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Rheumatology Advance Access originally published online on March 26, 2007
Rheumatology 2007 46(6):938-943; doi:10.1093/rheumatology/kel409
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A 5-yr longitudinal study of type IIA collagen synthesis and total type II collagen degradation in patients with knee osteoarthritis—association with disease progression

M. Sharif1, J. Kirwan2, N. Charni3, L. J. Sandell4, C. Whittles1 and P. Garnero3,5

1Department of Anatomy, University of Bristol 2Academic Rheumatology Unit, Bristol Royal Infirmary, Bristol, UK 3Molecular Markers, Synarc, Lyon, France 4Washington University School of Medicine, Department of Orthopaedic Surgery, St Louis, Missouri, USA 5Institut National de le Santé et de la Recherche Médicale (INSERM) Research Unit 664, Lyon, France

Correspondence to: M. Sharif, Department of Anatomy, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK. E-mail: mo.sharif{at}bris.ac.uk.


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Objectives. The 5-yr longitudinal study tested the hypothesis that serum and urinary markers of type II collagen metabolism would be associated with radiological progression of disease in patients with mild-to-moderate knee osteoarthritis (OA).

Methods. Synthesis of type IIA collagen and degradation of total type II collagen were assessed in 135 patients with mild-to-moderate knee OA over 5 yrs using serum concentration of the N-propeptide of collagen type IIA (PIIANP) and urinary excretion of crosslinked C-telopeptide (CTX-II), respectively. The markers were measured at baseline, 2, 3 and 5 yrs’ follow-up corresponding to X-ray time points. Analysis of variance (ANOVA) was performed to determine longitudinal changes over 5 yrs in the biomarkers in all patients and between progressors and non-progressors.

Results. Complete X-ray progression data over 5 yrs, serum PIIANP and urinary CTX-II were available for 84/135 patients. There were 24 progressors and 60 non-progressors. Overall, over the 5-yr study period average PIIANP and CTX-II levels were higher in progressors compared with non-progressors (P < 0.05 for both, ANOVA). The patients with serum PIIANP in the highest quartile of 5-yr levels of PIIANP had a significantly higher risk of progression than the other patients [relative risk (95% CI): 3.2 (1.1–9.2)]. Increased levels of urinary CTX-II were also associated with a higher risk of progression with a relative risk (95% CI) of 3.4 (1.2–9.4) in patients with 5-yr levels above the median. The risk of progression was highest in patients with 5-yr levels of PIIANP in the highest quartile and/or CTX-II in the two highest quartiles with a relative risk (95% CI) of progression, 11.8 (2.5–54).

Conclusions. The data presented here suggest that progression of knee OA is associated with alterations of systemic levels of biological markers of type II collagen metabolism. The data also suggest that the combined measurement of serum PIIANP and urinary CTX-II may be useful to identify patients with knee OA at increased risk of disease progression.

KEY WORDS: Type II collagen, Synthesis, Degradation, Osteoarthritis, Disease outcome


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
Osteoarthritis (OA) is a heterogeneous complex joint disease of unknown aetiology. It is the most common joint disease, affecting about 10% of the population over the age of 50 yrs and epidemiological studies suggest that the knee is the most important and common site causing pain and disability [1, 2]. The bone and joint decade [3] has provided an impetus for research into the pathogenesis of OA and other joint diseases and has already led to a greater understanding of what causes and drives the joint destruction in OA. Thus, the animal studies have shown that there are subtle biochemical changes in articular cartilage and other joint tissues, well before any clinical or radiological evidence of joint destruction [4, 5], while studies involving patients with OA led to the hypothesis that progression of knee OA is phasic or cyclic [6, 7]. The phasic hypothesis for progression of knee OA is based on data from our earlier study of serum cartilage oligomeric matrix protein (COMP) showing that during the first year of follow-up there was a rise in COMP in a majority of the patients who progressed [6]. Our data from the new 5-yr longitudinal study provided further support for the phasic hypothesis [8].

