From: Subject: Temozolomide-Induced Myelodysplasia Date: Sat, 1 May 2010 09:33:31 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CAE911.5CDEEDB0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CAE911.5CDEEDB0 Content-Type: text/html; charset="utf-8" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833319/ =EF=BB=BF Temozolomide-Induced = Myelodysplasia
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Adv Hematol. 2010; 2010: 760402.=20
Published online 2010 = March 4.=20 doi:=20 10.1155/2010/760402.
PMCID:=20 = PMC2833319
Copyright=20 =C2=A9 2010 E. A. Natelson and D. Pyatt .
Temozolomide-Induced Myelodysplasia
Ethan A.=20 Natelson1* and David Pyatt2
1Department of Internal Medicine, = The=20 Methodist Hospital, Smith Tower 1001, 6550 Fannin Street, Houston, = TX=20 77030, USA
2School of Public Health, = University of=20 Colorado, Summit Toxicology, L.L.P., 1944 Cedaridge Circle, = Superior, CO=20 80027, USA
*Ethan A. Natelson : Email:=20 enatelson/at/tmhs.org
Academic Editor: = Maria R. Baer=20
Received July 23, 2009; Revised November = 17, 2009;=20 Accepted January 13, 2010.
This is an open access article = distributed under=20 the Creative Commons Attribution License, which permits = unrestricted use,=20 distribution, and reproduction in any medium, provided the = original work=20 is properly cited.
Abstract
A patient who had = received=20 temozolomide (TMZ) as a single agent in treatment of malignant = glioma=20 developed therapy-induced myelodysplasia (T-MDS). TMZ is an orally = active=20 imidazotetrazine which methylates guanine residues in DNA, = ultimately=20 causing single and double-strand DNA breaks leading to apoptotic = cell=20 death. TMZ does not chemically cross-link DNA and is considered a=20 nonclassical alkylating agent, similar in structure and activity = to=20 dacarbazine. Observations on this patient, and on similarly = treated=20 others, suggest that the cumulative dose threshold (CDT) for TMZ = that=20 predisposes to T-MDS and which may potentially lead to acute = myeloid=20 leukemia (T-AML) is around 18000 to 200003D"mg/sq m. Although the incidence of T-MDS and the = predisposing CDT=20 of TMZ may differ from that of other potentially leukemogenic = compounds=20 currently and formerly used as chemotherapeutic agents, all = alkylating=20 agents, including TMZ, should be considered potentially = leukemogenic when=20 administered long term.
Most instances of = myelodysplasia=20 (MDS) and acute myeloid leukemia (AML) are de novo or primary = illnesses,=20 and occur without known exogenous or environmental cause and at an = increasing incidence with advancing age [1=E2=80=933]. Failure of DNA repair mechanisms and the = physiologic=20 requirement for programmed DNA fracture and chromosome reassembly = during=20 normal hematopoiesis are possible endogenous causes [1].
Secondary forms of = MDS/AML are less=20 common and may occur in the setting of pre-existing hematological = or=20 systemic disorders, after exposure to environmental toxins, or = consequent=20 to treatment of malignancy or circumstances requiring prolonged=20 immunosuppression [4=E2=80=937]. More and more cases of event-related or = therapy-induced=20 MDS/AML are being recognized. Recent studies suggest that = individuals with=20 this subset of secondary MDS/AML may have particular = predisposing=20 genetic loci [8, 9]. It is generally believed that = secondary forms of=20 MDS/AML are more refractory to therapy than are de novo illnesses, = and as=20 recently reported, even with equivalent low-risk chromosome = aberrations=20 [10=E2=80=9312]. The bone marrow histopathology of T-MDS more = often=20 shows multilineage dysplasia, fibrosis and hypoplasia than is = observed in=20 de novo forms of MDS making comparable classification difficult = along=20 guidelines designed for de novo MDS [12, 13]. This seems particularly true of examples of=20 secondary MDS consequent to excessive occupational = exposures to=20 benzene, an obsolete chemotherapy drug [2, 14=E2=80=9317].
Alkylating agent-induced = MDS/AML was=20 first described after treatment of multiple myeloma with melphalan = [18]. Many subsequent observations suggested that = MDS/AML=20 after therapy with alkylating agents was not idiosyncratic, but = directly=20 related to their cumulative dose, regardless of mode of = administration [19]. The clinical features of such = secondary AML=20 syndromes include a MDS phase in as many as 70% of cases [2, 4, 5]. By contrast, de novo AML typically begins = abruptly=20 without a period of MDS. There also appears to be a latency period = and a=20 window of opportunity, from exposure to onset of hematologic = neoplasm,=20 generally described as between 2 and 10 years after a potentially=20 leukemogenic CDT is reached [5]. Certain cytogenetic aberrations in bone marrow = cells are=20 also more likely to occur after exposure to alkylating agents. = Such=20 aberrations involve variable losses of genetic material from = chromosomes 5=20 and 7 in as many as 50=E2=80=9370% of cases [2=E2=80=935, 10]. Moreover, some alkylating agents may be far = more=20 leukemogenic than others, and the CDT for each compound varies=20 considerably [6, 7, 19, 20]. Expanded use of a newer alkylating agent, = TMZ,=20 developed to facilitate central nervous system drug penetration in = patients with cerebral neoplasms, has become a standard of care = [21, 22]. Unfortunately, its mechanism of action = suggests major=20 efficacy only for central nervous system tumors bearing specific = genetic=20 markers [23, 24]. The increasing reports of MDS/AML syndromes = following=20 the use of TMZ serve as a reminder that alkylating agents cannot = be safely=20 used continuously and long-term unless the intent is palliation, = rather=20 than cure.
