Time for Initial Response to Steroids is a Major Prognostic Factor In

Time for Initial Response to Steroids Is a Major Prognostic Factor inIdiopathic Nephrotic Syndrome

Marina Vivarelli, MD, Eleonora Moscaritolo, MD, Aggelos Tsalkidis, MD, Laura Massella, MD, and Francesco Emma, MD

Objective To identify early prognostic factors for idiopathic nephrotic syndrome (INS) in childhood.Study design A retrospective analysis of 103 patients with INS at onset, all treated in a single center with the sameinduction protocol, was conducted. Minimum length of follow-up was 2 years; median length of follow-up was 43months. Survival data were assessed with Cox-Mantel analysis. Predictive values were estimated with receiver op-erating characteristic curves.Results The median time of response to steroid therapy was 7 days. A significant association was found betweenthe interval from onset of steroid therapy to remission and the risk of relapsing within 3 months after steroid therapydiscontinuation (P < .0001). A similar association was found between the time to achieve remission and the risk ofdeveloping frequent relapsing or steroid-dependent nephrotic syndrome (P < .0001), the prescription of mainte-nance steroid therapy (P < .003), and the prescription of all other non-steroid drugs (P < .0001) during follow-up.Patients with non-relapsing and infrequent relapsing nephrotic syndrome had a median time to achieve remission<7 days; in patients with frequent relapsing and steroid-dependent nephrotic syndrome, this median was >7 days.Conclusion The interval from onset of steroid therapy to remission is an accurate early prognostic factor in INS.(J Pediatr 2010;156:965-71).

Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in childhood.1 Currently, all children with INSare treated at onset with steroids. Although most children will respond to treatment, the optimal duration and dosage ofsteroid therapy at onset and during subsequent relapses is debated.2 For each patient, the challenge resides in finding a ther-

apeutic strategy that allows maximal steroid sparing while limiting the relapse rate, on the basis of the child’s clinical responseand drug-related adverse effects.

This is particularly difficult at the beginning of the disease, because of the lack of reliable indicators that allow the identifi-cation patients who will respond poorly or will have a high propensity to relapse. Thereafter, the frequency of relapses inrelation to steroid treatment permits the classification of INS in subtypes reflecting disease severity.3

This classification has been shown to have a prognostic value that exceeds the relevance of renal pathology findings.4,5

Accordingly, a renal biopsy is not indicated in the initial examination of most children with steroid-sensitive INS.In recent years, 3 studies have highlighted that the rapidity of the initial response to steroid treatment represents an impor-

tant prognostic indicator for children with INS.6-8 To confirm these findings in a large and homogeneous cohort of patients, weretrospectively analyzed the clinical records of 103 patients with INS who were all followed from disease onset in the same centerand have all been treated with the same induction protocol.

AUC Area under the curve

CsA Cyclosporin A

CYP Cyclophosphamide

FR Frequent relapsing

HR Hazard ratio

INS Idiopathic nephrotic synd

IR Infrequent relapsing

ISKDC International Study of Kid

Disease in Children

Methods

A retrospective IRB-approved analysis was performed on all patients with INS who were seen at our pediatric nephrology unitbetween 1992 and 2006 and who met these criteria: (1) patients were followed without interruption since disease onset; all sec-ondary referrals were excluded; (2) the induction treatment corresponded to the International Study of Kidney Disease in Chil-dren (ISKDC) protocol (see below) and was initiated at our institution; (3) complete remission was achieved without the needof additional medications (eg, all steroid-resistant patients were excluded); (4) a minimum follow-up period of 2 years was

From the Division of Nephrology and Dialysis, BambinoGesu Children’s Hospital and Research Institute, Rome,Italy (M.V., E.M., L.M., F.E.); and Department ofPediatrics, University Hospital of Alexandroupolis,Democritus University of Thrace-Medical School,Alexandroupolis, Greece (A.T.)

Supported by the E-RARE Project ‘‘PodoNet: EU Con-sortium for Clinical, Genetic and Experimental Researchinto Hereditary Diseases of the Podocyte.’’ The authorsdeclare no conflicts of interest

0022-3476/$ - see front matter. Copyright � 2010 Mosby Inc.