Type II collagen is the most abundant protein of cartilage matrix and alterations in turnover of this molecule are believed to play a role in the progressive loss of cartilage in OA. Type II procollagen is synthesized in two splice forms, type IIA and type IIB. Type IIA contains an additional 207 base pair exon (exon 2) encoding the 69 amino acid cysteine-rich domain in the N-propeptide; it is expressed mainly by fetal tissues but can be re-expressed in osteoarthritic cartilage [9] suggesting that the measurement of serum N-propeptide of type IIA collagen (PIIANP) may represent a biological marker of phenotypic changes of chondrocytes. The degradation of mature matrix type II collagen can be assessed by measuring the urinary excretion of crosslinked C-telopeptide (CTX-II) [10]. Previous studies in patients with established knee or advanced hip OA, measuring biochemical markers at a single time point have shown that serum PIIANP and CTX-II were associated with radiological progression over subsequent short-term periods [11–13], but there is no information on changes of these biochemical markers over long-term periods. Accordingly, the aim of this study was to analyse the longitudinal changes of serum PIIANP and urinary CTX-II and their association with radiological progression in patients with knee OA followed prospectively for 5 yrs.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Conclusions
 Acknowledgements
 References
 
135 patients with persistent (>3 months) pain in one or both knees and definite radiographic evidence of OA in at least one knee as considered by the screening clinician were recruited from a survey of knee pain [14], general practices and hospital rheumatology out-patient clinics. Individuals who appeared at screening to have normal radiographs or a Kellgren and Lawrence (KL) grade IV [15] by the rheumatologists or have other forms of joint disease (e.g. rheumatoid arthritis) and conditions that prevented repeated attendance were excluded from entry to the original cohort study. However, after centralized and standardized reading of the radiographs (see further), it appeared that a few of the patients had a KL grade of 0 or IV. Approval for the study was given by the institutional review board (Research Ethics Committee) of the United Bristol Healthcare NHS Trust, Bristol, UK. Age, gender, body mass index (BMI), pain [visual analogue scale (VAS), 0–100 mm] and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [16] were recorded at baseline to describe the patient cohort.

Radiographs
Radiographs of both knees were obtained at baseline and at 2, 3, and 5 yrs. A standardized protocol was adopted, based on that used in an earlier analysis of the reproducibility of readings of individual radiographic features [17]. Straight antero-posterior radiographs were taken with the patient standing. The X-ray packet was placed under the feet in a standard position in relation to the film cassette. On the first occasion, the outline of the feet was drawn on the packet, and this was used to position the feet on subsequent occasions. All radiographs obtained at study entry and over the 5 yrs of follow-up were interpreted during several sessions, in random order, with the identity labels concealed. Two experienced readers independently classified each knee for severity using the 0 – IV KL grading system [15], an atlas of the grading system being available for reference. Where classification differed by one grade, the lower grade was used. Where it differed by two or more grades the radiographs were reviewed together by both observers after all other scoring had been completed and an agreed grade allocated. The readers measured the joint space width (JSW) as the narrowest inter-bone distance in the medial and lateral compartments. JSW was measured to the nearest 0.5 mm using a transparent ruler and taken as the average of the two readers. Where measurements differed by more than 2 mm, the readers reviewed the radiographs together after all other scoring had been completed and without knowledge of the original measurement, and agreed on a final measurement.

Progressors and non-progressors were identified by criteria used previously in studies employing the same radiography protocol [18, 19] and consisting of either a ≥2 mm reduction in the width of the tibiofemoral joint space in either knee or total knee replacement (TKR) surgery for either knee occurring during the 5-yr follow-up.

Blood and urine samples
Serum and urine samples were collected at baseline, 2, 3 and 5 yrs’ follow-up, as we have obtained knee radiographs at these time points. Blood samples were collected in early morning clinics in plain glass tubes, allowed to clot, and centrifuged at 2800 rpm for 10 minutes. Fasting, second-morning, void urine samples were also collected. Both serum and urine aliquots were kept frozen at –70°C until required for the biomarker assays.

