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S= kip to=20 main page content

Angiogenic Factors in Plasma of Brain Tumour=20 Patients

¹Department of Internal Medicine III, Division of=20 Nephrology and Dialysis, Medical University of Vienna, Austria =
²Department of Neurosurgery, Medical University of = Vienna,=20 Austria

Correspondence to: Ludwig = Wagner, MD,=20 Medical University of Vienna, Department of Internal Medicine III, = Waehringer=20 Guertel 18-20, A-1090 Vienna, Austria. Tel: +43 1 40400 4319, Fax: +43 = 1 40400=20 7790, e-mail: ludwig.wagner{at}meduniwien.ac.at =

Abstract

Background: Angiopoiesis and angiopoietic growth factors are = of=20 considerable importance in the development and progression of = intracranial=20 tumours. However, knowledge of the plasma detectability of distinct = angiogenic=20 factors in patients with brain tumour is very limited. This study = evaluates the=20 plasma concentrations of the angiogenic factors angiopoietin-2 (Ang-2), = vascular=20 endothelial growth factor (VEGF) and platelet-derived growth factor BB = (PDGF-BB)=20 in patients with brain tumour. Patients and Methods: Plasma samples of = 78=20 patients suffering from various types of intracranial tumours = (glioblastoma=20 multiforme, GBM, n=3D22; astrocytoma, n=3D12; meningioma, n=3D16; and = intracranial=20 metastasis, n=3D28) were analysed. For determination of plasma = concentrations of=20 angiogenic factor, highly specific enzyme-linked immuno sorbent assays = (ELISAs)=20 were used. Results: Ang-2 plasma concentration in GBM patients was = significantly=20 lower when compared with that in patients with meningioma and = intracranial=20 metastasis. Highest levels of VEGF concentrations were detected in = plasma=20 derived from patients suffering from meningioma. Interestingly, VEGF = plasma=20 levels depended on the number of intracranial lesions, with = significantly higher=20 concentrations in patients with 3 or more lesions when compared with = those with=20 2 or fewer lesions. However, no correlation between the survival time of = the=20 patients and the plasma levels of the tested growth factors was = obtained. Plasma=20 levels of PDGF-BB did not differ between the individual tumour groups.=20 Conclusion: The detectability of the angiogenic factors Ang-2 and VEGF, = as well=20 as of PDGF-BB, in the plasma of patients suffering from various types of = brain=20 tumours is described. The plasma detectability of the individual = angiopoetic=20 factors seems to depend at least partly on the tumour type as well as on = tumour=20 progression. This might be of prognostic and therapeutic relevance.=20

Keywords:

Primary brain tumours are classified into 4 malignancy = groups as=20 defined by the World Health Organisation (WHO) (1). = The most=20 malignant tumour is the glioblastoma, also known as glioblastoma = multiforme=20 (GBM). Although chemotherapy, radiotherapy and surgical methods have = progressed=20 enormously in recent years, the prognosis of GBM patients is still very = limited=20 (2). =

Angiogenesis plays a crucial role in tumour growth, = particularly in=20 GBM. The unique structure of brain vessels, consisting of endothelial = cells=20 (EC), pericytes and astrocytes, is abnormal in these tumours. There are = many=20 growth factors and cytokines involved in the complex mechanism of = angiogenesis.=20 Vascular endothelial growth factor (VEGF) is a secreted dimer with=20 characteristic kinase domain receptor binding sites (3, = 4). = Based on=20 its potential to increase vascular permeability, Senger and collegues = were the=20 first to hypothesize an involvement of VEGF in angiogenesis (5).=20 Development of abnormal vascular structures in mice lacking VEGF has = encouraged=20 this hypothesis (6).=20 Endothelial expression of VEGF was detected in all angiogenesis stages, = namely=20 survival, proliferation, migration and permeability, underlining the = central=20 role of this growth factor in new vessel formation (7).=20 Up-regulation of VEGF transcription in tumour cells due to hypoxia (8, = 9) = represents=20 a stimulus for angiogenesis. Notably, in gliomas, expression levels of = VEGF and=20 its receptor highly correlate with their malignancy grade (10).=

Angiopoietins have been identified as one of the most = important growth=20 factors involved in the VEGF signalling pathway (11, = 12).= Upon=20 stimulation, angiopoietin-1 and -2 (Ang-1 and -2) are secreted and act=20 via the Tie 2 tyrosine kinase receptor (13).= In mice,=20 alterations of the expression levels of angiopoietins and their receptor = Tie 2=20 resulted in a high extent of vessel malformations. Thus the potential = role of=20 the angiopoietin/Tie 2 receptor system in angiogenesis has been = suggested (11, = 14-<= A=20 class=3Dxref-bibr id=3Dxref-ref-16-1=20 href=3D"http://ar.iiarjournals.org/content/29/2/731.full#ref-16">16).= Ang-1=20 induces auto-phosphorylation of the tyrosine kinase-dependent Tie 2 = receptor,=20 whereas Ang-2 is a natural antagonist (16).= In GBM,=20 Ang-1 was highly expressed in tumour cells and Ang-2 was predominantly = present=20 in ECs (17-<= A=20 class=3Dxref-bibr id=3Dxref-ref-19-1=20 href=3D"http://ar.iiarjournals.org/content/29/2/731.full#ref-19">19).= It is=20 hypothesized that Ang-1 promotes angiogenesis in GBM (20, = 21),= whereas=20 Ang-2 serves as an early marker of tumour angiogenesis in astrocytomas = (22).=

In addition to the potential permissive function between = VEGF and=20 angiopoietins in glioma progression (23),= =20 platelet-derived growth factor (PDGF) might also be relevant for vessel=20 formation and cell migration in brain angiogenesis (24, = 25).=

In analogy to primary brain tumours, an adequate blood = supply is of=20 similar importance for the formation and progression of brain = metastases, which=20 represent 50% of all malignant brain tumours (1). = Although=20 the mediators of the formation of intracranial metastases are still = under=20 investigation, data already exist showing the central role of VEGF = signalling in=20 this process in mice (26, = 27).=

Elevated expression of vascular growth factors Ang-2, VEGF = and PDGF-BB=20 in various types of brain tumours is a well-known fact, however their = plasma=20 detectability in vivo has not been investigated yet. Based on = the=20 importance of angiopoesis in tumour development, the determination of = their=20 plasma levels might be a useful clinical tool. This study is aimed at = the=20 evaluation of the plasma detectability of distinct angiopoetic factors = in=20 patients suffering from brain tumours and at the comparison of their = plasma=20 levels in dependence of the individual tumour type.

Previous=20 Section Nex= t=20 Section

Patients and Methods

Study population. The study participants were = patients at the=20 Department of Neurosurgery, Medical University of Vienna, between = November 2005=20 and August 2007. All blood samples were taken from forearm veins prior = to the=20 resection of intracranial tumours or any other treatment modalities. A = written=20 informed consent was received from each patient prior to vein puncture. = The=20 study was approved by the local Ethics Committee. The diagnosis for each = group=20 was made by histological investigation of surgically removed tumour = tissue by=20 experienced pathologists.

Sample collection. The blood samples were collected = into 7 ml=20 vacutainer EDTA tubes and were immediately cooled on ice. Subsequently, = plasma=20 was separated from cells by centrifugation at 3200 rpm for 10 min at = 4=C2=B0C and=20 immediately frozen in aliquots at -80=C2=B0C for further use. The exact = time points=20 of blood sampling and freezing were documented. All blood samples were = taken=20 between 5 to 6.30 p.m., 6 to 15 days after the first diagnosis of the = malignant=20 tumours.