All rights reserved. 10.1016/j.jpeds.2009.12.020

rome

ney

NR Non-relapsing

NS Nephrotic syndrome

OR Odds ratio

PDN Prednisone

PPV Positive predictive value

ROC Receiver operating curves

SD Steroid-dependent

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THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 156, No. 6

available; and (5) no severe infection that could interfere withthe initial response to steroids was reported during the firstweeks of treatment.

During the study period, 194 patients with steroid-sensi-tive INS were referred to our institution. Of these patients,85 were excluded because they were secondary referrals, be-cause incomplete data were available, or because they hadbeen treated with modified induction protocols. In addition,6 patients were excluded for prolonged fever (temperature>37.5�C for >4 days) or overt infection (pneumonia) at thetime of their first episode of nephrotic syndrome (NS).Therefore, 103 patients met the study inclusion criteria.

All patients were initially treated according to the ISKDCprotocol with prednisone (PDN) at 60 mg/m2/day for 4weeks, followed by 40 mg/m2/day for 4 weeks.9 Remissionwhile receiving steroid therapy was defined as the disappear-ance of proteinuria, on the basis of daily urinary dipstick re-cording results reported as ‘‘negative’’ or ‘‘trace’’ for at least 3consecutive days. The time to response was defined as thenumber of days between the first steroid dose and the firstday with ‘‘negative’’ or ‘‘trace’’ dipstick results. Relapse wasdefined as a dipstick result $3 for at least 3 consecutive days.

Children were classified for the purpose of the study ac-cording to their evolution during the first year of disease, fol-lowing standard criteria that have been summarized byEhrich et al.3 These allow the classification of patients withINS as steroid-dependent (SD), frequent relapsing (FR), in-frequent relapsing (IR), or non-relapsing (NR). For the lastgroup, patients had to remain relapse-free for at least 2 years.

After the first episode of NS, treatment was customized foreach patient depending on disease evolution. Patients withFRNS and SDNS began treatment with low-dose mainte-nance steroids (10-30 mg/m2 on alternate days), followedby cyclosporin A (CsA) when the disease was not adequatelycontrolled, adjusting the dose to reach target C2 levels of 300to 600 ng/mL. Before 1998, 19 patients received a course ofcyclophosphamide (CYP; 150 mg/kg cumulative dose for8-12 weeks). During these years, this treatment was used asthe first line of therapy for steroid dependency, before initi-ating CsA. Twelve patients received ramipril or amlodipinefor blood pressure control after starting CsA.

Several patients initially classified as having IRNS receivedalternate day steroid therapy in the following years becausethey developed FRNS or secondary steroid dependency.Twenty-nine children, mostly with FRNS, received treatmentwith levamisole (2-2.5 mg/kg 3-5 times per week; Table I).

Medical records were retrospectively analyzed. In 7 cases,partial medical history that was missing from the medical re-cord was obtained with telephone interview or during a fol-low-up clinic. Because of archival problems, documentationof laboratory values was available in 88 of 103 patients (fewerfor some variables that were not systematically measured inall patients; Table I).

Statistical AnalysisAnalyses were performed with SPSS software for Windowsversion 11.5.1 (SPSS Inc., Chicago, Illinois). Continuous

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values were compared with the Mann-Whitney U test. Uni-variate analysis for dichotomous values was performed withbinary logistic regression. Survival data were analyzed withthe Kaplan-Meyer curve and compared with the log-ranktest. Relapse-free survival was recorded as ‘‘0 days’’ for pa-tients who had a relapse during the induction therapy. There-fore, the estimated probability at time 0 of the Kaplan-Meyercurves indicates the probability of relapse before PDN couldbe discontinued. The influence of independent variables onsurvival data was evaluated with Cox-Mantel analysis. Multi-variate analyses were performed on unadjusted variables thatreached a P level <.10 in the univariate analysis. Receiver op-erating characteristic (ROC) curves were used to evaluate thesensibility and specificity of selected independent variables.Positive predictive values (PPV) were computed by usingthe online Vassar College clinical calculator (http://faculty.vassar.edu/lowry/VassarStats.html).

Continuous data are expressed as mean plus or minus SD,when they passed normality tests (Kolmogorov–Smirnov andShapiro–Wilk); otherwise, they are expressed with their me-dian value and range. The 95% confidence intervals are indi-cated in squared brackets in the text. All P values are 2-sidedand considered significant when <.05.

