From: "Saved by Windows Internet Explorer 8" Subject: Questioning the 'neuroprotective' hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia? -- Moncrieff 198 (2): 85 -- The British Journal of Psychiatry Date: Fri, 18 Feb 2011 16:49:32 -0000 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CBCF8B.D123F6F0" X-MimeOLE: Produced By Microsoft MimeOLE V6.0.6002.18263 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CBCF8B.D123F6F0 Content-Type: text/html; charset="Windows-1252" Content-Transfer-Encoding: quoted-printable Content-Location: http://bjp.rcpsych.org/cgi/content/full/198/2/85 Questioning the 'neuroprotective' hypothesis: does = drug treatment prevent brain damage in early psychosis or schizophrenia? = -- Moncrieff 198 (2): 85 -- The British Journal of Psychiatry
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The British Journal of = Psychiatry=20 (2011) 198: 85-87. doi: 10.1192/bjp.bp.110.085795
=A9 2011 The Royal College of=20 Psychiatrists
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Editorials

Questioning the =91neuroprotective=92 hypothesis: does drug = treatment prevent=20 brain damage in early psychosis or=20 schizophrenia?

Joanna Moncrieff, MRBS, MSc, MD, = MRCPsych

Department of Mental Health Sciences, University = College=20 London, 67=9673 Riding House Street, London W1W 7EJ, UK. Email: j.moncrieff{at}ucl.ac.uk

Declaration of interest =

J.M. is the co-chair person of the = Critical=20 Psychiatry Network.


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ABSTRACT
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
3D"Neuropathological findings
3D"Duration of untreated psychosis
3D"Evidence on neuroprotection
3D"Conclusions
3D"REFERENCES
 
The = idea=20 that psychotic disorders are characterised by progressive=20 neurodegeneration that can be reversed by drug treatment is=20 used to justify early treatment of increasing numbers of = mostly=20 young people. I argue that there is little evidence to = support=20 the view that old- or new-generation antipsychotics are=20 =91neuroprotective=92, and some evidence that the drugs = themselves may be=20 responsible for the decline in brain matter observed in some=20 studies.


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INTRODUCTION
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
3D"Neuropathological findings
3D"Duration of untreated psychosis
3D"Evidence on neuroprotection
3D"Conclusions
3D"REFERENCES
 
Joanna Moncrieff (pictured) is a senior lecturer at=20 University College London and a consultant psychiatrist at = the=20 North East London Foundation Trust.

Almost 7 million prescriptions for antipsychotic drugs were = issued=20 outside hospital in England in 2008, an increase of 48% since = 1998.1 Data=20 from the USA also indicate dramatically increased rates of=20 prescription of antipsychotics to young people over recent=20 years.2 Ideas=20 about the benefits of early drug treatment in psychosis, = along with=20 other factors such as the marketing of bipolar = disorder,3 are=20 likely to have contributed to the increasing prescription of = these=20 drugs.

The importance of starting drug treatment early, and of = continuing=20 treatment in people who would like to stop, is often = justified=20 by the prevalent belief that schizophrenia or psychosis = involves=20 a progressive loss of brain tissue that can be arrested or=20 reduced by treatment with antipsychotic drugs.4=20 Accordingly, the drugs are sometimes referred to as having=20 =91neuroprotecive=92 properties. This belief is founded on a = variety of=20 evidence, all of which is debatable and open to other=20 interpretations.


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Brain imaging research
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
3D"Neuropathological findings
3D"Duration of untreated psychosis
3D"Evidence on neuroprotection
3D"Conclusions
3D"REFERENCES
 
The = main=20 area believed to support the =91neuroprotection=92 hypothesis = is brain=20 imaging research illustrating that people with schizophrenia = or=20 psychosis show a progressive reduction in brain volume and an = enlargement of ventricles and cerebral spinal fluid. All such = studies, however, involve people who have taken long-term=20 antipsychotic medication. A large study showing greater = decline in=20 brain volume in patients with first-episode psychosis taking=20 haloperidol compared with olanzapine has been interpreted as=20 indicating the neuroprotective effects of olanzapine.5 The=20 authors acknowledged, however, that the study might also be=20 interpreted as demonstrating differential drug-induced changes.=20 Supporting the latter interpretation, a study of macaque = monkeys=20 treated with therapeutic doses of olanzapine and haloperidol=20 for 18 months found an 8% reduction in mean fresh brain = weight=20 in monkeys treated with haloperidol and 11% in those on = olanzapine=20 compared with non-drug-treated controls.6=20