A 64-year-old = previously=20 healthy right-handed man experienced the sudden onset of grand mal = seizures. Cranial CT scans demonstrated a small left temporal lobe = lesion.=20 Microscopic examination after its excision showed histology = consistent=20 with astrocytoma, and clear tumor margins. He received = postoperative=20 radiation therapy, along with small oral doses of TMZ as a=20 radiosensitizer. This drug was then continued at 2003D"mg/sq m/day, 5 days each month, for 18 courses (total = dose,=20 approximately 20,0003D"mg/sq m or 40,0003D"mg). Pretreatment blood counts gave entirely normal = values.=20 Transient leukopenia and thrombocytopenia occurred during = chemotherapy,=20 but the patient did not require use of hematological growth = promoting=20 factors or blood component transfusion. His blood counts returned = to=20 normal, but several months after completion of all therapy, a mild = pancytopenia became evident, and gradually worsened. Three years = after=20 treatment, the peripheral blood film demonstrated macrocytosis and = typical=20 bilobed Pelger-Huet granulocytes [25]. The bone marrow examination at that time = showed normal=20 total cellularity but demonstrated 3% blast forms and trilineage=20 dysplasia. Conventional cytogenetics and FISH (fluorescent in = situ=20 hybridization) probes confirmed isolated monosomy 7 in 80% of = the=20 marrow metaphases and no alterations in chromosome 5. A diagnosis = of=20 high-risk MDS was evident. Allogeneic bone marrow transplantation = was=20 contemplated, but 5 months after his diagnosis of MDS, recurrence = of the=20 brain tumor was identified in the left frontal lobe behind the = optic=20 nerve. Re-biopsy confirmed astrocytoma, and he received additional = radiation therapy along with a course of azacitidine for his MDS. = This=20 latter treatment resulted in a severe pancytopenia, but eight = months=20 later, his blood counts were considerably improved from those = obtained at=20 the time of his bone marrow examination, and he was essentially=20 asymptomatic. He died from progression of the cerebral neoplasm 43 = months=20 following its initial diagnosis without conversion from MDS to=20 AML.
Kyle, in 1970, first = called=20 attention to the leukemogenic potential of the alkylating agent,=20 melphalan, when used in the treatment of multiple myeloma [18]. The importance of a CDT among alkylating = agents as a=20 cause of secondary AML was soon appreciated with analysis = of=20 studies reporting the incidence of AML following increasing cycles = of MOPP=20 (mechlorethamine, vincristine, procarbazine, prednisone) = chemotherapy for=20 Hodgkin's lymphoma [19]. Greene emphasized the duration of treatment = and the=20 total dose administered as predictive of a greater leukemic risk = following=20 administration of cyclophosphamide, perhaps the alkylating agent = most=20 thoroughly studied in regard to secondary AML [26]. The potentially leukemogenic cumulative dose = for=20 cyclophosphamide has been estimated at 20,0003D"mg and is about ten-fold that seen with another = well-studied=20 alkylating agent, chlorambucil [19]. The alkylating agent/CDT concept in = leukemogenesis has=20 been reconfirmed in a more recent study demonstrating the = appearance of,=20 and abrupt rise in, the incidence of secondary AML in = patients=20 treated for breast cancer and receiving cyclophosphamide in doses = above=20 8,0003D"mg/sq m along with other agents [6]. This increased risk of T-MDS/AML was not = observed in=20 patients treated with lower doses. For other types of = chemotherapeutic=20 agents that may cause secondary AML/MDS, such as = topoisomerase II=20 inhibitors, the mean latency is shorter, and different chromosome=20 aberrations such as balanced translocations are common [4]. The existence of a CDT is probable but less = well-defined=20 since these agents are often used in combination chemotherapy.=20 Additionally, a prodrome of MDS is far less common [2, 4, 5, 7, 11].
TMZ is a novel chemotherapy drug = that is=20 structurally related to dacarbazine. It has the advantage of a = rapid=20 absorption following oral administration with almost 100% = bioavailability.=20 Moreover, drug levels in the central nervous system are = 30=E2=80=9340% of TMZ=20 plasma concentrations [27, 28]. As such, this drug has gained much attention = as=20 front-line therapy for malignant gliomas, for which effective = therapy=20 remains poor. TMZ does not undergo significant liver metabolism = and=20 hydrolyzes rapidly to form the active alkylating metabolite in = plasma.=20
TMZ is considered a non-classical = alkylating=20 agent in that it does not cross-link DNA strands. Its metabolites=20 methylate DNA, particularly on guanine sites. The formation of=20 O6-methylguanine generates single and/or double strand = DNA=20 breaks when the affected cell line attempts to repair this = alteration via=20 mismatch repair mechanisms and apoptosis results.=20 O6=E2=80=93methylguanine-DNA methyltransferase (MGMT) = plays a critical=20 role in protecting cells from alkylating agents that target=20 O6-guanine, including TMZ [29, 30]. This enzyme transfers the inappropriate = methyl group=20 from the guanine to a cysteine residue which signals for its=20 proteasome-mediated degradation destruction via an ubiquitination = pathway=20 [31]. Thus, TMZ mediated apoptosis appears to be = especially=20 effective in MGMT negative tumors or in tumors with a = hypermethylated MGMT=20 promoter [28, 31]. For this reason knowledge of the MGMT = promoter status=20 provides clinically useful information regarding the potential = efficacy to=20 TMZ and other alkylating agents in a variety of tumor systems [30]. Additional studies report that TMZ also = induces cell=20 cycle arrest at the G2-M checkpoint and /or disrupts tubulin = formation [32, 33].