Measurements of serum PIIANP and urinary CTX-II
Serum PIIANP was measured by a newly developed ELISA (PIIANP, Linco, St Louis, MO, USA) using a polyclonal antibody raised against recombinant GST-human type II procollagen exon 2 fusion protein [20]. This antibody is specific for the type IIA of the N-propeptide of type II collagen and western-blot analysis of human OA serum showed that it did not cross-react with circulating proteins that share homologies with the PIIANP sequence such as thrombospondin and von-Willebrand factor [21]. The enzyme-linked immunosorbent assay (ELISA) used in the current study employed the same antibody and standard as the one used previously [21, 22], but in a different assay format. The current assay is based on the competition between circulating PIIANP and recombinant fusion protein GST-exon 2 for the binding to the polyclonal antibody immobilized on a micro-titre plate, whereas the recombinant fusion protein GST-exon 2 was immobilized in the previous version of the assay [21]. These technical modifications did not alter the specificity of the assay but resulted in improved precision and increase in the absolute serum levels of PIIANP. Intra- and inter-assay CVs were <9 and 14%, respectively and recovery of different concentrations of spiked recombinant fusion protein GST-exon 2 spiked into serum ranged from 97% to 112%. Urinary CTX-II, a marker of total type II collagen degradation, was measured by a competitive ELISA (Cartilaps, Nordic Bioscience, Herlev, Denmark) based on a mouse monoclonal antibody raised against the EKGPDP sequence of human type II collagen C-telopeptide [23]. Intra- and inter-assay CVs were <8 and 15%, respectively. Urinary CTX-II measurements were corrected for urinary creatinine measured by a standard colorimetric assay based on the method of Jaffe using the kit from Konelab (Espoo, Finland). Intra- and inter-assay variations were <2.9 and 3.8%, respectively.

Measurements of serum PIIANP, urinary CTX-II and urinary creatinine were done in duplicate and performed in batch analyses with all samples (at baseline and at 2, 3 and 5 yrs) from the same individual patient run in the same assay to reduce the impact of analytical inter-assay variability.

Statistical analysis
The reproducibility of knee JSW measurements was assessed by duplicate readings of a random sample of 20 radiographs. The 95% critical difference of JSW was calculated as 1.96 x (S.D./square root of 2). One-way ANOVA was used to analyse changes in serum PIIANP and urinary CTX-II over the 5-yr study period on log-transformed data. The distribution of PIIANP and CTX-II during the study between progressors and non-progressors and their changes over time were compared using ANOVA on log-transformed data. The rate of change for the two markers between the progressors and non-progressors was also determined, however, the power is limited due to the imprecision of the estimation of rate of change and because of the low number of progressors available. To determine the effect of surgery, data from the eight patients for whom pre- and post-surgery PIIANP and CTX-II levels were available were compared.

The relationship between 5-yr mean levels of serum PIIANP and urinary CTX-II was analysed by logistic regression analysis using levels of biochemical markers as continuous or dichotomous variables. For continuous variable analyses, we investigated the risk of progression per S.D. increase of serum PIIANP or urinary CTX-II levels (after log-transformation of the data). For dichotomous analyses, patients were categorized in quartiles of 5-yr mean levels of serum PIIANP or CTX-II. In these analyses, the mean 5-yr values were used as previously suggested for longitudinal data of biomarkers in OA [24] in order to have the more accurate estimate of the levels of each marker and to have the maximum number of patients, due to some missing samples. Finally, the sensitivity and specificity for each marker alone and combination of both were calculated.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Conclusions
 Acknowledgements
 References
 
From the initial 135 patients, entry and 5-yr follow-up X-rays were available for 115 and 20 were lost to follow-up. The critical difference of JSW measurement for the medial compartment was 1.5 mm. Thus, a variation of this distance or more in the medial joint space has a 95% probability of representing real change in the compartment rather than random variations in measurement.

The demographic, clinical and radiographic details of all the patients including those lost to follow-up are summarized in Table 1. A large proportion of the patients had KL grade III, but the majority of the patients had more than 3 mm of JSW left. There were no significant differences at baseline in these variables between the patients lost to follow-up and those that completed the 5-yr study. The mean [95% confidence interval (CI)] overall loss of medial compartment joint space in the patients taken together was 0.18 (0.17) mm. Complete X-ray progression data over 5 yrs, serum PIIANP and urinary CTX-II were available for 84 patients. The baseline characteristics of these patients were similar to those of the initial cohort (Table 1). There were no significant differences in the concentrations of PIIANP and CTX-II pre- and post-surgery in the eight patients for whom complete data were available before and after surgery (data not shown).