The great majority of studies of individuals who are drug-naive = or=20 have received only minimal treatment, do not show the global = deficit=20 in brain volume commonly associated with patients who have = received=20 drug treatment, including, most importantly, the only three = studies=20 involving people with long-term conditions who had not been = exposed=20 to drug treatment.7 Results=20 from two studies of people considered to be at high risk of=20 psychosis are also believed to demonstrate progressive brain = tissue=20 loss prior to and in the early stages of psychotic illness. = Many=20 of the Australian cohort, however, were taking antipsychotic=20 medication during some of the follow-up period.8 In the=20 Edinburgh study, high-risk individuals who progressed to = psychosis=20 showed greater temporal lobe reduction than those who did not = progress, but did not differ from controls.9=20 Overall, therefore, imaging studies provide little evidence = of=20 progressive brain tissue loss in non-drug-treated patients = with=20 schizophrenia. Moreover, the effects of drug treatment have = not been=20 excluded as a cause of the tissue loss seen in some studies = of=20 drug-treated patients.7=20


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Neuropathological findings
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
Neuropathological findings
3D"Duration of untreated psychosis
3D"Evidence on neuroprotection
3D"Conclusions
3D"REFERENCES
 
Post-mor= tem=20 studies have generally not found the large-scale neuronal = loss and=20 gliosis characteristic of neurodegenerative disorders in the = brains=20 of people with schizophrenia, although there is some evidence = of=20 local reduction of neuronal sub-populations and local loss of = dendritic spines and length.10=20 Again, however, all studies have involved people on long-term = medication. Some studies with drug-naive patients have found = reduced=20 serum levels of brain derived neurotrophic factor = (BDNF),11 but=20 this finding is not specific to schizophrenia, and BDNF has = also been=20 found to be involved in mood disorders and the stress = response.=20 Although schizophrenia has been suggested to involve = increased or=20 abnormal apoptosis, several studies confirm that markers of=20 apoptosis in neurodegenerative disorders such as = Alzheimer=92s=20 disease are not raised in post-mortem tissue from patients = with=20 chronic schizophrenia, and the role of apoptosis earlier on = in the=20 condition remains speculative.12=20


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Duration of untreated psychosis
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
3D"Neuropathological findings
3D"Duration=20 of untreated psychosis
3D"Evidence on neuroprotection
3D"Conclusions
3D"REFERENCES
 
Another = frequently cited, indirect strand of evidence for the = hypothesis that=20 schizophrenia arises from progressive brain pathology that = can be=20 arrested by drug treatment is the association found in some = studies=20 (although not all) between the duration of untreated = psychosis and=20 outcome. However, it has long been recognised that conditions = with a=20 long and insidious early course are frequently more severe = than those=20 with a sudden onset. Duration of untreated psychosis is = strongly=20 related to mode of onset13 and=20 other characteristics of the psychosis itself,14=20 which makes it likely that it is simply a proxy measure of a=20 more severe underlying condition. Research on duration of=20 untreated psychosis and outcome has not adequately controlled = for=20 mode of onset and other potential confounding factors.15=20

Trials of early intervention have shown some positive results, = but=20 have not analysed the role of medication over and above other = aspects=20 of the intervention, and long-term results are disappointing=20 (reviewed in Bosanac et al).15 Two=20 trials of drug treatment for young people at high risk of = psychosis=20 suggested that the rate of conversion to psychosis was = reduced,=20 although not by a statistically significant degree in the = larger=20 of the two trials.16 A=20 larger naturalistic study has so far found that drug = treatment has=20 not reduced the onset of psychosis.17=20


3Darrow=20
Evidence on neuroprotection
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
3D"Neuropathological findings
3D"Duration of untreated psychosis
3D"Evidence=20 on neuroprotection
3D"Conclusions
3D"REFERENCES
 