Lacking ability to cross-link DNA, = TMZ has=20 less direct toxicity to hematopoietic progenitor cells than = classical=20 alkylating agents. As a result, myelosuppression is relatively = mild and=20 not often dose-limiting. However, scattered reports describe = prolonged=20 myelosuppression and even aplastic anemia, in addition to the = delayed=20 syndromes of T-MDS/AML following therapy with TMZ [34=E2=80=9336]. Hypermethylation-induced gene silencing is a = feature of=20 MDS and secondary AML, in comparison with de novo AML and = may=20 have something to do with the lack of response to standard = chemotherapy in=20 these syndromes and could also favor the induction of T-MDS/AML = [37].
Currently, TMZ is used in = treatment of various=20 types of gliomas, typically in concert with radiation therapy and = as a=20 radiosensitizing agent [38]. In more recent reports, it has been combined = with other=20 agents with different mechanisms of action in an attempt to find a = more=20 potent treatment advantage over radiation alone following = debulking=20 neurosurgery [39, 40]. TMZ has also been studied as a = chemotherapeutic agent=20 in melanoma and other solid tumors and in hematological disorders = but=20 little clinical data as yet exists.
The patient reported here received = TMZ at a=20 total dose of 20,0003D"mg/sq m prior to the diagnosis of T-MDS. In another = instance=20 where TMZ was used primarily as a single agent, the total dose=20 administered before onset of T-MDS was quite similar, at = 18,750mg/sq m [41]. In a series of 7 patients with gliomas, all = of whom=20 received TMZ and who later developed alkylating agent-induced MDS, = 2 were=20 treated with TMZ alone at doses of 24,000 and 28,0003D"mg/sq m prior to T-MDS/AML. The median dose of TMZ in = this cohort=20 was 18,0003D"mg/sq m, but 5 of the 7 patients had also received = substantial=20 therapy with other chemotherapeutic agents [21]. In the patient reported here, and in the 3 = additional=20 patients previously reported who developed T-MDS following TMZ = alone, MDS=20 was confirmed 28 to 36 months following treatment. Additional = occurrences=20 of T-MDS/AML in patients receiving TMZ in the treatment of gliomas = have=20 been described, but the use of multiple chemotherapy drugs in = these=20 patients prevents any conclusions about the contributions of = individual=20 compounds [42, 43].
Benzene is an obsolete = chemotherapeutic agent=20 briefly used in the early approach to treatment of chronic myeloid = leukemia [1]. It continues to be of major scientific interest = because=20 it is a well-known potential cause of secondary MDS/AML = via=20 occupational exposures at high cumulative dose levels [1, 2, 44=E2=80=9347]. Its mechanism of action is unknown, but it = has been=20 termed a radiomimetic compound because of the similarity in the = myeloid=20 cell chromosome aberrations it may produce to those identified = after both=20 therapeutic radiation exposure and following treatment with = alkylating=20 agents. Some of the metabolites of benzene also exhibit = anti-topoisomerase=20 II activity, the importance of which in terms of its mechanism of=20 leukemogenesis is debated [44=E2=80=9346]. Regulatory agencies, epidemiological studies = and=20 peer-reviewed medical literature typically cite cumulative benzene = exposures in excess of 403D"ppm years as the minimum exposure required to = potentially cause=20 secondary MDS/AML [2, 47, 48]. However, exposure levels well in excess of = these values=20 may not result in a statistically significant excess incidence of = AML [49, 50].
In order to compare potentially = leukemogenic=20 doses of benzene with those of other chemicals, the typical = exposure=20 metric of ppm-years must be converted to the more clinically = relevant=20 mg/sq m. An estimate of the mg absorbed dose of benzene given a = constant=20 13D"ppm (323D"mg/m3 =3D 13D"ppm) inhalation over an 8 hour daily work schedule = during a 250=20 day work year and continuing over a 40 year period employing = standard=20 measurements for respiratory rate, tidal volume and absorbed dose, = would=20 yield a value around 92,0003D"mg. Assuming the worker measured 23D"sq m in body surface area, this would suggest that the = minimum=20 CDT necessary to predispose to secondary MDS/AML would be about = 46,000mg/sq m. With controls on the amount of benzene = allowable as a=20 trace contaminant in modern solvents, it has become more difficult = to=20 achieve the cumulative dose levels required to initiate = leukemogenesis in=20 workers in developed countries [51]. The wide range of the estimated CDT necessary = to=20 predispose to secondary MDS/AML for selected and = well-studied=20 modern chemotherapeutic agents including TMZ and in comparison = with=20 benzene is shown in = Table 1 [6, 7, 18=E2=80=9320, 26, 47].
Most individuals = receiving=20 exceptionally large doses of alkylating agents over an extended = period do=20 not develop T-MDS/AML. This also is true in patients receiving TMZ = [22]. However, considering the limited survival of = those with=20 malignant gliomas, in comparison with the wide range of latency in = alkylating agent-induced MDS/AML, it is understandable why more = examples=20 of this hematological complication have not been described. This=20 relatively short survival interval also makes it more difficult to = compare=20 the incidence of leukemogenesis from TMZ with that caused by = alkylating=20 agents commonly used in the treatment of neoplasms which are = associated=20 with a long survival, such as Hodgkin's lymphoma, testicular = cancer and=20 breast cancer. Nevertheless, patients and their physicians should = be aware=20 that prolonged use of TMZ as a single agent is not innocuous and = carries=20 the potential to cause T-MDS/AML. The CDT that predisposes to = these=20 hematological syndromes estimated on limited case material appears = to be=20 around 18,000 to 20,0003D"mg/sq m. Based on the extensive medical literature on = the=20 subject, any alkylating agent in long-term administration must = always be=20 considered potentially leukemogenic.