ELISA assays for Ang-2, VEGF and PDGF-BB. These = analyses=20 were performed with commercially available ELISA kits (Quantikine=C2=AE = Human VEGF,=20 Quantikine=C2=AE Human Ang-2 and Quantikine=C2=AE Human PDGF-BB = Immunoassay, all from=20 R&D Systems, Minneapolis, MN, USA) according to the manufacturer's=20 instructions. Briefly, standards were prepared using the provided = recombinant=20 proteins. One hundred =CE=BCl of assay diluent followed by 50 =CE=BCl of = either standard=20 or plasma sample were added to each well and incubated for 2 h on a = constant=20 shaker at room temperature. Subsequently, wells were washed 3 to 4 times = with=20 washing buffer (R&D Systems) using the ELX Auto strip Washer (Biotex = Instruments, Winooski, VT, USA) and 200 =CE=BCl of conjugate were added = to each well.=20 After an additional incubation period of 2 h under constant shaking at = room=20 temperature, which was followed by the described washing procedure, 200 = =CE=BCl of=20 substrate solution was applied to each well and samples were incubated = for 30=20 min under light protection. The reaction was stopped by addition of stop = solution (50 =CE=BCl) and the ELISA plate was read at 450 nm within 30 = min using=20 Powerwave ELISA reader (Biotec Instruments, Winooski, VT, USA). The = limit of=20 quantification was specific for each assay and given as 8.3 pg/ml for = Ang-2, 5.0=20 pg/ml for VEGF and 15 pg/ml for PDGF-BB.

View this table:

Table I.=20

Demographic data of brain tumour = patients separated=20 into four groups.

Statistical analysis. Statistical analyses were = performed=20 with SPSS Version 11.0 (SPSS, Chicago, IL, USA). Comparisons between = groups were=20 calculated using unpaired Student's t-test. The differences = were=20 considered as significant when p=E2=89=A40.05. Parameters are = indicated as=20 grouped mean values=C2=B1S.D. The association between the 3 angiogenesis = factors were=20 evaluated with Pearson's correlation coefficient. The same test was used = for=20 performing a correlation analysis between the survival rates of brain = tumour=20 patients in different groups.

Pre= vious=20 Section Nex= t=20 Section

Results

Patient characteristics. In this study, blood = samples were=20 collected from a total of 78 patients suffering from malignant or benign = brain=20 tumours undergoing either a neurosurgical investigation or = tumour-directed=20 intervention. The study participants suffered from one of the following = brain=20 tumours: meningioma (n=3D16); GBM WHO Grade IV (n=3D22); astrocytoma WHO = II-III=20 (n=3D12); intracranial metastasis (n=3D28). In the metastasis group, the = primary=20 tumours consisted of lung carcinoma (n=3D16), renal cell carcinoma = (n=3D5), breast=20 cancer (n=3D3), melanoma (n=3D2) and thyroid carcinoma (n=3D1). For = detailed patient=20 characteristics, see Table = I.

Plasma concentrations of Ang-2, VEGF and PDGF-BB in the = study=20 population. In a first step, the Ang-2 concentration in peripheral = blood=20 samples was measured (Figure = 1A).=20 Although Ang-2 was detectable in all plasma samples, a strong = interindividual=20 variability was observed, which depended at least partly on the tumour = type.=20 Interestingly, the mean Ang-2 concentration in the GBM group = (351.95=C2=B1213.56=20 pg/ml) was much lower than that observed in patients with meningioma=20 (571.2=C2=B1263.28 pg/ml, p<0.007), or those with = intracranial metastasis=20 (565=C2=B1305.27 pg/ml, p<0.007). In patients suffering from = astrocytomas, the plasma concentrations (378.95=C2=B1193.33 pg/ml) were = similar to=20 those observed in GBM patients, which was significantly lower than the = Ang-2=20 plasma levels of patients with meningioma (p<0.05).

View larger version:

Figure 1.=20

Ang-2 (A) and VEGF (B) plasma levels of = four brain=20 tumour patient groups. A, The Ang-2 concentration was significantly = lower in the=20 GBM group when compared with that in the meningioma (**p<0.007) and=20 intracranial metastasis population (**p<0.007). In the astrocytoma = group,=20 Ang-2 levels were lower in comparison to the meningioma group = (*p<0.05) (ast:=20 astrocytoma, glio: glioblastoma multiforme, men: meningioma, met: = intracranial=20 metastasis). B, The VEGF plasma levels paralleled the Ang-2 plasma = concentration=20 in brain tumour patients. VEGF levels were significantly lower in GBM = patients=20 than in patients suffering from intracranial metastasis (*p<0.03). =

As expected, the concentration of VEGF paralleled those = measured for=20 Ang-2 (Figure = 1B). The=20 VEGF plasma concentrations of the intracranial metastasis group = (50.3=C2=B170.5=20 pg/ml) were significantly higher than those of patients suffering from = GBM=20 (15.50=C2=B122.5 pg/ml, p<0.03). However, no statistically = significant=20 difference was detected between the plasma VEGF levels of the GBM and = the=20 meningioma groups.

Although PDGF-BB was detectable in all tested plasma = samples, the=20 plasma concentrations of this growth factor differed only marginally = between the=20 individual tumour groups.

View larger version:

Figure 2.=20

VEGF plasma levels with regard to the = extent of=20 intracranial metastasis. Intracranial metastasis patients were separated = into=20 those with 2 or fewer and those with 3 or more intracranial tumour = lesions. The=20 VEGF concentration of the group with two or fewer lesions (n=3D20) was=20 significantly lower than that of the group with three and more lesions = (n=3D8):=20 ***p<0.00001.

Correlation of Ang-2, VEGF and PDGF-BB plasma levels = with the=20 number of intracranial metastases. Intracranial metastasis strongly = depends=20 on the generation of new blood vessels. Therefore, the plasma levels of = Ang-2,=20 VEGF and of PDGF-BB in patients bearing 1 or 2 metastatic lesions = (n=3D20) were=20 compared with those of patients exhibiting 3 or more intracranial = metastatic=20 lesions (n=3D8). Whereas there was no significant difference between = groups with=20 respect to the Ang-2 and PDGF-BB plasma concentrations, the plasma = concentration=20 of VEGF (Figure = 2) was=20 significantly higher in patients suffering from 3 or more metastatic = lesions=20 when compared with patients suffering from fewer than 3 metastatic = lesions=20 (18.2=C2=B116.5 pg/ml versus 126.9=C2=B191.3 pg/ml; = p<0.0001).

Correlation of Ang-2, VEGF and PDGF-BB plasma levels = with patient=20 survival. The expression levels of distinct angiopoietic factors = have been=20 shown to depend on the tumour malignancy grade. Therefore, the plasma = levels of=20 Ang-2, VEGF and PDGF-BB were correlated with the patients' survival = time. The=20 individual survival data were obtained from the hospital records. Data = were=20 available for 17 of the GBM patients, of whom all had died; for 28 = patients=20 suffering from intracranial metastasis, of whom 19 had died; of 12 = astrocytoma=20 patients, of whom 1 had died at the time of this study. The mean = survival=20 periods of the GBM patients and of the patients suffering from = intracranial=20 metastasis were 8=C2=B19 months and 8=C2=B18 months, respectively. The = survival data were=20 compared with the plasma levels of the individual growth factors using = Pearson's=20 correlation coefficient. However, none of the 3 growth factors was found = to=20 correlate with the survival of the patients.

Pre= vious=20 Section Next=20 Section

Discussion

Similar to other tumour entities, angiopoiesis is of = central=20 importance in brain tumour growth. The role of angiopoietic factors in = the=20 development of brain tumours was extensively studied with respect to = mRNA and=20 protein at the tissue level, however, no data has been presented about = their=20 plasma detectability in this type of tumour patients.