Results

The sex ratio and age at onset of INS reflect known frequen-cies for INS (Table I). Median length of follow-up was 43months (range, 24-165 months). As indicated, approximatelytwo-thirds of patients had FRNS or SDNS, and 9 patients didnot have a relapse after their first episode. No patient receivedmethylprednisolone boluses to achieve complete remission.

The median time of response to steroid therapy was 7 days,with 97% of patients responding within 28 days (Figure 1,A). With Cox-Mantel analysis, at the univariate level, a strongassociation between the interval from onset of steroid therapyto remission and the risk of relapsing within 3 months aftersteroid therapy discontinuation was shown (hazard ratio,1.07 [1.04-1.1] per day of persisting proteinuria, P < .0001;Table II).

As shown in Table III, a similar association was found atthe multivariate level between the time to achieve remissionon steroid therapy and the risk of developing FRNS or SDNS(odds ratio [OR], 1.39 [1.17-1.66], P < .0001), the prescrip-tion of maintenance steroid therapy (OR, 1.47 [1.15-1.87], P< .003), and the prescription of all other non-steroid drugs(OR, 1.38 [1.18-1.62], P < .0001) during follow-up. No sig-nificant association was found with the use of levamisole.With univariate analysis, a significant association or tendencywas also found between the risk of early relapse and serumphosphate (P = .03) and cholesterol levels (P = .08). These re-sults were not confirmed at the multivariate level (Table II).

When patients with INS were subdivided in categories, themedian time for the initial response to PDN was significantlydifferent in groups and increased progressively, movingtoward steroid dependency (Figure 1, B). Patients with

Vivarelli et al

http://faculty.vassar.edu/lowry/VassarStats.html

http://faculty.vassar.edu/lowry/VassarStats.html

Table I. Patient characteristics

Units

nmean

median%

± SD (range) n

Cohort characteristicsYear of onset year 1992-2006 103Sex Male : female 74 : 29 71.8% : 28.2% 103Season Autumn-Winter : Spring-Summer 53 : 50 51.5% : 48.5% 103Age of onset years 3.4 (0.6 - 12.3) 103Length of follow-up months 43 (24 - 165) 103

Clinical characteristicsHeight SDS 0.5 � 1.1 103Weight SDS 1.2 � 1.6 103Body mass index SDS 0.8 � 1.5 103Systolic blood pressure SDS 0.7 � 1.0 103Diastolic blood pressure SDS 1.1 � 0.9 103

Classification of NSNon relapser 9 8.7% 103Infrequent relapser 25 24.3% 103Frequent relapser 25 24.3% 103Steroid-dependent 44 42.7% 103

TreatmentMaintenance steroid therapy 69 70.0% 103Other non steroid drugs 62 60.2% 103Cyclosporin A 40 38.8% 103Levamisole 29 28.2% 103Cyclophosphamide 19 18.4% 103

Laboratory measuresMicroscopic hematuria 41.3% 88U protein/creatinine ratio mg/mg 11.2 (2.5-24.0) 88Serum Na mmol/L 135 � 3.5 88Serum K mmol/L 4.3 � 0.7 88Serum Ca mmol/L 2.03 � 0.15 88Serum P mmol/L 1.55 � 0.32 88Serum cholesterol mmol/L 10.0 � 3.0 88Serum triglycerides mmol/L 2.64 � 2.10 76Serum proteins g/L 47.1 � 6.5 88Serum albumin g/L 17.3 � 5.9 88Serum a2 globulins % total serum proteins 37.7 � 10.4 51Serum g globulins % total serum proteins 7.9 � 3.5 51Serum immunoglobulin A g/L 1.04 (0.26-3.51) 51Serum immunoglobulin G g/L 2.55 (0.34-9.16) 51

SDS, Standard deviation score.

June 2010 ORIGINAL ARTICLES

NRNS and IRNS had a median time of response to steroidtherapy at disease onset <7 days (Figure 1, B), whereas themedian time for response was >7 days in patients withFRNS and SDNS.