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  		TABLE 1. Baseline characteristics of the patients used in this study

 
During the 5-yr follow-up there was a significant increase of PIIANP (P < 0.0001) in all patients but on average the urinary CTX-II levels did not change significantly (Fig. 1). There was no correlation between baseline levels of CTX-II and PIIANP (R2 = 0.004; P = 0.61) or their respective changes during follow-up (R2 < 0.04; P = 0.99).


Figure 1
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  		FIG. 1. Longitudinal changes in serum concentrations of PIIANP (A), a marker of type IIA collagen synthesis and urinary concentrations of CTX-II (B), an index of total type II collagen degradation in 84 patients with mild knee OA. Urinary CTX-II levels were normalized for the urinary creatinine (Cr) concentration (ng/mmol Cr). Data are shown as mean and S.E.M.

 
The patients were divided into those who progressed as defined earlier and those who did not progress. There were 24 progressors and 60 non-progressors. Of the 24 progressors, nine progressed by surgery and these patients had also lost ≥2 mm tibiofemoral JSW prior to surgery. The mean (S.D.) age and BMI of the non-progressors and progressors were similar [62.0 (10.5) vs 63.3 (8.7) yrs, P = 0.62 and 29.5 (4.9) vs 31.4 (6.3) kg/m2, P = 0.13, respectively]. The ratio of the male:female [(26/34 vs 13/11, P = 0.47 in non-progressors and progressors, respectively] and the minimum JSWs of the medial compartment [mean (S.D.) 3.3 (1.9) vs 3.9 (2.1) mm, P = 0.24] were also similar between the two groups. As shown in Fig. 2, over the 5-yr period serum PIIANP and urinary CTX-II were found to be higher in the progressors compared to the non-progressors (P < 0.05 for both by ANOVA). Serum PIIANP increased in both groups over the 5-yr study period (Fig. 2A). In contrast, urinary CTX-II remained stable in the non-progressors but showed an early rise in the progressors (Fig. 2B). When only the baseline values were considered, serum PIIANP and urinary CTX-II levels were also higher in progressors than non-progressors, although the difference did not reach statistical significance (P = 0.14 and 0.08, respectively).


Figure 2
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  		FIG. 2. Sequential changes of serum PIIANP (A) and urinary CTX-II (B) levels in 24 progressive ({blacksquare}) and 60 non-progressive (•) patients with mild knee OA. Urinary CTX-II levels were normalized for the urinary creatinine (Cr) concentration (ng/mmol Cr). Data are expressed as mean and S.E.M. ANOVA P < 0.05 between progressors and non-progressors for both PIIANP and CTX-II.

 
When used as a continuous variable, each S.D. increase of mean 5-yr levels of PIIANP was associated with a relative risk of progression of 1.75 (95% CI: 1.02–3.01). Each S.D. increase of mean 5-yr levels of urinary CTX-II was associated with a relative risk (95% CI) of progression of 2.02 (1.20–3.41). Patients were then classified in quartiles of mean 5-yr levels of serum PIIANP or CTX-II. As shown in Fig. 3, the relationships between increased levels of these biomarkers and the proportion of progressors were not linear. For serum PIIANP compared with patients with levels in the first quartile, the proportion of progressors increased in quartile 2, then decreased in quartile 3 and increased again in quartile 4, although the proportion of progressors in quartile 4 was only slightly higher than in quartile 2 (Fig. 3). Compared with patients with mean 5-yr PIIANP levels in quartile 1, the relative risk (95% CI) of progression was 5.85 (1.07–32), 2.24 (0.36–13.8) and 8.64 (1.59–46.8) for patients with PIIANP levels in quartile 2, 3 and 4, respectively. For urinary CTX-II, the percentage of progressors increased in quartile 3 with no further increase in quartile 4. Based on this non-monotonic relationship especially for serum PIIANP, we further evaluated the risk of progression associated with levels of serum PIIANP in the highest quartile or urinary CTX-II above the median compared with the rest of the population.