This paper describes considerable plasma values of the = angiopoietic=20 factors Ang-2, VEGF and PDGF-BB in samples derived from meningioma = patients as=20 well as in the plasma of patients suffering from brain metastasis. In = contrast,=20 especially in plasma derived from GBM and to a similar extent in the = plasma of=20 patients with astrocytoma, concentrations of Ang-2 were significantly = lower than=20 those of patients with meningioma and intracranial metastasis. No = significant=20 difference was found between the individual tumour entities with respect = to the=20 PDGF-BB concentrations. Earlier studies performed on brain tumours = including GBM=20 and astrocytoma demonstrated high tissue expression levels of Ang-2 (17, = 19).= =20 Additionally, there are several studies showing high tissue expression = as well=20 as high plasma concentrations of this factor in association with other=20 extracerebral neoplasias (28, = 29).= Thus,=20 the finding of low Ang-2 plasma concentration in GBM patients was = surprising.=20 One possible explanation for this discrepancy might result from the = highly=20 specific characteristics of central nervous vasculature. The varying = ability of=20 distinct substances to penetrate the blood-brain barrier is a well-known = fact.=20 Moreover, alterations of the blood-brain barrier in association with = central=20 nervous system neoplasias are frequently observed. Although little is = known=20 about the potency of Ang-2 to pass the blood-brain barrier, altered = blood-brain=20 barrier permeability for these factors might explain the difference = between the=20 reported tissue expression levels and the plasma concentrations of = Ang-2. In=20 this context, the high expression levels of angiopoietic factor = receptors, which=20 have been observed especially in GBMs, are of additional interest (17).= Rapid=20 receptor binding and the resulting absence of these factors in the = plasma might=20 also contribute to the phenomenon of low plasma concentration of Ang-2 = in the=20 circulation of patients suffering from high Ang-2-expressing GBM.

As reported earlier (12),= Ang-2=20 and VEGF are synergistically involved in the formation of new blood = vessels.=20 Thus, a correlation of the plasma concentrations of VEGF and Ang-2 in = GBM=20 patients was expected. However, the data did not show any significant=20 correlation. This might be due to high interindividual differences of = VEGF=20 concentrations within the same group in the study population. = Interestingly, the=20 VEGF concentration was significantly higher in patients with = intracranial=20 metastasis when compared with patients suffering from GBM. Previously, = VEGF was=20 found to be highly detectable in the plasma derived from various kinds = of=20 primary solid tumours (30-<= A=20 class=3Dxref-bibr id=3Dxref-ref-33-1=20 href=3D"http://ar.iiarjournals.org/content/29/2/731.full#ref-33">33).= Thereby=20 the high VEGF levels detected within the intracranial metastasis group = might=20 reflect the high tumour load of these patients. Moreover, a limited = permeability=20 of the blood-brain barrier as well as rapid intracerebral degradation at = the=20 site of secretion might additionally contribute to the relatively low = VEGF=20 concentrations in the plasma derived from GBM patients.

A correlation of VEGF and PDGF-BB expression levels was = demonstrated=20 in distinct tumours, which led to the hypothesis that PDGF-BB represents = one of=20 the key mediators in angiogenesis (34).= =20 Secretion of VEGF in angiogenic and metastatic procedures may be an = indirect=20 effect of PDGF-BB stimulation (35).= =20 Therefore, the absence of a significant correlation between the plasma = levels of=20 VEGF and PDGF-BB in our study population was surprising. On the one = hand, this=20 might be due to autocrine stimulatory effects on the mRNA, which has = been=20 observed for VEGF and PDGF-BB, as well as for Ang-2 and VEGF (36-<= A=20 class=3Dxref-bibr id=3Dxref-ref-38-1=20 href=3D"http://ar.iiarjournals.org/content/29/2/731.full#ref-38">38).= On the=20 other hand, in analogy to the observation concerning the difference = between=20 Ang-2 expression and plasma detectability, this finding might be due to=20 additional factors influencing the release of PDGF-BB from tumour tissue = into=20 the circulation.

Malignant brain tumours have a poor prognosis, which is in = part due=20 to delayed diagnosis but also due to their aggressive growth potential = with=20 limited therapeutic options. Plasminogen activator inhibitor (PAI-1) (39),= glial=20 fibrillary acidic protein (40),= low=20 molecular weight caldesman (41),= =20 cathepsin D (42) = and=20 others were suggested to represent potential plasma markers for brain = tumour=20 diagnosis and surveillance. With respect to the importance of vascular = growth=20 factors in tumour biology with potential implications on new therapeutic = options, these data on plasma levels of angiopoietic factors might form = the=20 basis to extend the diagnostic armamentarium in neuro-oncology. In this = context,=20 the recently reported success of VEGF-targeted therapies in GBM = treatment seems=20 of specific interest (43).= Although=20 no data are available for the potential application of this treatment = modality=20 for brain metastasis, the high plasma levels of angiopoietic factors = found in=20 our patients with multiple brain metastases suggests the applicability = of VEGF=20 blockade-based therapeutic regimes for this selected patient group. The = success=20 of therapeutic strategies involving the inhibition of growth factor = pathways=20 strongly depends on the identification of susceptible patients. = Therefore, the=20 identification of plasma-detectable vascular growth factors in the = course of=20 brain tumours might be not only of diagnostic, but also of prognostic = and=20 therapeutic relevance.

Pre= vious=20 Section Next=20 Section

Footnotes

- Received September = 15, 2008.=20
- Revision received = December 6,=20 2008.
- Accepted December = 15, 2008.=20
Copyright=C2=A9 2009=20 International Institute of Anticaner Research (Dr. John G. = Delinassios), All=20 rights reserved