Taken together, these data indicate that the time of re-sponse to steroid therapy at disease onset is an accurate pre-dictor of the risk of developing a severe form of INS. This isfurther illustrated in Figure 1, C. As shown, all patients whorequired >14 days of PDN to achieve remission were pro-jected to have a relapse within 3 months after steroid discon-tinuation, and 50% had a relapse while still receiving steroids.Conversely, nearly all patients who responded within 7 daysremained relapse-free during the induction treatment, andapproximately 50% were still in remission 3 months after ste-roid discontinuation. Patients who achieved remission dur-ing the second week of treatment had an intermediateresponse. Most patients remained in remission while receiv-ing steroids, but most had a relapse within 1 to 2 months. Alldifferences in these 3 groups were statistically significant (P <.01, log-rank test).

Time for Initial Response to Steroids Is a Major Prognostic Facto

Likewise, Figure 1, D shows the probability of requiringadditional treatment with CsA, CYP, or both. After 4 yearsof disease, two-thirds of patients who required >7 days toachieve a complete remission at onset received additionaltreatment with these drugs, as compared with less thanone-third of patients who responded within 1 week(P < .001). No statistically significant difference was observedbetween patients responding in the second week and patientsresponding after >2 weeks of PDN treatment.

ROC analysis was performed to define the clinical rele-vance of these results. As shown in Figure 2, the areas underthe curves (AUC) were statistically significant (P < .001), in-dicating a good performance of the ‘‘time to achieve remis-sion at onset’’ as a classifier measurement to predict earlyrelapse, steroid dependency, or frequent relapses and theneed for treatment with CsA, CYP, or both (Figure 2).

These data were translated in more practical clinical termsby calculating the PPV for each of these outcomes. As illus-trated in Figure 2, patients who did not respond within 1week of treatment had >90% chance of having a relapse

r in Idiopathic Nephrotic Syndrome 967

Figure 1. Response to steroid treatment and evolution of nephrotic syndrome. A, Cumulative probability of complete remissionaccording to the duration of the initial treatment with PDN. B, Time to achieve remission according to subtypes of INS. Boxesindicate the 25th, 50th, and 75th percentiles; error bars indicate the 5th and 95th percentiles; and filled circles indicate meanvalues. C, Probability of relapse after steroid discontinuation according to the time required to achieve the initial remission. Theprobability at time 0 indicates the probability of relapsing before PDN discontinuation. P < .001 for all comparison in the 3 groups(log-rank test). D, Probability of initiating treatment with CsA or CYP according to the time required to achieve the initial re-mission. P < .001 when comparing patients who achieved remission within 7 days with the other subgroups; P = .14 whencomparing patients who responded in the second week and patients who required >2 weeks of treatment to achieve completeremission (log-rank test). Vertical bars indicate censored values.


within 3 months when treated with the ISKDC protocol or ofdeveloping FRNS/SDNS (Figure 2, D and E). These probabil-ities were close to 100% when patients were not in remissionwithin 2 weeks of steroid treatment initiation. The probabil-ity of requiring additional treatment with CsA, CYP, or bothincreased more gradually, becayse this outcome was less fre-quent, and reached 70% when patients did not achievedcomplete remission within 10 days (Figure 2, F). This lateranalysis was restricted to the first 2 years of disease, becausefollow-up was available during this period for all patients.

Discussion

To date, steroids remain the mainstay initial course in thetreatment of INS.2 Standard steroid therapy achieves remis-

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sion in most patients and permits definition of INS subtypes.Patients that are resistant to steroids have a worse prognosisand carry mutations in constitutive podocyte genes in a sig-nificant proportion of cases.10,11

Classification of patients who are steroid sensitive in dif-ferent subgroups is useful to define the long-term prognosis,because patients with FRNS and SDNS generally have a lon-ger and more severe disease course and are less likely toachieve permanent remission before adulthood.10,12,13 Thisimplies that children with FRNS and SDNS undergo a step-wise escalation of treatment during their first year of diseaseand are treated with high cumulative doses of steroids ina short period, which can generate significant adverse effects,including growth stunting, hypertension, obesity, andhirsutism.1