Acknowledgment
This work is funded by The = Methodist Hospital=20 Department of Medicine Annual 2009 Budget. This manuscript has = previously=20 been submitted to Advances in Hematology.
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51. Williams PR, Panko JM, Unice K, = Brown JL,=20 Paustenbach DJ. Occupational exposures associated with = petroleum-derived=20 products containing trace levels of benzene. Journal of Occupational and Environmental=20 Hygiene. 2008;5(9):565=E2=80=93574.=20 [PubMed]
Articles from Advances in=20 Hematology are provided here courtesy of
Hindawi Publishing=20 Corporation
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3D"Table<= /DIV>
= Table=20 1
Estimated = CDT for=20 selected potentially leukemogenic agents.

PubMed articles by these = authors

  • Natelson,=20 E.
  • Pyatt,=20 D.

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BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-bbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar-noheader .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-body-noheader { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tl .x-panel-header { COLOR: #333 } .x-panel-tc { 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BUTTON { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-text-icon .x-btn-menu-arrow-wrap .x-btn-center BUTTON = { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-over .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-right { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-center { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over BUTTON { COLOR: #111 } .x-toolbar .x-btn-click .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-left { BACKGROUND-IMAGE: url(../../img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-click .x-btn-right { BACKGROUND-IMAGE: 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PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } .port H5.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } .port H6.x-panel-header-text { PADDING-RIGHT: 0px; PADDING-LEFT: 0px; FONT-SIZE: 100%; PADDING-BOTTOM: = 0px; MARGIN: 0px; PADDING-TOP: 0px } DIV.x-panel-body { PADDING-RIGHT: 5px; PADDING-LEFT: 5px; PADDING-BOTTOM: 5px; = PADDING-TOP: 5px } .port .x-panel-header { PADDING-RIGHT: 3px; PADDING-LEFT: 5px; PADDING-BOTTOM: 4px; = PADDING-TOP: 5px } .x-panel { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-STYLE: solid; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-STYLE: = solid; BORDER-LEFT-STYLE: solid; BORDER-RIGHT-COLOR: #d0d0d0; = BORDER-BOTTOM-STYLE: solid } .x-panel-header { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/white-top-bottom.gif); = BORDER-LEFT: #d0d0d0 1px solid; COLOR: #333; BORDER-BOTTOM: #d0d0d0 1px = solid } .x-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-bbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tbar-noheader .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-body-noheader { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-mc .x-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tl .x-panel-header { COLOR: #333 } .x-panel-tc { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/top-bottom.gif) } .x-panel-tl { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif); = BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-tr { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif) } .x-panel-bc { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/top-bottom.gif) } .x-panel-bl { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif) } .x-panel-br { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/corners-sprite.gif) } .x-panel-mc { BACKGROUND: #f1f1f1 } .x-panel-mc .x-panel-body { BORDER-RIGHT: 0px; BORDER-TOP: 0px; BACKGROUND: none transparent scroll = repeat 0% 0%; BORDER-LEFT: 0px; BORDER-BOTTOM: 0px } .x-panel-ml { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/left-right.gif) } .x-panel-mr { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/left-right.gif) } .x-tool { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/tool-sprites.gif) } .x-panel-ghost { BACKGROUND: #e0e0e0 } .x-panel-ghost UL { BORDER-LEFT-COLOR: #b0b0b0; BORDER-BOTTOM-COLOR: #b0b0b0; = BORDER-TOP-COLOR: #b0b0b0; BORDER-RIGHT-COLOR: #b0b0b0 } .x-grid-panel .x-panel-mc .x-panel-body { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BORDER-LEFT: #d0d0d0 1px solid; BORDER-BOTTOM: #d0d0d0 1px solid } .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/button/btn-sprite.gif) } .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/button/btn-sprite.gif) } .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/button/btn-sprite.gif) } .x-border-layout-ct { BACKGROUND: #f0f0f0 } .x-accordion-hd { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/panel/light-hd.gif) } .x-layout-collapsed { BORDER-LEFT-COLOR: #e0e0e0; BORDER-BOTTOM-COLOR: #e0e0e0; = BORDER-TOP-COLOR: #e0e0e0; BACKGROUND-COLOR: #eee; BORDER-RIGHT-COLOR: = #e0e0e0 } .x-layout-collapsed-over { BACKGROUND-COLOR: #fbfbfb } .x-tip .x-tip-top { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-top-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-top-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-ft-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-bd-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-tip .x-tip-bd-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/qtip/tip-sprite.gif) } .