power Doppler flow indices between patients with and without uterine fibroids

 
Both groups had a comparable number of embryos transferred, pregnancy and implantation rates, multiple pregnancy rates and the pregnancy outcome (Table III).


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Table III. Comparison of treatment outcomes between patients with and without uterine fibroids

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Although fibroids are commonly encountered in infertile patients, the impact of intramural fibroids not distorting the uterine cavity on the success of assisted reproductive technologies remains controversial (Pritts, 2001Go; Surrey, 2003Go). Implantation and pregnancy rates were not impaired in patients with fibroids not distorting the uterine cavity (Seoud et al., 1992Go; Farhi et al., 1995Go; Ramzy et al., 1998Go; Jun et al., 2001Go; Surrey et al., 2001Go; Check et al., 2002Go; Ng and Ho, 2002Go; Yarali and Bukulmez, 2002Go; Oliveira et al., 2004Go). On the contrary, others (Eldar-Geva et al., 1998Go; Stovall et al., 1998Go; Hart et al., 2001Go) reported that patients with intramural fibroids had significantly reduced implantation and pregnancy rates when compared with those without fibroids or with subserosal fibroids only. The majority (Seoud et al., 1992Go; Farhi et al., 1995Go; Eldar-Geva et al., 1998Go; Ramzy et al., 1998Go; Stovall et al., 1998Go; Jun et al., 2001Go; Surrey et al., 2001Go; Yarali and Bukulmez, 2002Go; Oliveira et al., 2004Go) of the above studies were retrospective. When only prospective studies are considered, Hart et al. (2001)Go demonstrated that an intramural fibroid halved the chances of an ongoing pregnancy, while Check et al. (2002)Go and Ng and Ho (2002)Go could not find an adverse effect of intramural fibroids on the pregnancy rate following IVF. In the present study, patients with and without fibroids had similar pregnancy and implantation rates, which supported the results of our previous study (Ng and Ho, 2002Go). The conflicting results may be partly attributable to differences in patient inclusion criteria and inconsistencies in the analysis of precise fibroid location and size (Surrey, 2003Go).

The causes of infertility associated with fibroids have not been clearly delineated. Therefore, a variety of hypotheses have been proposed to explain the association between infertility and fibroids, including potential effects on sperm transport (Hunt and Wallach, 1974Go), uterine contractility (Iosif and Akerlund, 1983Go), endometrial changes (Delighdish and Loewenthal, 1970Go; Farrer-Brown et al., 1971Go; Forssman, 1976) and implantation (Stevenson, 1964). IVF treatment provides a good model to study the implantation process. A good blood supply towards the endometrium is usually considered to be an essential requirement for normal implantation. Doppler ultrasound examination of uterine vessels allows a non-invasive assessment of the uterine blood flow, which may affect uterine receptivity and implantation (Friedler et al., 1996Go; Dickey, 1997Go). We previously demonstrated in patients with fibroids that non-pregnant patients had significantly lower uterine PI and RI compared with the pregnant patients (Ng and Ho, 2002Go). On the other hand, Surrey et al. (2001)Go could not find any difference in uterine PI taken in the mid-follicular phase of natural cycles between women with and without fibroids, preceding the IVF treatment. Doppler study of uterine arteries may not reflect the actual blood flow to the endometrium as the major compartment of the uterus is the myometrium and there is collateral circulation between uterine and ovarian vessels. Therefore, it is more logical to determine the endometrial blood flow more objectively by 3D ultrasound with power Doppler (Schild et al., 2000Go; Kupesic et al., 2001Go; Wu et al., 2003Go; Ng et al., 2004Go; Raine-Fenning et al., 2004Go).

To the best of our knowledge, this is the first study examining endometrial and subendometrial blood flow in patients with and without fibroids during IVF treatment. Smokers were excluded in the present study as smoking has been associated with a significantly lower endometrial VI and VFI (Raine-Fenning et al., 2004Go). Patients whose serum E2 concentration of ≥20 000 pmol/l on the day of HCG were not recruited because these excessive responders tend to have lower endometrial and subendometrial VI/VFI and a higher incidence of absent endometrial/subendometrial blood flow (Ng et al., 2004Go). In order to avoid the possible impact of other clinical factors on endometrial and subendometrial blood flow, patients with fibroids and controls without fibroids were matched with respect to the age of women, type of infertility and serum E2 on the day of HCG. In the present study, there was a lack of control for exogenous substances such as caffeine or antihistamine, which might have had an impact on blood flow measurements. We define 1 mm of the original myometrial–endometrial interface as the subendometrial region because the subendometrial region may extend beyond the uterine contour especially in the corneal region if 5 mm was taken (Ng et al., 2004Go). The fibroids, if present, would also not be included when 1 mm was used. Moreover, only the myometrium immediately underlying the endometrium exhibits a cyclic pattern of expression of steroid receptors similar to that of the endometrium (Noe et al., 1999Go).