At a=20 neuropathological level, ideas about drug treatment being=20 neuroprotective developed because of evidence that some = psychiatric=20 drugs, notably lithium, increase activity in some pathways=20 associated with neurotrophism and neurogenesis.18 The=20 functional implications of these findings are unclear, = however. One=20 study, for example, found that although lithium reduced = levels=20 of kainate-induced excitotoxic motor neuron cell death,=20 surviving cells were not undamaged.19 In=20 any case, evidence of antipsychotics has not consistently=20 demonstrated these sorts of effects.18=20 The view that new atypical antipsychotics have a particular=20 neuroprotective effect may derive from an animal study of = olanzapine=20 and clozapine that detected upregulation of the = neuroprotective=20 Bcl-2 (B-cell lymphoma 2) protein.20=20 However, Bcl-2 is also upregulated in neurodegenerative = disorders=20 such as Alzheimer=92s disease, where it is regarded as = evidence of a=20 compensatory mechanism. Other studies have not replicated = this=20 finding, but one study found increased activity of the=20 pro-apoptotic protease capase-3 in animals treated with old = and new=20 antipsychotics.21=20

Effects of antipsychotics, particularly atypicals, on cognitive=20 function is also cited as evidence of their neuroprotective=20 effects, but whether or not any antipsychotics improve = cognition=20 independently of symptoms remains uncertain. The suggested=20 superior effects of atypical antipsychotics have also been=20 questioned by the findings of the Clinical Antipsychotic = Trials=20 of Intervention Effectiveness (CATIE) study, in which the = greatest=20 long-term improvements in cognitive function were seen in the = perphenazine group.22=20

In contrast to ideas about neuroprotective effects, there is=20 suggestive evidence that antipsychotics reduce brain tissue=20 volume, as described above,7 and=20 they are known to cause the pathological brain syndrome known = as=20 tardive dyskinesia. Research suggests that as well as = involuntary=20 movements, tardive dyskinesia is associated with general = cognitive=20 decline, suggesting that antipsychotics can induce = generalised brain=20 dysfunction.23=20


3Darrow=20
Conclusions
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
3D"Neuropathological findings
3D"Duration of untreated psychosis
3D"Evidence on neuroprotection
3D"Conclusions
3D"REFERENCES
 
Antipsyc= hotics=20 are undoubtedly useful in suppressing the symptoms of = psychotic=20 conditions, but the evidence presented here suggests there is = little=20 basis to the belief that they reverse an underlying = neurodegenerative=20 process in people with schizophrenia or psychosis. = Neuropathological=20 studies do not support the idea that antipsychotic drugs, = including=20 the new or atypical antipsychotics, have neuroprotective = effects.=20 Some research suggests they may even contribute to the = decline in=20 brain volume seen in people with these diagnoses, and they = are known=20 to induce neurological damage in the form of tardive = dyskinesia in=20 some long-term users. The idea that antipsychotic drugs are=20 neuroprotective should not therefore be used as a = justification for=20 prescribing or continuing to prescribe them, if other = considerations=20 do not also support their use. Psychiatrists should be = particularly=20 cautious about the use of antipsychotics in the early or = prodromal=20 stages of psychosis, where, as others have pointed out, there = is=20 the potential to do much harm.15=20


3Darrow=20
REFERENCES
3D"TOP
3D"ABSTRACT
3D"INTRODUCTION
3D"Brain imaging research
3D"Neuropathological findings
3D"Duration of untreated psychosis
3D"Evidence on neuroprotection
3D"Conclusions
3D"REFERENCES
 
    1=20
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  14. Owens DC, Johnstone EC, Miller P, Macmillan JF, Crow TJ. Duration = of=20 untreated illness and outcome in schizophrenia: test of predictions in = relation to relapse risk. Br J Psychiatry 2010; 196: 296 = =96301.[Abstract/Free Full Text]15=20
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  16. McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods = SW, et=20 al. Randomized, double-blind trial of olanzapine versus placebo in = patients=20 prodromally symptomatic for psychosis. Am J Psychiatry 2006;=20 163: 790 =969.[Abstract/Free Full Text]17=20
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Received for publication = August=20 11, 2010. Accepted for publication September 15, 2010.