Previous=20 Section

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child:=0A= var hasSelected =3D false;=0A= var mostHdrList =3D null;=0A= if ($mostlist.length) {=0A= var hasItems =3D false;=0A= var hdrList =3D '
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';=0A= }=0A= else {=0A= hdrList +=3D '
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';=0A= }=0A= }=0A= );=0A= }=0A= hdrList +=3D '
';=0A= if (hasItems) {=0A= var header =3D $this.find("div.most-header h3");=0A= if (header.length) {=0A= header.after(hdrList);=0A= }=0A= }=0A= mostHdrList =3D $this.find("div.most-header ul");=0A= }=0A= // 3) if none of the items are selected, make the first one be=0A= if (((mostHdrList !=3D null) && mostHdrList.length) && = (!hasSelected)) {=0A= modClass(mostHdrList.find("li:first"), "most-cur-sel", "");=0A= modClass($this.children("ul").children("li:first"), "most-cur-sel", = "");=0A= }=0A= // 4) bind a handler to each heading li a to toggle = class=3D"most-cur-sel" for =0A= // that item and its corresponding item in the list below=0A= if (((mostHdrList !=3D null) && mostHdrList.length)) {=0A= mostHdrList.find("li a").click(=0A= function(e) {=0A= var curA =3D $(this);=0A= toggleMostSelection(e, $this, curA.text());=0A= }=0A= );=0A= }=0A= }=0A= );=0A= if (hadMostBoxes) {=0A= fixColHeights(-1);=0A= }=0A= }=0A= =0A= function toggleMostSelection(e, mostItemDiv, groupName) {=0A= if (mostItemDiv.length) {=0A= var hdrItems =3D mostItemDiv.find("div.most-header ul li");=0A= if (hdrItems.length) {=0A= hdrItems.each(=0A= function() {=0A= var hdrName =3D $(this).text();=0A= var isChoice =3D (hdrName =3D=3D groupName);=0A= if (isChoice) {=0A= modClass($(this), 'most-cur-sel', '');=0A= }=0A= else {=0A= modClass($(this), '', 'most-cur-sel');=0A= }=0A= }=0A= );=0A= }=0A= var listItems =3D mostItemDiv.children("ul").find("li");=0A= if (listItems.length) {=0A= listItems.each(=0A= function() {=0A= var itemName =3D $(this).children("h4").text();=0A= var isChoice =3D (itemName =3D=3D groupName);=0A= if (isChoice) {=0A= modClass($(this), 'most-cur-sel', '');=0A= }=0A= else {=0A= modClass($(this), '', 'most-cur-sel');=0A= }=0A= }=0A= );=0A= }=0A= }=0A= fixColHeights(-1);=0A= e.preventDefault();=0A= }=0A= =0A= function toggleCollapse(collapsibleEl, hideTagExpr, modTextTagExpr, = expandStr, contractStr) {=0A= if (typeof(expandStr) =3D=3D "undefined") {=0A= expandStr =3D getSiteOption('expandString','+');=0A= }=0A= if (typeof(contractStr) =3D=3D "undefined") {=0A= contractStr =3D getSiteOption('contractString','-');=0A= }=0A= =0A= var $this =3D collapsibleEl;=0A= if ($this.hasClass('collapsed')) {=0A= modClass($this, 'collapsible', 'collapsed');=0A= }=0A= else if ($this.hasClass('collapsible')) {=0A= modClass($this, 'collapsed', 'collapsible');=0A= }=0A= var $toToggle =3D $this.find(hideTagExpr);=0A= if ($toToggle.length) {=0A= $toToggle.toggle();=0A= }=0A= var $rewrite =3D $this.find(modTextTagExpr);=0A= if ($rewrite.length) {=0A= $rewrite.each(=0A= function(i, e) {=0A= var txt =3D $(e).text();=0A= if (txt =3D=3D expandStr) {=0A= $(e).empty().append(contractStr);=0A= }=0A= else if (txt =3D=3D contractStr) {=0A= $(e).empty().append(expandStr);=0A= }=0A= }=0A= );=0A= }=0A= }=0A= =0A= function setupDockBlock(col, dockId, dockClass, contentRules) {=0A= if ((col =3D=3D 2) || (col =3D=3D 3)) {=0A= var navOrigHeight =3D ((col =3D=3D 2) ? gColOrigHeights.col2 : = gColOrigHeights.col3);=0A= var gColNum =3D col;=0A= var gNav =3D ((col =3D=3D 2) ? gCol2 : gCol3);=0A= var gNavHeight =3D ((gNav.length) ? navOrigHeight : 0);=0A= var gNavTopOffset =3D (gNavHeight > 0 ? gNav.offset().top : 0);=0A= var gScrollPos =3D 0;=0A= var gNavDocked =3D false;=0A= /* this won't work in IE 6, so skip it /=0A= / article navigation docking block /=0A= $(window).scroll(function () {=0A= if (gNavHeight > 0 && !isIE6) {=0A= var offsets =3D getPageOffset();=0A= var origHeight =3D ((gColNum =3D=3D 2) ? gColOrigHeights.col2 : = gColOrigHeights.col3);=0A= var navBottom =3D (gNavTopOffset + origHeight) - offsets.y;=0A= if (gScrollPos !=3D offsets.y) {=0A= gScrollPos =3D offsets.y;=0A= if ((navBottom <=3D 0) && !gNavDocked) {=0A= / dock the nav /=0A= gNavDocked =3D true;=0A= addDockBlock(col, dockId, dockClass, contentRules);=0A= }=0A= else if (gNavDocked && (navBottom > 0)) {=0A= / undock the nav /=0A= gNavDocked =3D false;=0A= removeDockBlock(col, dockId);=0A= }=0A= }=0A= }=0A= });=0A= }=0A= }=0A= function addDockBlock(col, dockId, dockClass, contentRules) {=0A= // get direct children li elements only=0A= var colId =3D ("col-" + col);=0A= var newDiv =3D ' 1) {=0A= for (var i =3D 0; i < (contentRules.length - 1); i =3D i + 2) {=0A= var addTo =3D processDockingRule(contentRules[i]);=0A= var add =3D processDockingRule(contentRules[i + 1]);=0A= var addTarget, addVal;=0A= if (addTo.ruleType =3D=3D 'empty') {=0A= addTarget =3D newDivJQuery;=0A= }=0A= else if (addTo.ruleType =3D=3D 'jQuery') {=0A= addTarget =3D $(addTo.rule);=0A= }=0A= if (add.ruleType =3D 'jQuery') {=0A= var addJQEl =3D $(add.rule);=0A= if (addJQEl.length) {=0A= addVal =3D addJQEl.clone();=0A= }=0A= else {=0A= addVal =3D '';=0A= }=0A= }=0A= else if (add.ruleType =3D 'html') {=0A= addVal =3D add.rule;=0A= }=0A= if (addTarget.length && !(addVal =3D=3D '')) {=0A= addTarget.append(addVal);=0A= }=0A= else {=0A= }=0A= }=0A= }=0A= var newDockJQrule =3D "#" + colId + " #" + dockId;=0A= var newDock =3D $(newDockJQrule);=0A= if (newDock.length) {=0A= prepCollapsibles(newDockJQrule + " div.collapsible, " + newDockJQrule = + " div.collapsed", false);=0A= newDock.fadeIn(250);=0A= }=0A= }=0A= =0A= function processDockingRule(rule) {=0A= var retObj =3D new Object();=0A= retObj.empty =3D (((rule !=3D undefined) && (!(rule =3D=3D ''))) ? = false : true);=0A= if (rule =3D=3D '') {=0A= retObj.ruleType =3D 'empty';=0A= }=0A= else if (/^\$$.+$$/.test(rule)) {=0A= retObj.ruleType =3D 'jQuery';=0A= retObj.rule =3D rule.replace(/^\$$(.