Vivarelli et al

Table II. Cox-Mantel analysis

Independent variables Units HR 5% CI 95% CI P value

Univariate analysisYear of onset year 0.96 0.90 1.03 nsSex Male : female 1.25 0.79 1.98 nsSeason Autumn-Winter : Spring-Summer 0.95 0.64 1.43 nsAge of onset Years 0.95 0.88 1.03 nsHeight SDS 1.03 0.85 1.25 nsWeight SDS 1.09 0.94 1.27 nsBody mass index SDS 1.07 0.92 1.25 nsSystolic blood pressure SDS 0.87 0.68 1.13 nsDiastolic blood pressure SDS 0.87 0.65 1.17 nsTime for response to steroids days 1.07 1.04 1.10 <.0001Microscopic hematuria yes 0.85 0.53 1.37 nsUrine protein / creatinine mg/mg 1.02 0.99 1.05 nsSerum Na mmol/L 0.98 0.91 1.06 nsSerum K mmol/L 1.02 0.71 1.47 nsSerum Ca mmol/L 0.45 0.08 2.68 nsSerum P mmol/L 0.36 0.14 0.89 .03Serum cholesterol mmol/L 1.08 0.99 1.18 .08Serum triglycerides mmol/L 1.01 0.90 1.14 nsSerum proteins g/L 0.99 0.96 1.04 nsSerum albumin g/L 0.96 0.91 1.01 nsSerum a2 globulins % 1.00 0.98 1.04 nsSerum g globulins % 1.05 0.94 1.18 nsSerum immunoglobulin A g/L 0.85 0.47 1.53 nsSerum immunoglobulin G g/L 0.93 0.80 1.07 nsSerum immunoglobulin M g/L 0.99 0.87 1.11 ns

Multivariate analysisTime for response to steroids days 1.09 1.05 1.14 <.0001Serum P mmol/L 0.46 0.17 1.21 nsSerum cholesterol mmol/L 1.06 0.97 1.16 ns

ns, Not significant.


It should also be emphasized that even when classifying pa-tients helps define their prognosis and allows for data compar-ison in clinical trials, subtypes of INS represent a continuumspectrum of the disease that extends from non-relapsing INSto severe steroid dependency, which varies with time in indi-vidual patients and is influenced by treatment.

Currently, the ISKDC classification of INS remains themost widely used. This classification was developed in the1970s and was based on a standard initial treatment protocolthat has been progressively modified by several groups, as ev-idence has emerged favoring a more prolonged initial courseof steroids.2,14 Accordingly, the duration of remission in ourcohort was short in comparison with studies that have adop-ted longer steroid schedules,2 and we no longer use theISKDC protocol in our Division. However, the consistencyin our induction protocol in the study period has provideda very good opportunity to evaluate prognostic factors ofINS in a very homogenous group of patients.

Table III. Logistic regression

Independent variable Dependent variables OR 5% CI 95% CI P value

Time for responseto steroids

FRNS or SDNS 1.39 1.17 1.66 <.0001Maintenance steroid

therapy1.47 1.15 1.87 <.003

All other non-steroiddrugs

1.38 1.18 1.62 <.0001


Currently, very few early prognostic indicators have beenconsistently identified in INS. In recent years, however, 3 dif-ferent studies have highlighted the relevance of recording thetime of response to steroid therapy at disease onset to predictthe subsequent course of INS. Costantinescu et al8 first re-ported in a cohort of 56 North American children that a pro-longed initial remission time was predictive of a morerelapsing course in patients without hematuria. Most of theirpatients were treated with the ISKDC protocol, and 76% oftheir patients were Caucasian, but their analysis was limitedto the first year of disease. In our cohort, we could not con-firm the relevance of hematuria in predicting INS severity,nor was it confirmed in a subsequent study by Yap et al.7

These authors have analyzed their experience in 25 years ina group of 91 predominantly Asian children with INS, witha minimum follow-up of 6 months. Most children weretreated following the ISKDC protocol, but 13 patients re-ceived a shorter course of PDN.7 Overall, their results aresimilar to ours in predicting a significant increase in therisk of developing SDNS when remission was not achievedwithin 9 days.7 Finally, Letavernier et al6 recently have re-ported their experience in 35, mostly Caucasian, patientswho were treated with a longer induction schedule of PDNbetween 1999 and 2006 and had a minimum follow-up of12 months. Steroid dependency developed in patients in theircohort who did not achieve remission within 20 days; theyrequired treatment with CsA and most frequently receivedmethylprednisolone pulses. This observation extends the