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PADDING-LEFT: 2px; PADDING-RIGHT: 2px; = COLOR: white; FONT-SIZE: 77.5%; BORDER-TOP: medium none; BORDER-RIGHT: = medium none; PADDING-TOP: 2px } #header #authstring A { COLOR: white } #header #authstring A:visited { COLOR: white } #header #authstring A:active { COLOR: white } #header #hdr-login { POSITION: absolute; PADDING-BOTTOM: 5px; PADDING-LEFT: 10px; = PADDING-RIGHT: 0px; TOP: 30px; PADDING-TOP: 0px; LEFT: 756px } #header #hdr-login { COLOR: #0083a8 } #header #hdr-login LABEL { PADDING-BOTTOM: 2px; MARGIN: 0px; PADDING-LEFT: 0px; WIDTH: 80px; = PADDING-RIGHT: 0px; DISPLAY: block; FONT-SIZE: 87.5%; PADDING-TOP: 5px } #header #hdr-login INPUT { PADDING-BOTTOM: 0px; PADDING-LEFT: 0px; WIDTH: 110px; PADDING-RIGHT: = 0px; FONT-SIZE: 87.5%; PADDING-TOP: 0px } #header .header-qs INPUT { PADDING-BOTTOM: 0px; PADDING-LEFT: 0px; WIDTH: 110px; PADDING-RIGHT: = 0px; FONT-SIZE: 87.5%; PADDING-TOP: 0px } #header #hdr-login INPUT#hdr-login-signin { PADDING-BOTTOM: 0px; PADDING-LEFT: 5px; WIDTH: auto; PADDING-RIGHT: = 0px; HEIGHT: auto; VERTICAL-ALIGN: bottom; PADDING-TOP: 0px } #header .bar { POSITION: relative; PADDING-LEFT: 20px; HEIGHT: 60px; MARGIN-LEFT: = -20px; MARGIN-RIGHT: -20px } #footer .bar { POSITION: relative; PADDING-LEFT: 20px; HEIGHT: 60px; MARGIN-LEFT: = -20px; MARGIN-RIGHT: -20px } #header .bar { BACKGROUND-COLOR: #0083a8 } #footer .bar { BACKGROUND-COLOR: #0083a8 } #header .bar-inner { WIDTH: 960px; HEIGHT: 60px; COLOR: white } #header .bar-inner { BACKGROUND-COLOR: #00a0cc } #footer .footer-group { BACKGROUND-COLOR: #00a0cc } #header .header-qs { Z-INDEX: 1; POSITION: absolute; PADDING-BOTTOM: 7px; MARGIN: 0px; = PADDING-LEFT: 10px; WIDTH: 195px; PADDING-RIGHT: 5px; DISPLAY: block; = HEIGHT: 40px; TOP: 112px; PADDING-TOP: 10px; LEFT: 756px } #header .header-qs LABEL { POSITION: absolute; LEFT: -9999px } #header #hdr-login-signin-label { POSITION: absolute; LEFT: -9999px } #header #header-qs-search-label { POSITION: absolute; LEFT: -9999px } #header 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Opera = requires=0A= the Sun Java Runtime Environment .=0A= =0A= by Andrew Gregory=0A= http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A= =0A= This work is licensed under the Creative Commons Attribution License. To = view a=0A= copy of this license, visit = http://creativecommons.org/licenses/by-sa/2.5/ or=0A= send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, = California=0A= 94305, USA.=0A= =0A= Attribution: Leave my name and web address in this script intact.=0A= =0A= Not Supported in Opera=0A= ----------------------=0A= * user/password authentication=0A= * responseXML data member=0A= =0A= Not Fully Supported in Opera=0A= ----------------------------=0A= * async requests=0A= * abort()=0A= * getAllResponseHeaders(), getAllResponseHeader(header)=0A= =0A= */=0A= // IE support=0A= if (window.ActiveXObject && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= var msxmls =3D new Array(=0A= 'Msxml2.XMLHTTP.5.0',=0A= 'Msxml2.XMLHTTP.4.0',=0A= 'Msxml2.XMLHTTP.3.0',=0A= 'Msxml2.XMLHTTP',=0A= 'Microsoft.XMLHTTP');=0A= for (var i =3D 0; i < msxmls.length; i++) {=0A= try {=0A= return new ActiveXObject(msxmls[i]);=0A= } catch (e) {=0A= }=0A= }=0A= return null;=0A= };=0A= }=0A= // Gecko support=0A= /* ;-) */=0A= // Opera support=0A= if (window.opera && !window.XMLHttpRequest) {=0A= window.XMLHttpRequest =3D function() {=0A= this.readyState =3D 0; // = 0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A= this.status =3D 0; // HTTP status codes=0A= this.statusText =3D '';=0A= this._headers =3D [];=0A= this._aborted =3D false;=0A= this._async =3D true;=0A= this._defaultCharset =3D 'ISO-8859-1';=0A= this._getCharset =3D function() {=0A= var charset =3D _defaultCharset;=0A= var contentType =3D = this.getResponseHeader('Content-type').toUpperCase();=0A= val =3D contentType.indexOf('CHARSET=3D');=0A= if (val !