+)$$/,"$1");=0A= }=0A= else {=0A= retObj.ruleType =3D 'html';=0A= retObj.rule =3D rule;=0A= }=0A= return retObj;=0A= }=0A= =0A= function removeDockBlock(col, dockId) {=0A= var dockedNav =3D $("div#" + dockId);=0A= if(dockedNav.length) {=0A= dockedNav.fadeOut(250, function() { dockedNav.remove(); });=0A= }=0A= }=0A= =0A= =0A= function updateFormInput(labelMatchString, inputMatchString, = defaultColorString, textColorString) {=0A= if ((defaultColorString =3D=3D null) || (defaultColorString =3D=3D '')) = {=0A= defaultColorString =3D "#A0A0A0";=0A= }=0A= if ((textColorString =3D=3D null) || (textColorString =3D=3D '')) {=0A= textColorString =3D "black";=0A= }=0A= var label =3D $(labelMatchString);=0A= var input =3D $(inputMatchString);=0A= if (input.length) {=0A= if ((label.length) && (input.val() =3D=3D '')) {=0A= input.val(label.text()).css("color",defaultColorString);=0A= }=0A= input.focus(=0A= function(e) {=0A= if ((label.length) && ($(this).val() =3D=3D label.text())) {=0A= $(this).val('').css("color",textColorString);=0A= }=0A= }=0A= );=0A= input.blur(=0A= function(e) {=0A= if ((label.length) && ($(this).val() =3D=3D '')) {=0A= $(this).val(label.text()).css("color",defaultColorString);=0A= }=0A= }=0A= );=0A= }=0A= var parentForm =3D label.parents("form").eq(0);=0A= if (parentForm.length) {=0A= parentForm.submit(=0A= function() {=0A= if ((label.length) && (input.length) && (input.val() =3D=3D = label.text())) {=0A= input.val('');=0A= }=0A= return true;=0A= }=0A= );=0A= }=0A= }=0A= =0A= function checkUnloadedImgs(lookupRule) {=0A= if (lookupRule =3D=3D null) {=0A= lookupRule =3D "img";=0A= }=0A= var imageNum =3D -1;=0A= var images =3D $(lookupRule);=0A= if (images.length) {=0A= imageNum =3D 0;=0A= images.each(=0A= function() {=0A= //if ($(this).height() =3D=3D 0) {=0A= if (this.offsetHeight =3D=3D 0) {=0A= imageNum++;=0A= }=0A= }=0A= );=0A= }=0A= return imageNum;=0A= }=0A= =0A= function fixHeightForImages(iter, numImagesToLoad, lookupRule) {=0A= if (lookupRule =3D=3D null) {=0A= lookupRule =3D "img";=0A= }=0A= if (numImagesToLoad > 0) {=0A= var lastNumImagesToLoad =3D numImagesToLoad;=0A= var newNumImagesToLoad =3D checkUnloadedImgs(lookupRule);=0A= if (newNumImagesToLoad < lastNumImagesToLoad) {=0A= fixColHeights(1);=0A= if ((newNumImagesToLoad > 0) && (iter < 10)) {=0A= setTimeout("fixHeightForImages(" + (iter+1) + "," + = newNumImagesToLoad + ",'" + lookupRule + "')", 1000);=0A= }=0A= }=0A= }=0A= }=0A= function getColInfo(colJQEl) {=0A= var colInfo =3D { valid: false, height: 0, bottom: 0, lastElBottom: 0, = extra: 0, fix: false };=0A= if (colJQEl.length) {=0A= var c =3D colJQEl.children();=0A= if (c.length) {=0A= colInfo.height =3D getObjHeight(colJQEl);=0A= colInfo.bottom =3D colJQEl.offset().top + colInfo.height;=0A= var last =3D c.eq(c.length - 1);=0A= colInfo.lastElBottom =3D last.offset().top + getObjHeight(last);=0A= colInfo.extra =3D colInfo.bottom - colInfo.lastElBottom;=0A= colInfo.valid =3D true;=0A= }=0A= }=0A= return colInfo;=0A= }=0A= function checkColHeights() {=0A= var colToFix =3D 0;=0A= if (gIsMultiCol && ((gColOrigHeights.main + gColOrigHeights.col2 + = gColOrigHeights.col3) > 0)) {=0A= var colMainInfo =3D getColInfo(gColMain);=0A= var col2Info =3D getColInfo(gCol2);=0A= var col3Info =3D getColInfo(gCol3);=0A= if (colMainInfo.valid && (gColLows.main =3D=3D 0)) { gColLows.main =3D = colMainInfo.lastElBottom; }=0A= if (col2Info.valid && (gColLows.col2 =3D=3D 0)) { gColLows.col2 =3D = col2Info.lastElBottom; }=0A= if (col3Info.valid && (gColLows.col3 =3D=3D 0)) { gColLows.col3 =3D = col3Info.lastElBottom; }=0A= // check if low point in any column has changed=0A= if ((colMainInfo.valid) && (colMainInfo.lastElBottom !=3D = gColLows.main)) {=0A= colMainInfo.fix =3D true;=0A= }=0A= if ((col2Info.valid) && (col2Info.lastElBottom !=3D gColLows.col2)) {=0A= col2Info.fix =3D true;=0A= }=0A= if ((col3Info.valid) && (col3Info.lastElBottom !=3D gColLows.col3)) {=0A= col3Info.fix =3D true;=0A= }=0A= // check for columns not having same bottom points=0A= if ((colMainInfo.valid) &&=0A= (((col2Info.valid) && (colMainInfo.height < col2Info.height)) ||=0A= ((col3Info.valid) && (colMainInfo.height < col3Info.height)))) {=0A= colMainInfo.fix =3D true;=0A= }=0A= if ((col2Info.valid) &&=0A= (((colMainInfo.valid) && (col2Info.height < colMainInfo.height)) ||=0A= ((col3Info.valid) && (col2Info.height < col3Info.height)))) {=0A= col2Info.fix =3D true;=0A= }=0A= if ((col3Info.valid) &&=0A= (((colMainInfo.valid) && (col3Info.height < colMainInfo.height)) ||=0A= ((col2Info.valid) && (col3Info.height < col2Info.height)))) {=0A= col3Info.fix =3D true;=0A= }=0A= =0A= if (colToFix > -1) {=0A= if (colMainInfo.valid && colMainInfo.fix) {=0A= if ((col2Info.valid && col2Info.fix) || (col3Info.valid && = col3Info.fix)) {=0A= colToFix =3D -1;=0A= }=0A= else { colToFix =3D 1; }=0A= }=0A= else if (col2Info.valid && col2Info.fix) {=0A= if (col3Info.valid && col3Info.fix) {=0A= colToFix =3D -1;=0A= }=0A= else { colToFix =3D 2; }=0A= }=0A= else if (col3Info.valid && col3Info.fix) {=0A= colToFix =3D 3;=0A= }=0A= }=0A= =0A= if (colToFix !=3D 0) {=0A= fixColHeights(colToFix);=0A= }=0A= if (colMainInfo.valid) { gColLows.main =3D colMainInfo.lastElBottom; }=0A= if (col2Info.valid) { gColLows.col2 =3D col2Info.lastElBottom; }=0A= if (col3Info.valid) { gColLows.col3 =3D col3Info.lastElBottom; }=0A= }=0A= setTimeout("checkColHeights()", 5000);=0A= }=0A= function fixColHeights(colChanged) {=0A= if (gIsMultiCol) {=0A= var setAll =3D false;=0A= if (colChanged =3D=3D 1) {=0A= if (gColMain.length) {=0A= setObjHeight(gColMain,'auto');=0A= gColOrigHeights.main =3D getObjHeight(gColMain);=0A= }=0A= }=0A= else if (colChanged =3D=3D 2) {=0A= if (gCol2.length) {=0A= setObjHeight(gCol2,'auto');=0A= gColOrigHeights.col2 =3D getObjHeight(gCol2);=0A= }=0A= }=0A= else if (colChanged =3D=3D 3) {=0A= if (gCol3.length) {=0A= setObjHeight(gCol3,'auto');=0A= gColOrigHeights.col3 =3D getObjHeight(gCol3);=0A= }=0A= }=0A= else {=0A= if (colChanged =3D=3D -1) {=0A= // force resize all 3=0A= if (gColMain.length) { setObjHeight(gColMain,'auto'); }=0A= if (gCol2.length) { setObjHeight(gCol2,'auto'); }=0A= if (gCol3.length) { setObjHeight(gCol3,'auto'); }=0A= }=0A= gColOrigHeights.main =3D ((gColMain.length) ? = (getObjHeight(gColMain)) : 0);=0A= gColOrigHeights.col2 =3D ((gCol2.length) ? (getObjHeight(gCol2)) : 0);=0A= gColOrigHeights.col3 =3D ((gCol3.length) ? (getObjHeight(gCol3)) : 0);=0A= setAll =3D true;=0A= }=0A= if ((gColOrigHeights.main + gColOrigHeights.col2 + = gColOrigHeights.col3) > 0) {=0A= var colInfo;=0A= var maxH =3D Math.max(Math.max(gColOrigHeights.main, = gColOrigHeights.col2), gColOrigHeights.col3);=0A= if ((gColMain.length) && ((gColOrigHeights.main < maxH) || = (getObjHeight(gColMain) > maxH) || setAll)) {=0A= setObjHeight(gColMain, maxH);=0A= colInfo =3D getColInfo(gColMain);=0A= if (colInfo.valid) { gColLows.main =3D colInfo.lastElBottom; }=0A= }=0A= if ((gCol2.length) && ((gColOrigHeights.col2 < maxH) || = (getObjHeight(gCol2) > maxH) || setAll)) {=0A= setObjHeight(gCol2, maxH);=0A= colInfo =3D getColInfo(gCol2);=0A= if (colInfo.valid) { gColLows.col2 =3D colInfo.lastElBottom; }=0A= }=0A= if ((gCol3.length) && ((gColOrigHeights.col3 < maxH) || = (getObjHeight(gCol3) > maxH) || setAll)) {=0A= setObjHeight(gCol3, maxH);=0A= colInfo =3D getColInfo(gCol3);=0A= if (colInfo.valid) { gColLows.col3 =3D colInfo.lastElBottom; }=0A= }=0A= }=0A= }=0A= }=0A= =0A= function getObjHeight(obj) {=0A= if (obj instanceof jQuery) {=0A= return obj.get(0).offsetHeight;=0A= }=0A= else if (obj instanceof Array) {=0A= return obj[0].offsetHeight;=0A= }=0A= else {=0A= return obj.offsetHeight;=0A= }=0A= }=0A= function getObjWidth(obj) {=0A= if (obj instanceof jQuery) {=0A= return obj.get(0).offsetWidth;=0A= }=0A= else if (obj instanceof Array) {=0A= return obj[0].offsetWidth;=0A= }=0A= else {=0A= return obj.offsetWidth;=0A= }=0A= }=0A= function setObjHeight(obj, h) {=0A= if (typeof(h) =3D=3D 'number') {=0A= h =3D "" + h + "px";=0A= }=0A= if (obj instanceof jQuery) {=0A= obj.get(0).style.height =3D h;=0A= }=0A= else if (obj instanceof Array) {=0A= obj[0].style.height =3D h;=0A= }=0A= else {=0A= obj.style.height =3D h;=0A= }=0A= }=0A= function setObjWidth(obj, w) {=0A= if (typeof(w) =3D=3D 'number') {=0A= w =3D "" + w + "px";=0A= }=0A= if (obj instanceof jQuery) {=0A= obj.get(0).style.width =3D w;=0A= }=0A= else if (obj instanceof Array) {=0A= obj[0].style.width =3D w;=0A= }=0A= else {=0A= obj.style.width =3D w;=0A= }=0A= }=0A= =0A= / num pixels top of page has been scrolled offscreen /=0A= function getPageOffset() {=0A= var offset =3D new Object();=0A= if( typeof( window.pageXOffset ) =3D=3D 'number' ) {=0A= offset.x =3D window.pageXOffset;=0A= offset.y =3D window.pageYOffset;=0A= } else if( document.body && ( document.body.scrollTop ) ) {=0A= offset.x =3D document.body.scrollLeft;=0A= offset.y =3D document.body.scrollTop;=0A= } else if( document.documentElement && ( = document.documentElement.scrollTop ) ) {=0A= offset.x =3D document.documentElement.scrollLeft;=0A= offset.y =3D document.documentElement.scrollTop;=0A= }=0A= return offset;=0A= }=0A= function getViewportDim() {=0A= var dim =3D new Object();=0A= // non-IE=0A= if (typeof window.innerWidth !=3D 'undefined') {=0A= dim.x =3D window.innerWidth;=0A= dim.y =3D window.innerHeight;=0A= }=0A= // IE6 in standards compliant mode=0A= else if (typeof document.documentElement !=3D 'undefined'=0A= && typeof document.documentElement.clientWidth !=3D=0A= 'undefined' && document.documentElement.clientWidth !=3D 0) {=0A= dim.x =3D document.documentElement.clientWidth;=0A= dim.y =3D document.documentElement.clientHeight;=0A= }=0A= // older versions of IE=0A= else {=0A= dim.x =3D document.getElementsByTagName('body')[0].clientWidth;=0A= dim.y =3D document.getElementsByTagName('body')[0].clientHeight;=0A= }=0A= return dim;=0A= }=0A= =0A= function newWindowTargets() {=0A= var newWins =3D $("a.in-nw");=0A= if (newWins.length) {=0A= newWins.each(=0A= function() {=0A= var $this =3D $(this);=0A= $this.attr("target", "_blank");=0A= modClass($this, 'in-nw-vis', 'in-nw');=0A= }=0A= );=0A= }=0A= }=0A= =0A= function getSiteOption(optionName, defaultVal) {=0A= if (typeof(defaultVal) =3D=3D "undefined") {=0A= defaultVal =3D gSiteOptionUnknown;=0A= }=0A= if (gSiteOptions =3D=3D undefined) {=0A= return defaultVal;=0A= }=0A= else if (gSiteOptions[optionName] =3D=3D undefined) {=0A= return defaultVal;=0A= }=0A= else {=0A= return gSiteOptions[optionName];=0A= }=0A= }=0A= =0A= function addPartHeaders(req) {=0A= req.setRequestHeader('Accept', 'application/xhtml+xml');=0A= req.setRequestHeader('Range', 'part=3Dvariant-contents');=0A= }=0A= function addCommonHeaders(req) {=0A= if (typeof(callbackToken) !=3D 'undefined') {=0A= req.setRequestHeader('X-Token', callbackToken);=0A= }=0A= }=0A= function allowsCookies() {=0A= if (hasTestCookie()) {=0A= return true;=0A= }=0A= else {=0A= setTestCookie();=0A= return hasTestCookie();=0A= }=0A= }=0A= function setTestCookie() {=0A= setCookie('cks','allowed',7,'/',null,null);=0A= }=0A= function hasTestCookie() {=0A= var ckVal =3D getCookie('cks');=0A= if ((ckVal !=3D null) && (ckVal =3D=3D 'allowed')) {=0A= return true;=0A= }=0A= else {=0A= return false;=0A= }=0A= }=0A= =0A= var UIPrefsCk=3D{=0A= name: "UIPrefs",=0A= expDays: 3652,=0A= path: '/'=0A= };=0A= =0A= function prefDefined(name) {=0A= var val =3D getPrefValue(name);=0A= if (val =3D=3D null) {=0A= return false;=0A= }=0A= else {=0A= return true;=0A= }=0A= }=0A= function getPrefValue(name) {=0A= var prefArray =3D getPrefArray();=0A= if (prefArray) {=0A= name =3D convertPrefString(name);=0A= var match =3D name + ":";=0A= for (var i =3D 0; i < prefArray.length; i++) {=0A= if (prefArray[i].indexOf(match) =3D=3D 0) {=0A= return prefArray[i].substring(match.length);=0A= }=0A= else if (prefArray[i] =3D=3D name) {=0A= // name only, no value, return boolean true=0A= return true;=0A= }=0A= }=0A= }=0A= return null;=0A= }=0A= function convertPrefString(str) {=0A= if (str) {=0A= return str.replace(/[,:=3D]/g,"");=0A= }=0A= return str;=0A= }=0A= function removePref(name) {=0A= var prefArray =3D getPrefArray();=0A= name =3D convertPrefString(name);=0A= if (prefDefined(name)) {=0A= var newArray =3D new Array(prefArray.length - 1);=0A= var match =3D name + ":";=0A= var newArrIndex =3D 0;=0A= for (var i =3D 0; i 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' + expandStr + 'Author Affiliations