Figure 2. ROC curves and PPVs. A-C, ROC curves showing the discriminating performance of the time-to-response to steroidsin predicting early relapse within 3 months after steroid discontinuation, FRNS, or SDNS and the prescription of CsA, CYP, orboth within the first 2 years of disease. The shape of the curve indicates the sensitivity and specificity of the independent variablein predicting the outcome. The more convex the curve, approaching the upper-left corner (maximal sensitivity and specificity),the higher the predictive value of the independent variable (time-to-response to steroids). D-F, PPV for the same outcomes. Graylines indicate the 95% CIs.


results of the earlier 2 groups, by using prescription of non-steroid drugs as a marker for disease severity, but is limited bythe small number of patients, preventing survival analysis toaccount for uneven lengths of follow-up.6

Our study confirms and expands the results of these 3studies. The retrospective nature of the analysis constitutesa limitation of our study, although these data are extremelydifficult to obtain prospectively, because of the small inci-dence of INS in the pediatric population (2-3 in 100 000).1

To overcome the possibility of introducing selection biases,we have used strict selection criteria and excluded all second-ary referral patients who may have had more severe disease.Although subsequent treatments were individualized afterthe first relapses, our overall strategy has remained uniform.This is indirectly confirmed with our analysis showing no in-fluence of the year of onset of INS on the likelihood of initi-ating CsA or CYP. It is also unlikely that physicians may havebeen biased in their prescriptions by the time for the initialresponse to steroids, because this was not considered infor-mative until recently.

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To generate more robust results, a minimum follow-up of2 years was required. This allowed the definition of an imme-diate end-point (time to the first relapse), a short-term out-come measurement (subclasses of INS in the first year ofdisease), and a medium-term end-point (initiation of steroidsparing treatments). These later end-points have been shownto be good surrogates of the long-term outcome.13,15

Although there is a clear continuum in our results, they al-low to define 3 groups of patients on the basis of the initialresponse to steroids within the first week, in the secondweek, or after >2 weeks of treatment.

Patients who are fast responders (within 7 days) have a sig-nificantly higher chance to remain in remission after steroiddiscontinuation and lower chance of requiring additionalmedication with time, suggesting that they may be treatedwith a relatively short initial course of steroids. However, pa-tients who respond later would probably benefit from a pro-longed initial course of steroid with a gradual taperingextending 4 to 6 months. Whether this approach should beapplied in the clinical practice requires prospective studies

Vivarelli et al


and should not be advocated, in our opinion, solely on thebasis of the present data.

However, late responders who require >14 days of treat-ment to achieve remission clearly represent a more difficultcategory, as also pointed out by Letavernier et al.6 Not onlydo these patients relapse rapidly and often require early addi-tion of a second drug, but they also tend to relapse during theinduction treatment. Therefore, lengthening the initial ste-roid course is unlikely to achieve a prolonged remission,and treatment should probably be intensified during the firstweeks after diagnosis. As proposed by Letavernier et al,6 a bo-lus of methylprednisolone might be anticipated when remis-sion is not achieved by day 20. Alternatively, a second drugmight be introduced more rapidly. To date, very limited in-formation is available on this second strategy. The Arbeitsge-meinschaft fur Padiatrische Nephrologie has performeda randomized multicenter study comparing a standard 12weeks PDN induction protocol with or without 8 weeks ofCsA treatement.15 Its results showed that patients treatedwith a combination of these 2 drugs had a later relapse andthe effect lasted for at least 1 year. As new and less nephro-toxic treatments become available, such as mofetil micophe-nolate, this category of patients is a clear target to test thisstrategy in prospective trials.

Pediatricians caring for children with a first episode of INSshould be aware of the relevance of the time of response tosteroid therapy at disease onset as an early prognostic factorin INS, with patients requiring >7 days of steroid therapy toachieve remission being more likely to prove challenging inthe subsequent course of their disease. n

The authors thank Gilda Stringini, Marcella Greco, and AlessandraGianviti for their assistance in preparing the manuscript.

Submitted for publication Aug 6, 2009; last revision received Oct 14, 2009;

accepted Dec 10, 2009.


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