Figure 3
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  		FIG. 3. Percentage of progressive patients according to mean 5-yr levels of biomarkers of type II collagen metabolism. Serum PIIANP (A) and urinary CTX-II (B) levels [normalized for the urinary creatinine (Cr) concentration (ng/mmol Cr)] are expressed in quartiles (Q).

 
As shown in Table 2, patients with mean 5-yr levels of serum PIIANP in the highest quartile had a 3.2-fold (P = 0.03) higher risk of progression compared to patients with levels in the lowest three quartiles. Similarly, patients with urinary CTX-II levels above the median had a 3.4-fold (P = 0.02) higher risk of progression than patients with levels below the median. When both serum PIIANP and urinary CTX-II were included in a multivariable logistic model, each marker significantly (P = 0.02 and P = 0.01, respectively) and independently of each other was associated with progression of the disease. Patients with increased levels of serum PIIANP and/or urinary CTX-II had the highest risk of progression than the patients with increased levels of one marker alone. After adjustment for age, gender, BMI and baseline minimum JSW, similar results were obtained with odds ratio (95% CI) of 3.2 (1.04–9.96), 5.6 (1.5–20.5) and 15.0 (3.0–76) for increased levels of PIIANP alone, CTX-II alone or combination of both markers.


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  		TABLE 2. Relative risk of progression with increased mean 5-yr levels of serum PIIANP and urinary CTX-II and combination of both markers

 
When the eight patients undergoing knee replacement therapy were excluded, similar results were obtained for all above analyses (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Conclusions
 Acknowledgements
 References
 
This cohort of patients with predominantly medial tibiofemoral OA was established to determine the sequential change in biochemical markers and its relationship with radiographic changes over 5 yrs. Over the 5-yr study period, only 15% of the patients were lost to follow-up and there were no significant differences at entry in the demographic, clinical or radiographical measurements of these patients compared to the patients who completed the study. Furthermore, the clinical measures (WOMAC and VAS), X-ray changes and the demographic data were similar in progressors and non-progressors at baseline. Thus, this is a suitable cohort of patients to investigate the relationship between biochemical markers of cartilage metabolism measured sequentially to X-ray progression over 5 yrs.

One important finding reported here is that serum PIIANP increased progressively during the 5-yr follow-up in all patients, whereas urinary CTX-II remained stable in non-progressors but showed an early rise in the progressors. According to the KL grade, which is based on both osteophyte and joint space loss, the patients used in this study have fairly advanced OA although the vast majority of the patients had more than 3 mm of JSW left, suggesting that in terms of cartilage volume the cohort of patients have mild-to-moderate disease. Serum PIIANP reflects the synthesis of a minor fraction of total type II collagen and is also believed to be a marker of changes in chondrocyte phenotype. Thus, the increase over time in serum PIIANP may reflect an increase in type IIA collagen synthesis—which could be an indication of an attempt of cartilage repair which is a characteristic of early stages of OA [25, 26]—and/or a progressive change of cell phenotype from chondrocytes to pre-chondrocytes since PIIANP had been shown to be expressed by fetal and OA cartilage [9].

The second important finding reported in this study is that, disease progression in this population was associated with higher levels of serum PIIANP and higher levels of CTX-II. For CTX-II, this finding is consistent with recent studies which investigated the relationship between a single baseline measurement and disease progression evaluated over periods ranging from 1 to 6 yrs in patients with established knee or hip OA [12, 13, 22]. In our study, CTX-II was significantly higher in the progressors and remained high throughout the study period suggesting active degradation of type II collagen during the course of progression. Moreover, the rapid rise in CTX-II during the first 2 yrs of follow-up in the progressors may indicate a more aggressive course of the disease in these patients at an early stage and is consistent with data from our previous study showing a rapid increase in cartilage loss early in the course of the disease [27].