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i < args.length; i++) {=0A= if (args[i].toLowerCase().indexOf('legid=3D') =3D=3D 0) {=0A= id =3D args[i].substring(args[i].indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/related-web-pages/' + id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addRelatedURLs,=0A= complete: ajaxComplete=0A= });=0A= =0A= }=0A= }=0A= }=0A= }=0A= function getPatientInformData() {=0A= var pInformA =3D $("#cb-patientinform");=0A= if (pInformA.length) {=0A= var newA =3D 'Loading = patientINFORMation...';=0A= pInformA.replaceWith(newA);=0A= var href =3D pInformA.attr("href");=0A= var id =3D '';=0A= if (href && (href.indexOf('?') > 0)) {=0A= var args =3D href.substring(href.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= if (args[i].toLowerCase().indexOf('legid=3D') =3D=3D 0) {=0A= id =3D args[i].substring(args[i].indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/related-web-pages/patientinform/' + = id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addPatientInform,=0A= complete: ajaxComplete=0A= });=0A= =0A= }=0A= }=0A= }=0A= }=0A= function getISIRelated() {=0A= var relatedA =3D $("#cb-isi-similar-articles");=0A= if (relatedA.length) {=0A= var newA =3D 'Loading ISI = article data...';=0A= relatedA.replaceWith(newA);=0A= var href =3D relatedA.attr("href");=0A= var id =3D '';=0A= if (href) {=0A= var hrefDec =3D decodeURI(href);=0A= if ((hrefDec.indexOf('?') > 0)) {=0A= var args =3D hrefDec.substring(hrefDec.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= var argDec =3D decodeURIComponent(args[i]);=0A= if (argDec.toLowerCase().indexOf('access_num=3D') =3D=3D 0) {=0A= id =3D argDec.substring(argDec.indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/isi-links/has-related/' + = id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addISIRelated,=0A= complete: ajaxComplete=0A= });=0A= }=0A= }=0A= }=0A= }=0A= }=0A= function getISICiting() {=0A= var citingA =3D $("#cb-isi-citing-articles");=0A= if (citingA.length) {=0A= var newA =3D 'Loading ISI = citing article data...';=0A= citingA.replaceWith(newA);=0A= var href =3D citingA.attr("href");=0A= var id =3D '';=0A= if (href) {=0A= var hrefDec =3D decodeURI(href);=0A= if ((hrefDec.indexOf('?') > 0)) {=0A= var args =3D hrefDec.substring(hrefDec.indexOf('?') + 1).split('&');=0A= for (var i =3D 0; i < args.length; i++) {=0A= var argDec =3D decodeURIComponent(args[i]);=0A= if (argDec.toLowerCase().indexOf('access_num=3D') =3D=3D 0) {=0A= id =3D argDec.substring(argDec.indexOf('=3D') + 1);=0A= if (id.indexOf('#') > 0) {=0A= id =3D id.substring(0, id.indexOf('#'));=0A= }=0A= }=0A= }=0A= if (!(id =3D=3D '')) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + '/isi-links/' + id.replace(/;/,'/');=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addISICiting,=0A= complete: ajaxComplete=0A= });=0A= }=0A= }=0A= }=0A= }=0A= }=0A= function getEntrezLinks() {=0A= var entrezDiv =3D $("#cb-entrez-links-placeholder");=0A= if (entrezDiv.length) {=0A= var entrezA =3D entrezDiv.children("a");=0A= if (entrezA) {=0A= var host =3D document.location.protocol + "//" + = document.location.host;=0A= var ajaxUrl =3D host + entrezA.attr("href");=0A= $.ajax({=0A= url: ajaxUrl,=0A= dataType: "html",=0A= type: "GET",=0A= error: ajaxErr,=0A= success: addEntrezLinks,=0A= complete: ajaxComplete=0A= });=0A= }=0A= }=0A= }=0A= =0A= function ajaxErr(req, msg, e) {=0A= }=0A= function ajaxComplete(req, msg) {=0A= }=0A= function updateCBItem(cbItem, newHTML, hasData) {=0A= var parentItem =3D cbItem.parents("li").eq(0);=0A= cbItem.replaceWith(newHTML);=0A= if (!hasData) {=0A= // hide the parent li=0A= if (parentItem.length) {=0A= modClass(parentItem,"nodata","");=0A= // check if there are any siblings still being displayed=0A= var otherItems =3D parentItem.siblings();=0A= var allItemsEmpty;=0A= if (otherItems.length) {=0A= if (otherItems.length =3D=3D otherItems.filter(".nodata").length) {=0A= allItemsEmpty =3D true=0A= }=0A= else {=0A= allItemsEmpty =3D false;=0A= }=0A= }=0A= else {=0A= allItemsEmpty =3D true;=0A= }=0A= if (allItemsEmpty) {=0A= var cbsection =3D parentItem.parents("div.cb-section").eq(0);=0A= if (cbsection.length) {=0A= modClass(cbsection,"nodata","");=0A= }=0A= }=0A= }=0A= }=0A= // in frameset fix targets on child links, forms=0A= fixFrameLinks(parentItem.find("a,form"));=0A= fixColHeights(2);=0A= }=0A= function fixFrameLinks(jqItems) {=0A= if ((gIsFrameset !=3D null) && gIsFrameset) {=0A= jqItems.each(=0A= function(i) {=0A= var href =3D $(this).attr("href");=0A= var inFrameAnchor =3D ((href !=3D null) && = ((/frameset=3D/.test(href)) && (/#/.test(href))) || (href.substring(0,1) = =3D=3D '#'));=0A= if (!inFrameAnchor) {=0A= $(this).attr("target", "_top");=0A= }=0A= }=0A= );=0A= }=0A= }=0A= function addRelatedURLs(xhtmlData) {=0A= var cbA =3D $("#cb-loading-related-urls");=0A= if (gIsFrameset) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
Not = available in this view
', false);=0A= }=0A= }=0A= else if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= $("#related-urls").replaceWith(xhtmlData);=0A= fixColHeights(1);=0A= if (cbA.length) {=0A= updateCBItem(cbA, 'Related Web Pages', = true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
No related = web pages
', false);=0A= }=0A= }=0A= }=0A= function addPatientInform(xhtmlData) {=0A= var cbA =3D $("#cb-loading-patientinform");=0A= if (gIsFrameset) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
Not = available in this view
', false);=0A= }=0A= }=0A= else if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= $("#patientinform-links").replaceWith(xhtmlData);=0A= fixColHeights(1);=0A= if (cbA.length) {=0A= updateCBItem(cbA, 'patientINFORMation', true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
No = patientINFORMation available for this article
', false);=0A= }=0A= }=0A= }=0A= function addHWCiting(xhtmlData) {=0A= var cbA =3D $("#cb-loading-hw-cited");=0A= if (gIsFrameset) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
Not available = in this view
', false);=0A= }=0A= }=0A= else if (xhtmlData) {=0A= $("#content-block").append(xhtmlData);=0A= fixColHeights(1);=0A= if (cbA.length) {=0A= updateCBItem(cbA, 'View citing article = information', true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
No citing = articles
', false);=0A= }=0A= }=0A= }=0A= function addISIRelated(xhtmlData) {=0A= var cbA =3D $("#cb-isi-similar-articles");=0A= if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, xhtmlData, true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
No ISI = related articles
', false);=0A= }=0A= }=0A= }=0A= function addISICiting(xhtmlData) {=0A= var cbA =3D $("#cb-loading-isi-cited");=0A= if (xhtmlData && !(xhtmlData.indexOf('=3D 0)) {=0A= if (cbA.length) {=0A= updateCBItem(cbA, xhtmlData, true);=0A= }=0A= }=0A= else {=0A= if (cbA.length) {=0A= updateCBItem(cbA, '
No ISI citing = articles