=3D -1) {=0A= charset =3D contentType.substring(val);=0A= }=0A= val =3D charset.indexOf(';');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= val =3D charset.indexOf(',');=0A= if (val !=3D -1) {=0A= charset =3D charset.substring(0, val);=0A= }=0A= return charset;=0A= };=0A= this.abort =3D function() {=0A= this._aborted =3D true;=0A= };=0A= this.getAllResponseHeaders =3D function() {=0A= return this.getAllResponseHeader('*');=0A= };=0A= this.getAllResponseHeader =3D function(header) {=0A= var ret =3D '';=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A= ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A= }=0A= }=0A= return ret;=0A= };=0A= this.getResponseHeader =3D function(header) {=0A= var ret =3D getAllResponseHeader(header);=0A= var i =3D ret.indexOf('\n');=0A= if (i !=3D -1) {=0A= ret =3D ret.substring(0, i);=0A= }=0A= return ret;=0A= };=0A= this.setRequestHeader =3D function(header, value) {=0A= this._headers[this._headers.length] =3D {h:header, v:value};=0A= };=0A= this.open =3D function(method, url, async, user, password) {=0A= this.method =3D method;=0A= this.url =3D url;=0A= this._async =3D true;=0A= this._aborted =3D false;=0A= this._headers =3D [];=0A= if (arguments.length >=3D 3) {=0A= this._async =3D async;=0A= }=0A= if (arguments.length > 3) {=0A= opera.postError('XMLHttpRequest.open() - user/password not = supported');=0A= }=0A= this.readyState =3D 1;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= };=0A= this.send =3D function(data) {=0A= if (!navigator.javaEnabled()) {=0A= alert("XMLHttpRequest.send() - Java must be installed and = enabled.");=0A= return;=0A= }=0A= if (this._async) {=0A= setTimeout(this._sendasync, 0, this, data);=0A= // this is not really asynchronous and won't execute until the = current=0A= // execution context ends=0A= } else {=0A= this._sendsync(data);=0A= }=0A= }=0A= this._sendasync =3D function(req, data) {=0A= if (!req._aborted) {=0A= req._sendsync(data);=0A= }=0A= };=0A= this._sendsync =3D function(data) {=0A= this.readyState =3D 2;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= // open connection=0A= var url =3D new java.net.URL(new = java.net.URL(window.location.href), this.url);=0A= var conn =3D url.openConnection();=0A= for (var i =3D 0; i < this._headers.length; i++) {=0A= conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A= }=0A= this._headers =3D [];=0A= if (this.method =3D=3D 'POST') {=0A= // POST data=0A= conn.setDoOutput(true);=0A= var wr =3D new = java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A= wr.write(data);=0A= wr.flush();=0A= wr.close();=0A= }=0A= // read response headers=0A= // NOTE: the getHeaderField() methods always return nulls for me :(=0A= var gotContentEncoding =3D false;=0A= var gotContentLength =3D false;=0A= var gotContentType =3D false;=0A= var gotDate =3D false;=0A= var gotExpiration =3D false;=0A= var gotLastModified =3D false;=0A= for (var i =3D 0; ; i++) {=0A= var hdrName =3D conn.getHeaderFieldKey(i);=0A= var hdrValue =3D conn.getHeaderField(i);=0A= if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A= break;=0A= }=0A= if (hdrName !=3D null) {=0A= this._headers[this._headers.length] =3D {h:hdrName, = v:hdrValue};=0A= switch (hdrName.toLowerCase()) {=0A= case 'content-encoding': gotContentEncoding =3D true; break;=0A= case 'content-length' : gotContentLength =3D true; break;=0A= case 'content-type' : gotContentType =3D true; break;=0A= case 'date' : gotDate =3D true; break;=0A= case 'expires' : gotExpiration =3D true; break;=0A= case 'last-modified' : gotLastModified =3D true; break;=0A= }=0A= }=0A= }=0A= // try to fill in any missing header information=0A= var val;=0A= val =3D conn.getContentEncoding();=0A= if (val !=3D null && !gotContentEncoding) = this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A= val =3D conn.getContentLength();=0A= if (val !=3D -1 && !gotContentLength) = this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A= val =3D conn.getContentType();=0A= if (val !