In our study, we found that overall patients who progressed had higher serum PIIANP levels over 5 yrs than non-progressors, although the difference on baseline values did not reach statistical significance. In a previous study of 52 patients with established knee OA, it was reported that patients with baseline levels below the lower limit of healthy controls had a significantly larger decrease of JSW over the subsequent year than the other patients, although as in the current study there was no significant difference in mean values between the two groups at baseline [22]. More recently, Sugiyama et al. [28] found that increased synovial fluid levels of PIICP, which reflects the synthesis of both type IIA and type IIB collagens, were associated with a more rapid progression over 4 yrs in a cohort of patients with knee pain, but not yet radiographic joint damage. Finally, Nelson et al. [29] in a cross-sectional study reported that serum PIICP was decreased in patients with OA of undefined stage compared to healthy controls, although synovial fluid levels were increased. The reasons for the discrepancies between the studies relating levels of type II collagen synthesis markers and OA remain to be determined but could be related to some of the following factors: PIIANP reflects specifically the synthesis of type IIA collagen which is only a minor fraction of total type II collagen as measured by PIICP. Consequently, these two biological markers may react differently with OA and disease progression. Synovial fluid levels of markers reflect local alterations whereas serum levels reflect whole body cartilage turnover. Difference in disease progression assessment and follow-up periods between the studies could also be involved, our current study being the longest and the only one that has repeated measurements of biochemical markers. The levels of type II collagen synthesis markers may also vary with the stage of the disease, as suggested by the histological data discussed above [25]. It is interesting to note that in our former study [22], only patients with established disease participating in a clinical trial were investigated. These patients may thus be characterized by a decreased capacity of cartilage repair and tissue mass, both mechanisms which are likely to result in decreased systemic levels of biochemical markers of type II collagen synthesis. The patients used in the current study come from a community-based cohort with relatively mild OA. Clearly additional studies in patients with different stages of disease and measuring concomitantly markers reflecting the synthesis of collagen IIA, collagen IIB and total type II collagen using serum PIICP are needed to address these questions.

There are a number of limitations to this study. The statistically significant association between serum PIIANP and progression was rather modest and non-linear and therefore should be interpreted with caution. Secondly, the number of patients who showed progression was relatively small, thus reducing the statistical power and resulting in wide CIs in the estimation of relative risks. Thirdly, the changes in the two knees of each patient were not concurrent on the radiographs, as is evidenced, for example, by the fact that some ‘worst’ knees (from the point of view of pain) had no radiographic features of OA at entry. The reading of the radiographs was standardized, but did not employ the most up-to-date techniques. The study was undertaken before the introduction of the method of Buckland-Wright and colleagues [30, 31], and we ourselves have recommended their wider adoption based on additional investigations in some of the patients reported in the present study [32]. The new methods do not invalidate previous methods as long as they are used within their own limits, as is the case in the present study. The use of a more detailed measurement of joint space, for example using high-resolution digital callipers, might have slightly reduced the variance in measurement, but it is unlikely to affect the overall results using this method of taking radiographs. Finally, some patients progressed early in the period of observation, others progressed later, and some progressed both early and late. All these difficulties will tend to obscure any relationship between pathology in a single joint and changes in systemic levels of biomarkers. However, in spite of these drawbacks, there was a difference between patients who progressed and those who did not. This signal emerged from the data in spite of the ‘noise’ created by the relatively crude X-ray methods available at the time of the study, which is, however, counterbalanced by the long-term follow-up.


   Conclusions
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
Acknowledgements
 References
 
Even before the start of the bone and joint decade [3], researchers have been working hard to find suitable surrogate markers for the OA disease processes and although a huge range of possible biomarkers have been investigated only a few, such as COMP [8, 33] and CTX-II [12, 13, 22], seem to be reliable and emerging as possible surrogate markers for cartilage loss. The data presented in this report suggest that concentrations of markers reflecting type II collagen metabolism early in the disease process may be useful to discriminate between patients whose joints are likely to deteriorate and those who will not progress.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
References
 
The authors would like to thank Prof. S. Frankel for access to the Avon and Somerset Survey of Health and Fabrice Juillet for expert technical assistance. They are also grateful to the Arthritis Research Campaign, UK; Hoffmann-La Roche Ltd, Switzerland and the NHS Executive South West R&D Directorate, Bristol, UK, for financial support.

L.J.S. received a Pfizer Strategic Alliance for the study of the biology of PIIANP.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusions
 Acknowledgements
 References
 

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Submitted 5 May 2006; Accepted 7 November 2006


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