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/bg.gif) #f0f4f5 repeat-x left = top; BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = BORDER-RIGHT-COLOR: #d0d0d0 } .x-toolbar BUTTON { COLOR: #444 } .x-toolbar .x-btn-menu-arrow-wrap .x-btn-center BUTTON { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-text-icon .x-btn-menu-arrow-wrap .x-btn-center BUTTON = { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/btn-arrow.gif) } .x-toolbar .x-btn-over .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-over BUTTON { COLOR: #111 } .x-toolbar .x-btn-click .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-click .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-click .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-pressed .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .x-btn-menu-active .x-btn-center { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/toolbar/tb-btn-sprite.gif) } .x-toolbar .ytb-sep { BACKGROUND-IMAGE: = url(/core/extjs/ext-2.1/resources/images/default/grid/grid-split.gif) } .x-tab-panel-header { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-footer { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-header { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-footer { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } UL.x-tab-strip-top { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-strip-bg.gif) #dbdbdb = repeat-x left top; BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: = #d0d0d0; PADDING-TOP: 2px; BORDER-RIGHT-COLOR: #d0d0d0 } UL.x-tab-strip-bottom { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-strip-btm-bg.gif); = BORDER-BOTTOM-COLOR: #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; = BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-strip SPAN.x-tab-strip-text { COLOR: #333 } .x-tab-strip-over SPAN.x-tab-strip-text { COLOR: #111 } .x-tab-strip-active SPAN.x-tab-strip-text { COLOR: #333 } .x-tab-strip-disabled .x-tabs-text { COLOR: #aaaaaa } .x-tab-strip-top .x-tab-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-top .x-tab-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-top .x-tab-strip-inner { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tabs-sprite.gif) } .x-tab-strip-bottom .x-tab-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-inactive-right-bg.gif) } .x-tab-strip-bottom .x-tab-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-inactive-left-bg.gif) } .x-tab-strip-bottom .x-tab-strip-active .x-tab-right { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-right-bg.gif) } .x-tab-strip-bottom .x-tab-strip-active .x-tab-left { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-btm-left-bg.gif) } .x-tab-strip .x-tab-strip-closable A.x-tab-strip-close { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-close.gif) } .x-tab-strip .x-tab-strip-closable A.x-tab-strip-close:hover { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/tab-close.gif) } .x-tab-panel-body { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #fff; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-bbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-tbar .x-toolbar { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-panel-header-plain .x-tab-strip-spacer { BORDER-LEFT-COLOR: #d0d0d0; BACKGROUND: #eaeaea; BORDER-BOTTOM-COLOR: = #d0d0d0; BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-tab-scroller-left { BORDER-LEFT-COLOR: #aeaeae; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/scroll-left.gif); = BORDER-BOTTOM-COLOR: #aeaeae; BORDER-TOP-COLOR: #aeaeae; = BORDER-RIGHT-COLOR: #aeaeae } .x-tab-scroller-right { BORDER-LEFT-COLOR: #aeaeae; BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/tabs/scroll-right.gif); = BORDER-BOTTOM-COLOR: #aeaeae; BORDER-TOP-COLOR: #aeaeae; = BORDER-RIGHT-COLOR: #aeaeae } .x-window-proxy { BORDER-LEFT-COLOR: #b0b0b0; BACKGROUND: #e0e0e0; BORDER-BOTTOM-COLOR: = #b0b0b0; BORDER-TOP-COLOR: #b0b0b0; BORDER-RIGHT-COLOR: #b0b0b0 } .x-window-tl .x-window-header { COLOR: #555 } .x-window-tc { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/top-bottom.png) } .x-window-tl { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/left-corners.png) } .x-window-tr { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/right-corners.png) } .x-window-bc { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/top-bottom.png) } .x-window-bl { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/left-corners.png) } .x-window-br { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/right-corners.png) } .x-window-mc { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BACKGROUND: #e8e8e8; BORDER-LEFT: #d0d0d0 1px solid; BORDER-BOTTOM: = #d0d0d0 1px solid } .x-window-ml { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/left-right.png) } .x-window-mr { BACKGROUND-IMAGE: = url(/core/ext.ncbi/1/img/oldentrez/window/left-right.png) } .x-panel-ghost .x-window-tl { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-collapsed .x-window-tl { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-window-plain .x-window-mc { BORDER-RIGHT: #eee 1px solid; BORDER-TOP: #d0d0d0 1px solid; = BACKGROUND: #e8e8e8; BORDER-LEFT: #d0d0d0 1px solid; BORDER-BOTTOM: #eee = 1px solid } .x-window-plain .x-window-body { BORDER-RIGHT: #d0d0d0 1px solid; BORDER-TOP: #eee 1px solid; = BACKGROUND: none transparent scroll repeat 0% 0%; BORDER-LEFT: #eee 1px = solid; BORDER-BOTTOM: #d0d0d0 1px solid } BODY.x-body-masked .x-window-mc { BACKGROUND-COLOR: #e4e4e4 } BODY.x-body-masked .x-window-plain .x-window-mc { BACKGROUND-COLOR: #e4e4e4 } .x-html-editor-wrap { BORDER-LEFT-COLOR: #d0d0d0; BORDER-BOTTOM-COLOR: #d0d0d0; = BORDER-TOP-COLOR: #d0d0d0; BORDER-RIGHT-COLOR: #d0d0d0 } .x-panel-noborder .x-panel-body-noborder { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: = 0px; BORDER-RIGHT-WIDTH: 0px } .x-panel-noborder .x-panel-header-noborder { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM: #d0d0d0 = 1px solid; BORDER-RIGHT-WIDTH: 0px } .x-panel-noborder .x-panel-tbar-noborder .x-toolbar { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM: #d0d0d0 = 1px solid; BORDER-RIGHT-WIDTH: 0px } .x-panel-noborder .x-panel-bbar-noborder .x-toolbar { BORDER-TOP: #d0d0d0 1px solid; BORDER-LEFT-WIDTH: 0px; = BORDER-BOTTOM-WIDTH: 0px; BORDER-RIGHT-WIDTH: 0px } .x-window-noborder .x-window-mc { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; BORDER-BOTTOM-WIDTH: = 0px; BORDER-RIGHT-WIDTH: 0px } .x-window-plain .x-window-body-noborder { BORDER-TOP-WIDTH: 0px; BORDER-LEFT-WIDTH: 0px; 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(moveToY > 0 ? moveToY : moveToYDefault)=0A= }=0A= catch (e) {}=0A= =0A= var wLeftTopCornerOptions =3D ',left=3D' + moveToX + ',top=3D' + = moveToY + ',screenX=3D' + moveToX + ',screenY=3D' + moveToY=0A= =0A= allOptions =3D allOptions + wLeftTopCornerOptions=0A= =0A= w =3D window.open (link, windowname, allOptions)=0A= w.focus()=0A= =0A= link.target=3Dwindowname=0A= =0A= return false;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function focuswin(windowname)=0A= {=0A= windowname =3D String(windowname).replace(/-/g, "_")=0A= w =3D = window.open("",windowname,"menubar=3Dyes,scrollbars=3Dyes,toolbar=3Dyes,l= ocation=3Dyes,status=3Dyes,directories=3Dyes,resizable=3Dyes");=0A= w.focus();=0A= =0A= return true;=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseString (inStr)=0A= {=0A= var outStr =3D ''=0A= =0A= for (i =3D0; i <=3D inStr.length; i++)=0A= {=0A= outStr =3D inStr.charAt(i) + outStr=0A= }=0A= =0A= return outStr=0A= }=0A= =0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function reverseAndReplaceString (inStr, findStr, newStr)=0A= {=0A= return reverseString(inStr).replace(findStr, newStr)=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function initUnObscureEmail (className, innerHTML)=0A= {=0A= =0A= try{=0A= if (window.addEventListener)=0A= window.addEventListener('load', function() {unObscureEmail = (className, innerHTML)}, false)=0A= else if (window.attachEvent)=0A= window.attachEvent('onload', function() {unObscureEmail = (className, innerHTML)})=0A= }catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function unObscureEmail (className, innerHTML)=0A= {=0A= try {=0A= if (typeof(unObscuredEmails) =3D=3D 'undefined')=0A= unObscuredEmails =3D new Array()=0A= =0A= if (! unObscuredEmails[className])=0A= {=0A= =0A= var elmnts =3D document.getElementsByTagName("span")=0A= for (var i =3D 0, len =3D elmnts.length; i < len; i++)=0A= {=0A= if (elmnts.item(i).className.indexOf(className, " ") = !=3D -1)=0A= {=0A= elmnts.item(i).innerHTML =3D innerHTML;=0A= unObscuredEmails[className] =3D true=0A= =0A= }=0A= }=0A= }=0A= }=0A= catch(e){=0A= }=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function pubMedDbLinkSubmit(control) {=0A= try{=0A= if (control.pubmedOption)=0A= control =3D control.pubmedOption=0A= if (control.options)=0A= location.href =3D = control.options[control.options.selectedIndex].value;=0A= }=0A= catch(e){}=0A= return false;=0A= }=0A= =0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= // elements "a", "area" with "ref" attribute report to redirect utility = before dereferencing link=0A= //=0A= function initRedirectClicks(report_url) {=0A= =0A= if (report_url && typeof jQuery !=3D 'undefined')=0A= jQuery(document).click(function(e) {=0A= =0A= //=0A= if (!e) return true;=0A= //=0A= if (e.shiftKey || e.altKey || e.ctrlKey) return true;=0A= //=0A= var target =3D jQuery(e.target).closest("a[ref], area[ref]");=0A= if (!target || target.length =3D=3D 0) return true;=0A= //=0A= var ref =3D target.attr("ref");=0A= var href =3D target.attr("href")=0A= =0A= // special processing of href element for pubmed's authors=0A= if (typeof (href) !=3D 'undefined' && = href.indexOf('sites/entrez') && href.indexOf('%5Bauth%5D'))=0A= {=0A= var newHref =3D replacePubMedUnsupportedChars(href);=0A= if (newHref !=3D href)=0A= target.attr("href", newHref)=0A= }=0A= =0A= // append ref with value of href if 'redirect-to-url' is = missing in ref.=0A= if (typeof (ref) !