=3D null && !gotContentType) = this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A= val =3D conn.getDate();=0A= if (val !=3D 0 && !gotDate) this._headers[this._headers.length] = =3D {h:'Date', v:(new Date(val)).toUTCString()};=0A= val =3D conn.getExpiration();=0A= if (val !=3D 0 && !gotExpiration) = this._headers[this._headers.length] =3D {h:'Expires', v:(new = Date(val)).toUTCString()};=0A= val =3D conn.getLastModified();=0A= if (val !=3D 0 && !gotLastModified) = this._headers[this._headers.length] =3D {h:'Last-modified', v:(new = Date(val)).toUTCString()};=0A= // read response data=0A= var reqdata =3D '';=0A= var stream =3D conn.getInputStream();=0A= if (stream) {=0A= var reader =3D new java.io.BufferedReader(new = java.io.InputStreamReader(stream, this._getCharset()));=0A= var line;=0A= while ((line =3D reader.readLine()) !=3D null) {=0A= if (this.readyState =3D=3D 2) {=0A= this.readyState =3D 3;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= }=0A= reqdata +=3D line + '\n';=0A= }=0A= reader.close();=0A= this.status =3D 200;=0A= this.statusText =3D 'OK';=0A= this.responseText =3D reqdata;=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onload) {=0A= this.onload();=0A= }=0A= } else {=0A= // error=0A= this.status =3D 404;=0A= this.statusText =3D 'Not Found';=0A= this.responseText =3D '';=0A= this.readyState =3D 4;=0A= if (this.onreadystatechange) {=0A= this.onreadystatechange();=0A= }=0A= if (this.onerror) {=0A= this.onerror();=0A= }=0A= }=0A= };=0A= };=0A= }=0A= // ActiveXObject emulation=0A= if (!window.ActiveXObject && window.XMLHttpRequest) {=0A= window.ActiveXObject =3D function(type) {=0A= switch (type.toLowerCase()) {=0A= case 'microsoft.xmlhttp':=0A= case 'msxml2.xmlhttp':=0A= case 'msxml2.xmlhttp.3.0':=0A= case 'msxml2.xmlhttp.4.0':=0A= case 'msxml2.xmlhttp.5.0':=0A= return new XMLHttpRequest();=0A= }=0A= return null;=0A= };=0A= }=0A= ------=_NextPart_000_0000_01CBCF8B.D123F6F0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://bjp.rcpsych.org/javascript/ajax/utility.js /************************************************************************= *****=0A= * javascript/ajax/utility.js=0A= *=0A= * Utility functions for working with XMLHttpRequest data.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Copy XML nodes into an HTMLElement. This effectively=0A= * clones XML markup which uses XHTML naming conventions=0A= * into an HTML DOM.=0A= */=0A= function copy_xml_to_html(src, dst) {=0A= if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A= var e =3D document.createElement(src.nodeName);=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], e);=0A= }=0A= for (var i =3D 0; i < src.attributes.length; i++) {=0A= var n =3D src.attributes[i].name;=0A= var v =3D unescape_xml_string(src.attributes[i].value); =0A= e.setAttribute(n, v);=0A= if (n =3D=3D "class") {=0A= e.className =3D v;=0A= }=0A= else if (n =3D=3D "style") {=0A= set_css_style(v, e, "");=0A= }=0A= }=0A= dst.appendChild(e);=0A= }=0A= else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A= dst.appendChild(document.createTextNode(src.nodeValue));=0A= }=0A= }=0A= =0A= /* =0A= * It is unclear that this is the right thing to be calling=0A= * from copy_xml_to_html, but it appears that Safari decides=0A= * to convert & to the NCR #, and then encodes that=0A= * NCR to &%26%2338;. So, I'm going to treat the DOM Attr=0A= * value as a plain string, and run our XML string input=0A= * through the decoding routine below.=0A= */=0A= function unescape_xml_string(s) {=0A= return s.replace(/'/g, "'")=0A= .replace(/'/g, "'")=0A= .replace(/"/g, "\"")=0A= .replace(/"/g, "\"")=0A= .replace(/>/g, ">")=0A= .replace(/>/g, ">")=0A= .replace(/</g, "<")=0A= .replace(/</g, "<")=0A= .replace(/&/g, "&")=0A= .replace(/&/g, "&");=0A= }=0A= =0A= /*=0A= * Parse set of CSS rules and apply them to an element.=0A= * This is quite horrifying, but I'm unable to determine=0A= * how else to handle this with IE 6. FireFox and other=0A= * sane browsers let you simply set the style attribute=0A= * or use e.style.setProperty(rule, value, priority),=0A= * IE 6 appears to have neither of these capabilities..