Patients with fibroids had significantly higher endometrial volume than those without fibroids. The significance of this difference was not clear, but endometrial volume measured by 3D ultrasound has not been shown to be predictive of pregnancy (Raga et al., 1999Go; Yaman et al., 2000Go; Schild et al., 2001Go). We could not demonstrate any significant differences in endometrial and subendometrial 3D power Doppler indices measured on the day of TUGOR between patients with and without intramural fibroids. It is possible that the assessment of endometrial blood flow may be affected by the presence of fibroids, although we did not observe any significant difference in endometrial and subendometrial 3D power Doppler flow indices between women in the control group and those with posterior fibroids only and between patients with anterior and posterior intramural fibroids. We performed power Doppler ultrasound examination on the day of TUGOR for logistic reasons, although ultrasound examination immediately prior to the transfer would be closer to the time of implantation. A longitudinal study of endometrial and endometrial blood flow in the early luteal phase may be warranted as changes in the endometrial and subendometrial blood flow in the early luteal phase may be different between patients with and without fibroids, as shown in excessive ovarian responders (Ng et al., 2004Go). In the present study, power Doppler ultrasound examinations were not performed in the luteal phase because of concerns of the effects of power Doppler ultrasound on subsequent fetal development (Hershkovitz et al., 2002Go). It would also be interesting to examine endometrial and subendometrial blood flow in the natural cycle.

The size of fibroids can be expressed as the mean diameter of the largest fibroid (Seoud et al., 1992Go; Stovall et al., 1998Go; Ramzy et al., 1998Go; Ng and Ho, 2002Go; Oliveira et al., 2004Go), the mean of the sum of all fibroid diameters (Eldar-Geva et al., 1998Go; Surrey et al. 2001Go) and total volume (Surrey et al., 2001Go). In this study, we presented the total volume of fibroids because the endometrial and subendometrial blood flow was more likely to be affected by the total volume rather than other parameters (Sosic et al., 1996Go). The median total volume of fibroids in the present study was 6.8 cm3 with a wide range from 2.9 to 120.0 cm3. Although those with large fibroids were usually excluded from other studies (Farhi et al., 1995Go; Ramzy et al., 1998Go; Hart et al., 2001Go; Oliveira et al., 2004Go), patients with fibroids of any size were recruited in the present study. Patients with large fibroids were more likely to have been counselled to undergo myomectomy before referral to our unit for IVF treatment as symptoms such as dysmenorrhoea, menorrhagia and pressure symptoms tended to be more frequent and severe in these patients (Buttram and Reiter, 1981Go). Surrey et al. (2001)Go did not find any correlation between the diameter/volume of fibroids and implantation rate, while Oliveira et al. (2004)Go reported a lower pregnancy rate in patients with fibroids >4 cm in diameter. Although we could not show any correlation between the total volume of fibroids and endometrial and subendometrial 3D power Doppler flow indices, a much larger study will be required to examine the relationship between the total volume of the fibroids and the endometrial and subendometrial blood flow.

In the present study, normal uterine cavity was confirmed by 3D ultrasound alone on the day of HCG because many patients did not have ultrasound examination prior to the IVF treatment at our unit. Transvaginal ultrasound examination of the contour of the endometrium is an accurate tool in the identification of submucous fibroids when compared with hysterosalpingogram and hysteroscopy, with a sensitivity of 94–100% (Fedele et al., 1991Go; Narayan and Goswamy; 1993Go; Stadtmauer and Grunfeld, 1995Go). Diagnostic hysteroscopy and saline sonohysterography would be more accurate than ultrasound alone to delineate the relationship between intramural fibroids and the uterine cavity, which may be a confounding variable in this study. It was difficult to characterize the location of the intramural fibroids in relation to the endometrial cavity, which may be an important factor affecting blood flow to the endometrium and outcomes of the assisted reproduction treatment. Kurjak et al. (1992)Go reported significantly lower uterine PI and RI in vascularized fibroids than avascularized fibroids. Unfortunately, blood flow in the fibroids was not measured by 3D power Doppler ultrasound.

In conclusion, endometrial and subendometrial 3D power Doppler flow indices measured on the day of oocyte retrieval were similar in patients with and without small intramural fibroids. There was no correlation between the total volume of fibroids and endometrial and subendometrial 3D power Doppler flow indices in patients with fibroids.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was funded by both the Hong Kong Research Grant Council (HKU 7280/01M) and the Committee on Research and Conference Grants, The University of Hong Kong.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on August 18, 2004; resubmitted on September 27, 2004; accepted on October 6, 2004.