=3D 'undefined' && = ref.indexOf('redirect-to-url') =3D=3D -1)=0A= {=0A= ref =3D ref + '&redirect-to-url=3D' + = encodeURIComponent(href)=0A= //=0A= jQuery.ajax({=0A= type: "HEAD",=0A= url: report_url + '?' + ref,=0A= timeout: 1000,=0A= async: false=0A= });=0A= }=0A= =0A= return true;=0A= });=0A= };=0A= =0A= // function to replace unsupported charachters in author names to be = searchable in PubMed database.=0A= function replacePubMedUnsupportedChars (str)=0A= {=0A= // replace low 128 chars automatically=0A= str =3D str.replace(/%26%23(x000[0-7][0-9a-f])%3b/ig,=0A= function($0, $1){=0A= return (String.fromCharCode('0' + $1))=0A= }=0A= )=0A= // replace others based on map and if it is not in the map replace = with empty string.=0A= str =3D = str.replace(/%26%23(x[0-9a-f][0-9a-f][0-9a-f][0-9a-f][0-9a-f])%3b/ig,=0A= function($0, $1){=0A= return (pubmedUnsupportedCharMap[$1] ? = pubmedUnsupportedCharMap[$1] : '')=0A= }=0A= )=0A= return str;=0A= }=0A= //=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= // Based on script written by Dean Edwards, 2005=0A= // http://dean.edwards.name/=0A= =0A= var pmc_script =3D {=0A= addEvent: function(element, type, handler) {=0A= // assign each event handler a unique ID=0A= if (!handler.$$guid) handler.$$guid =3D this.addEvent_guid++;=0A= // create a hash table of event types for the element=0A= if (!element.events) element.events =3D {};=0A= // create a hash table of event handlers for each element/event pair=0A= var handlers =3D element.events[type];=0A= if (!handlers) {=0A= handlers =3D element.events[type] =3D {};=0A= // store the existing event handler (if there is one)=0A= if (element["on" + type]) {=0A= handlers[0] =3D element["on" + type];=0A= }=0A= }=0A= // store the event handler in the hash table=0A= handlers[handler.$$guid] =3D handler;=0A= // assign a global event handler to do all the work=0A= element["on" + type] =3D handleEvent;=0A= =0A= =0A= function handleEvent(event) {=0A= var returnValue =3D true;=0A= // grab the event object (IE uses a global event object)=0A= event =3D event || fixEvent(window.event);=0A= // get a reference to the hash table of event handlers=0A= var handlers =3D this.events[event.type];=0A= // execute each event handler=0A= for (var i in handlers) {=0A= this.$$handleEvent =3D handlers[i];=0A= if (this.$$handleEvent(event) =3D=3D=3D false) {=0A= returnValue =3D false;=0A= }=0A= }=0A= return returnValue;=0A= };=0A= =0A= function fixEvent(event) {=0A= // add W3C standard event methods=0A= event.preventDefault =3D fixEvent.preventDefault;=0A= event.stopPropagation =3D fixEvent.stopPropagation;=0A= return event;=0A= };=0A= =0A= fixEvent.preventDefault =3D function() {=0A= this.returnValue =3D false;=0A= };=0A= =0A= fixEvent.stopPropagation =3D function() {=0A= this.cancelBubble =3D true;=0A= };=0A= },=0A= =0A= // a counter used to create unique IDs=0A= addEvent_guid: 1,=0A= =0A= removeEvent: function(element, type, handler) {=0A= // delete the event handler from the hash table=0A= if (element.events && element.events[type]) {=0A= delete element.events[type][handler.$$guid];=0A= }=0A= }=0A= }=0A= =0A= =0A= // = *************************************************************************= ***=0A= // implementation of figure's popup using jQuery and = jQuery.fn.hoverIntent lib=0A= // it set appropriate handlers for all "a" elements with "figpopup" = class name.=0A= // = *************************************************************************= ***=0A= if (typeof jQuery !=3D 'undefined' && typeof jQuery.fn.hoverIntent !=3D = 'undefined') {=0A= (function($j) {=0A= // = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D hoverHandlers = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=3D=3D=0A= var hoverHandlers =3D function (opts) {=0A= this.config =3D {}=0A= this.self =3D this;=0A= this.__init(opts)=0A= }=0A= =0A= $j.fn.extend(hoverHandlers.prototype, {=0A= //=0A= __init: function(opts) {=0A= $j.fn.extend(this.config, opts)=0A= },=0A= //=0A= over: function (el) {=0A= var canvas =3D $j('.large-thumb-canvas', el)=0A= var prnt =3D canvas.parent();=0A= var win =3D $j(window)=0A= =0A= //=0A= if (canvas && prnt && win)=0A= {=0A= =0A= // collect necessary coordinates from all = intresting objects=0A= canvas.coords =3D this._x_coords(canvas, = 'canvas')=0A= prnt.coords =3D this._x_coords(prnt, = 'parent')=0A= win.coords =3D this._x_coords(win, = 'window')=0A= =0A= // replace @src with value of @hires, because = href hold high resolution image and src low one.=0A= $j('img', canvas).attr('src',=0A= function(){=0A= var hires =3D $j(this).attr("hires");=0A= return (typeof (hires) !=3D = 'undefined' && hires !=3D this.src)=0A= ? hires : this.src=0A= }=0A= )=0A= =0A= // make arrangement of canvas in the view port = nearby parent element.=0A= var cnvsRltvToPrnt =3D = this._x_arrange_canvas(canvas.coords, prnt.coords, win.coords)=0A= =0A= // visualize the canvas with images.