=0A= */=0A= function set_css_style(css, e, priority) {=0A= var rules =3D css.split(";");=0A= for (var i =3D 0; i < rules.length; i++) {=0A= var nvpair =3D rules[i].split(":");=0A= if (nvpair.length =3D=3D 2) {=0A= try {=0A= var name =3D nvpair[0]; /* style attribute */=0A= var value =3D nvpair[1]; /* attribute value */=0A= =0A= /*=0A= * For each possible style attribute, set the=0A= * appropriate style property in the element.=0A= */=0A= if (name =3D=3D "background") {=0A= e.style.background =3D value;=0A= }=0A= else if (name =3D=3D "background-attachment") {=0A= e.style.backgroundAttachment =3D value;=0A= }=0A= else if (name =3D=3D "background-color") {=0A= e.style.backgroundColor =3D value;=0A= }=0A= else if (name =3D=3D "background-image") {=0A= e.style.backgroundImage =3D value;=0A= }=0A= else if (name =3D=3D "background-position") {=0A= e.style.backgroundPosition =3D value;=0A= }=0A= else if (name =3D=3D "background-position-x") {=0A= e.style.backgroundPositionX =3D value;=0A= }=0A= else if (name =3D=3D "background-position-y") {=0A= e.style.backgroundPositionY =3D value;=0A= }=0A= else if (name =3D=3D "background-repeat") {=0A= e.style.backgroundRepeat =3D value;=0A= }=0A= else if (name =3D=3D "behavior") {=0A= e.style.behavior =3D value;=0A= }=0A= else if (name =3D=3D "border") {=0A= e.style.border =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom") {=0A= e.style.borderBottom =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-color") {=0A= e.style.borderBottomColor =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-style") {=0A= e.style.borderBottomStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-bottom-width") {=0A= e.style.borderBottomWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-collapse") {=0A= e.style.borderCollapse =3D value;=0A= }=0A= else if (name =3D=3D "border-color") {=0A= e.style.borderColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left") {=0A= e.style.borderLeft =3D value;=0A= }=0A= else if (name =3D=3D "border-left-color") {=0A= e.style.borderLeftColor =3D value;=0A= }=0A= else if (name =3D=3D "border-left-style") {=0A= e.style.borderLeftStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-left-width") {=0A= e.style.borderLeftWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-right") {=0A= e.style.borderRight =3D value;=0A= }=0A= else if (name =3D=3D "border-right-color") {=0A= e.style.borderRightColor =3D value;=0A= }=0A= else if (name =3D=3D "border-right-style") {=0A= e.style.borderRightStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-right-width") {=0A= e.style.borderRightWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-style") {=0A= e.style.borderStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top") {=0A= e.style.borderTop =3D value;=0A= }=0A= else if (name =3D=3D "border-top-color") {=0A= e.style.borderTopColor =3D value;=0A= }=0A= else if (name =3D=3D "border-top-style") {=0A= e.style.borderTopStyle =3D value;=0A= }=0A= else if (name =3D=3D "border-top-width") {=0A= e.style.borderTopWidth =3D value;=0A= }=0A= else if (name =3D=3D "border-width") {=0A= e.style.borderWidth =3D value;=0A= }=0A= else if (name =3D=3D "bottom") {=0A= e.style.bottom =3D value;=0A= }=0A= else if (name =3D=3D "clear") {=0A= e.style.clear =3D value;=0A= }=0A= else if (name =3D=3D "clip") {=0A= e.style.clip =3D value;=0A= }=0A= else if (name =3D=3D "color") {=0A= e.style.color =3D value;=0A= }=0A= else if (name =3D=3D "cssText") {=0A= e.style.Sets =3D value;=0A= }=0A= else if (name =3D=3D "cursor") {=0A= e.style.cursor =3D value;=0A= }=0A= else if (name =3D=3D "direction") {=0A= e.style.direction =3D value;=0A= }=0A= else if (name =3D=3D "display") {=0A= e.style.display =3D value;=0A= }=0A= else if (name =3D=3D "font") {=0A= e.style.font =3D value;=0A= }=0A= else if (name =3D=3D "font-family") {=0A= e.style.fontFamily =3D value;=0A= }=0A= else