', false);=0A= }=0A= }=0A= }=0A= function addEntrezLinks(xhtmlData) {=0A= var entrezDiv =3D $("#cb-entrez-links-placeholder");=0A= if (xhtmlData) {=0A= entrezDiv.empty().append(xhtmlData);=0A= fixFrameLinks(entrezDiv.find("a,form"));=0A= fixColHeights(2);=0A= }=0A= }=0A= function addDockedNav() {=0A= var slugEl =3D $("#slugline");=0A= // get direct children li elements only=0A= var artViews =3D $("#article-cb-main .cb-section ol:has(li = a[rel^=3D'view-']) > li").clone();=0A= var newDiv =3D '
';=0A= $("#col-2").append(newDiv);=0A= $("#col-2 #docked-nav").hide();=0A= var newDivJQuery =3D $("#docked-nav");=0A= newDivJQuery.append('
This Article
');=0A= $("#col-2 #docked-nav-views").append(artViews); /.append(artSupp);/=0A= $("#col-2 #docked-nav #docked-slug li").append(slugEl.clone());=0A= newDivJQuery.append($("#article-dyn-nav").clone());=0A= $("#col-2 #docked-nav").fadeIn(250);=0A= }=0A= =0A= =0A= function removeDockedNav() {=0A= var dockedNav =3D $("div#docked-nav");=0A= if(dockedNav.length) {=0A= dockedNav.fadeOut(250, function() { dockedNav.remove(); });=0A= }=0A= }=0A= ------=_NextPart_000_0000_01C9CF40.DB6CB180 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://ar.iiarjournals.org/shared/js/util/hw-col-expand.js var gViewportW =3D 0;=0A= var gDockedBoxLeft =3D 515;=0A= var gDockedBoxNoColsLeft =3D 950;=0A= var gColExpandDocked =3D false;=0A= var gHeaderScrollPos =3D 0;=0A= =0A= $(document).ready(function() {=0A= var isIE6 =3D ($.browser.msie && ($.browser.version.substr(0,2) =3D=3D = '6.'));=0A= =0A= $("div#content-block").prepend('
Expand+<\/span><\/a><\/li><\/ul><\/div>');=0A= =0A= if (isIE6) {=0A= $("div#content-option-box li#content-toggle = a").css("display","inline");=0A= }=0A= =0A= $("div#content-option-box li#content-toggle a").click(=0A= function(e) {=0A= var pageDiv =3D $("div.hw-gen-page");=0A= if (pageDiv.length) {=0A= var optionbox =3D $("div#content-option-box");=0A= var colsHidden =3D pageDiv.hasClass("hide-cols");=0A= if (colsHidden) {=0A= // show all columns=0A= modClass(pageDiv,'','hide-cols');=0A= modClass($(this),'','expanded');=0A= $("div#cols-min").remove();=0A= gIsMultiCol =3D true;=0A= if (optionbox.length) {=0A= optionbox.attr("title","Expand this column");=0A= optionbox.find("span.descr").text("Expand");=0A= }=0A= checkDockedColExpandLoc(true, 0);=0A= fixColHeights(-1);=0A= }=0A= else {=0A= // hide sidebar columns=0A= gIsMultiCol =3D false;=0A= modClass(pageDiv,'hide-cols','');=0A= modClass($(this),'expanded','');=0A= if (optionbox.length) {=0A= optionbox.attr("title","Show all columns");=0A= optionbox.find("span.descr").text("Minimize");=0A= }=0A= checkDockedColExpandLoc(true, 0);=0A= var colDivs =3D '
';=0A= for (var i=3D3; i>=3D2; i--) {=0A= var col =3D $("div#col-" + i);=0A= if (col.length) {=0A= colDivs =3D colDivs + '
<\/span><\/div>';=0A= }=0A= }=0A= colDivs =3D colDivs + '<\/div>';=0A= $("div#content-block").before(colDivs);=0A= var mincol, mincolspan;=0A= for (var j =3D 2; j <=3D 3; j++) {=0A= mincol =3D $("div#col-" + j + "-min");=0A= mincolspan =3D $("div#col-" + j + "-min span.view-more");=0A= if (mincol.length && mincolspan.length) {=0A= =0A= // call publisher cleanup function=0A= if (typeof localColMinF =3D=3D 'function') {=0A= localColMinF(mincol, j);=0A= }=0A= var x =3D j;=0A= //var colid =3D "col-" + x;=0A= mincolspan.hover(=0A= function() {=0A= var parentid =3D $(this).parent().attr("id");=0A= //var closebox =3D "
x
";=0A= if (parentid !=3D null) {=0A= var colstr =3D "div#" + = parentid.substring(0,parentid.indexOf('-min'));=0A= var col =3D $(colstr);=0A= if (col.length) {=0A= //col.prepend(closebox);=0A= var header =3D $("#header");=0A= var headerHeight =3D (header.length ? getObjHeight(header) : = 0);=0A= col.css("top", '' + headerHeight + "px");=0A= modClass(col,"palette","");=0A= col.css("height","auto");=0A= /=0A= $("#col-hover-close a").click(=0A= function(e) {=0A= var ancestors =3D $(this).parents();=0A= modClass(ancestors.eq(1), "", "palette");=0A= $("#col-hover-close").remove();=0A= e.preventDefault();=0A= }=0A= );=0A= /=0A= col.hover(=0A= function() {},=0A= function() {=0A= modClass($(this),"","palette");=0A= //$("#col-hover-close").remove();=0A= $(this).css("top",'');=0A= =0A= }=0A= );=0A= }=0A= }=0A= },=0A= function() {}=0A= );=0A= }=0A= else {=0A= }=0A= }=0A= }=0A= }=0A= e.preventDefault();=0A= }=0A= );=0A= =0A= / article navigation docking block /=0A= / this won't work in IE 6, so skip it /=0A= if (!isIE6) {=0A= gViewportW =3D getViewportDim().x;=0A= checkDockedColExpandLoc(true, 2000);=0A= checkColExpandDocking();=0A= $(window).scroll(function() { checkColExpandDocking(); });=0A= }=0A= =0A= });=0A= =0A= function checkColExpandDocking() {=0A= var header =3D $("#header");=0A= var headerTopOffset =3D (header.length ? header.offset().top : 0);=0A= var headerHeight =3D (header.length ? getObjHeight(header) : 0);=0A= if (headerHeight > 0) {=0A= var offsets =3D getPageOffset();=0A= var headerBottom =3D (headerTopOffset + headerHeight) - offsets.y + 50;=0A= if (gHeaderScrollPos !=3D offsets.y) {=0A= gHeaderScrollPos =3D offsets.y;=0A= if ((headerBottom <=3D 0) && !gColExpandDocked) {=0A= / dock the col expand button /=0A= gColExpandDocked =3D true;=0A= addDockedColExpand();=0A= checkDockedColExpandLoc(true, 0);=0A= }=0A= else if (gColExpandDocked && (headerBottom > 0)) {=0A= / undock the col expand button */=0A= gColExpandDocked =3D false;=0A= removeDockedColExpand();=0A= }=0A= }=0A= }=0A= }=0A= function addDockedColExpand() {=0A= var optionbox =3D $("div#content-option-box");=0A= if (optionbox.length) {=0A= optionbox.hide().addClass('option-box-docked').fadeIn(250);=0A= }=0A= }=0A= function checkDockedColExpandLoc(forceLocate, timerLen) {=0A= if (gColExpandDocked) {=0A= var newViewportW =3D getViewportDim().x;=0A= if (forceLocate || (newViewportW !=3D gViewportW)) {=0A= var dockedExpand =3D $("div#content-option-box");=0A= if (dockedExpand.length) {=0A= var newLeft =3D $("#content-block").offset().left +=0A= (gIsMultiCol ? gDockedBoxLeft : gDockedBoxNoColsLeft);=0A= if ((newViewportW - 50) < newLeft) {=0A= newLeft =3D (newViewportW - 50);=0A= }=0A= dockedExpand.css("left", ('' + newLeft + 'px'));=0A= }=0A= gViewportW =3D newViewportW;=0A= }=0A= }=0A= if (timerLen && (timerLen > 0)) {=0A= checkColExpandDocking();=0A= setTimeout("checkDockedColExpandLoc("+ forceLocate + "," + timerLen + = ")", timerLen);=0A= }=0A= }=0A= =0A= function removeDockedColExpand() {=0A= var optionbox =3D $("div#content-option-box");=0A= if (optionbox.length) {=0A= optionbox.removeClass('option-box-docked');=0A= }=0A= }=0A= ------=_NextPart_000_0000_01C9CF40.DB6CB180--