if (name =3D=3D "font-size") {=0A= e.style.fontSize =3D value;=0A= }=0A= else if (name =3D=3D "font-style") {=0A= e.style.fontStyle =3D value;=0A= }=0A= else if (name =3D=3D "font-variant") {=0A= e.style.fontVariant =3D value;=0A= }=0A= else if (name =3D=3D "font-weight") {=0A= e.style.fontWeight =3D value;=0A= }=0A= else if (name =3D=3D "height") {=0A= e.style.height =3D value;=0A= }=0A= else if (name =3D=3D "ime-mode") {=0A= e.style.imeMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-flow") {=0A= e.style.layoutFlow =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid") {=0A= e.style.layoutGrid =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-char") {=0A= e.style.layoutGridChar =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-line") {=0A= e.style.layoutGridLine =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-mode") {=0A= e.style.layoutGridMode =3D value;=0A= }=0A= else if (name =3D=3D "layout-grid-type") {=0A= e.style.layoutGridType =3D value;=0A= }=0A= else if (name =3D=3D "left") {=0A= e.style.left =3D value;=0A= }=0A= else if (name =3D=3D "letter-spacing") {=0A= e.style.letterSpacing =3D value;=0A= }=0A= else if (name =3D=3D "line-break") {=0A= e.style.lineBreak =3D value;=0A= }=0A= else if (name =3D=3D "line-height") {=0A= e.style.lineHeight =3D value;=0A= }=0A= else if (name =3D=3D "list-style") {=0A= e.style.listStyle =3D value;=0A= }=0A= else if (name =3D=3D "list-style-image") {=0A= e.style.listStyleImage =3D value;=0A= }=0A= else if (name =3D=3D "list-style-position") {=0A= e.style.listStylePosition =3D value;=0A= }=0A= else if (name =3D=3D "list-style-type") {=0A= e.style.listStyleType =3D value;=0A= }=0A= else if (name =3D=3D "margin") {=0A= e.style.margin =3D value;=0A= }=0A= else if (name =3D=3D "margin-bottom") {=0A= e.style.marginBottom =3D value;=0A= }=0A= else if (name =3D=3D "margin-left") {=0A= e.style.marginLeft =3D value;=0A= }=0A= else 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quoted-printable Content-Location: http://bjp.rcpsych.org/javascript/entrez/callback.js /************************************************************************= *****=0A= * javascript/entrez/callback.js=0A= *=0A= * Entrez Linking callback to populate content box.=0A= *=0A= * Copyright 2006 Board of Trustees of the Leland Stanford Junior = University.=0A= = *************************************************************************= ***/=0A= =0A= /*=0A= * Execute callback to fill content box with Entrez Linking information.=0A= */=0A= function entrez_callback(pmid, callback_url) {=0A= /*=0A= * MSIE 5.5 and below have issues with the JavaScript=0A= * used for Entrez Linking. For now we have to disable=0A= * the callback until we can track down a proper fix=0A= * (or everybody sanely upgrades to version 6 or 7!).=0A= */=0A= if (navigator) {=0A= var appname =3D navigator.appName;=0A= if (appname =3D=3D "Microsoft Internet Explorer") {=0A= var userAgent =3D navigator["userAgent"];=0A= var s =3D "MSIE ";=0A= var n =3D -1; =0A= if ((n =3D userAgent.indexOf(s)) !=3D -1) {=0A= var v =3D parseFloat(userAgent.substring(n+s.length));=0A= if (v < 6) {=0A= return;=0A= }=0A= }=0A= }=0A= }=0A= =0A= /*=0A= * Acquire table row element to update, initiate callback=0A= * to update table with Entrez Links.=0A= */=0A= var tr =3D document.getElementById('entrez_callback_'+pmid);=0A= if (!tr) {=0A= return;=0A= }=0A= var req =3D new XMLHttpRequest();=0A= if (!req) {=0A= return;=0A= }=0A= req.onreadystatechange =3D function() {=0A= if (req.readyState =3D=3D 4 && (req.status =3D=3D 200 || req.status = =3D=3D 304)) {=0A= var src =3D req.responseXML.documentElement;=0A= var dst =3D document.createDocumentFragment();=0A= for (var i =3D 0; i < src.childNodes.length; i++) {=0A= copy_xml_to_html(src.childNodes[i], dst);=0A= }=0A= var tbl =3D tr.parentNode;=0A= tbl.replaceChild(dst, tr);=0A= }=0A= }=0A= req.open('GET', callback_url, true);=0A= req.send(null);=0A= }=0A= ------=_NextPart_000_0000_01CBCF8B.D123F6F0--