=0A= canvas.css('top', cnvsRltvToPrnt.top + 'px')=0A= canvas.css('left', cnvsRltvToPrnt.left + 'px')=0A= canvas.css('display', 'block')=0A= } // canvas=0A= }, // over=0A= //=0A= out: function (el) {=0A= var canvas =3D $j('.large-thumb-canvas', el)=0A= canvas.css('display', 'none')=0A= },=0A= //=0A= _x_offset: function(el, elname) {=0A= var c =3D {}=0A= if (el[0] =3D=3D window )=0A= c =3D this._x_scroll(el, elname)=0A= else=0A= c =3D el.offset()=0A= //console.info('%s.offset {top,left} =3D {%s, %s}', = elname, c.top, c.left)=0A= return c=0A= },=0A= _x_scroll: function(el, elname) {=0A= var c =3D {top: el.scrollTop(), left: = el.scrollLeft()}=0A= //console.info('%s.scroll {top,left} =3D {%s, %s}', = elname, c.top, c.left)=0A= return c=0A= },=0A= _x_width: function(el, elname) {=0A= var w =3D el.outerWidth() || el.width()=0A= //console.info('%s.width =3D %s; outerWidth =3D = %s; width =3D %s', elname, w, el.outerWidth(), el.width())=0A= //IE: alert(elname + '.width =3D ' + w + '; = outerWidth =3D ' + el.outerWidth() + 'width =3D ' + el.width())=0A= return w=0A= },=0A= _x_height: function(el, elname) {=0A= var h =3D el.outerHeight() || el.height()=0A= // console.info('%s.height =3D %s', elname, h)=0A= return h=0A= },=0A= _x_coords: function(el, elname) {=0A= var size =3D { width: this._x_width (el, elname), = height: this._x_height(el, elname)}=0A= var coords =3D {=0A= scroll: this._x_scroll(el, elname),=0A= width: size.width,=0A= height: size.height,=0A= offset: this._x_offset(el, elname),=0A= size: size=0A= }=0A= return coords=0A= },=0A= _x_get_rltv_coord: function(trgtObj, baseObj, = label) {=0A= var c =3D {top: trgtObj.top - baseObj.top, left: = trgtObj.left - baseObj.left}=0A= //console.info("%s {top: %s, left: %s}", label, = c.top, c.left)=0A= return c=0A= },=0A= //=0A= _x_get_empty_space: function(objCoords, = objSize, viewPortCoords, viewPortSize, label) {=0A= var objRelToViewPort =3D = this._x_get_rltv_coord(objCoords, viewPortCoords, '_x_get_empty_space: = for ' + label);=0A= var c =3D {above: objRelToViewPort.top,=0A= below: viewPortSize.height - = (objRelToViewPort.top + objSize.height),=0A= left: objRelToViewPort.left,=0A= right: viewPortSize.width - = (objRelToViewPort.left + objSize.width)}=0A= $j.each(c, function(k, v){c[k] =3D (v < 0 ? 0 : v)})=0A= //console.info("%s {above: %s, below: %s, left: %s, = right: %s}", label, c.above, c.below, c.left, c.right)=0A= return c=0A= },=0A= //=0A= _x_get_bigest_space_area_name: function(spaces, label) {=0A= var sArr =3D [];=0A= for (k in spaces){ sArr[sArr.length] =3D {k: k, v: = spaces[k]} }=0A= // sort in reverse order=0A= sArr.sort (function(a,b){return ( a.v < b.v ? 1 : ( = a.v > b.v ? - 1 : 0 ) )})=0A= // console.info('%s: %s', label, sArr[0].k)=0A= return sArr[0].k=0A= },=0A= //=0A= _x_get_space_ratios: function(spaces, = viewPortSize, label) {=0A= var ratios =3D {above: 0, left: 0}=0A= if (viewPortSize.height > 0)=0A= ratios.above =3D spaces.above / = viewPortSize.height=0A= if (viewPortSize.width > 0)=0A= ratios.left =3D spaces.left / viewPortSize.width=0A= // console.info('ratio: %s {above: %s, left: %s}', = label, ratios.above, ratios.left)=0A= return ratios=0A= },=0A= _x_arrange_canvas: function(c_c, prnt_c, = viewp_c) {=0A= // then calculate empty space areas around parent = element of the canvas, which is ususally an anchor ("a" element)=0A= var emptySpacesArndPrntInViewPort =3D = this._x_get_empty_space (prnt_c.offset, prnt_c.size, viewp_c.offset, = viewp_c.size, 'emptySpacesArndPrntInWinPort')=0A= =0A= // get the area name, where the most linear space = avaiable=0A= var areaName =3D = this._x_get_bigest_space_area_name(emptySpacesArndPrntInViewPort, = viewp_c.size, 'spacios areaName')=0A= =0A= // calculate the proportions of area to be taken by = canvas in empty space area=0A= // relativly to the parent element.=0A= var ratios =3D = this._x_get_space_ratios(emptySpacesArndPrntInViewPort, viewp_c.size, = 'ratios')=0A= =0A= // calculate parent's coordinates relative to view = port=0A= var prntRltvToViewPort =3D = this._x_get_rltv_coord(prnt_c.offset, viewp_c.offset, = 'prntRltvToViewPort')=0A= =0A= // declare canvas relative coordinates=0A= var cnvsRltvToPrnt =3D {top: 0, left: 0}=0A= =0A= // choose appropriate location for placing canvas.=0A= // and choose the 1st element of an array as the one = with the biggest area around parent of canvas.=0A= // console.info ('place it at the %s', = bigestEmptySpaceAreaName)=0A= // calculations are relative to the left corner of = the parent element of canvas. (it has to have the css property = position:relative)=0A= switch (areaName)=0A= {=0A= case 'above':=0A= cnvsRltvToPrnt.top =3D - c_c.height=0A= cnvsRltvToPrnt.left =3D prnt_c.width * 0.5 - = c_c.width * ratios.left=0A= break;=0A= case 'below':=0A= cnvsRltvToPrnt.top =3D prnt_c.height=0A= cnvsRltvToPrnt.left =3D prnt_c.width * 0.5 - = c_c.width * ratios.left=0A= break;=0A= case 'left':=0A= cnvsRltvToPrnt.left =3D - c_c.width=0A= cnvsRltvToPrnt.top =3D prnt_c.height * 0.5 = - c_c.height * ratios.above=0A= break;=0A= case 'right':=0A= cnvsRltvToPrnt.left =3D prnt_c.width=0A= cnvsRltvToPrnt.top =3D prnt_c.height * 0.5 = - c_c.height * ratios.above=0A= break;=0A= }=0A= =0A= // recalculate canvas' coordinates relative to = parent into coordinates relative to view port.=0A= var cnvsRltvToViewPort =3D {=0A= top: prntRltvToViewPort.top + = cnvsRltvToPrnt.top,=0A= left: prntRltvToViewPort.left + = cnvsRltvToPrnt.left=0A= }=0A= //console.info("cnvsRltvToPrnt {top:%s, left: %s}", = cnvsRltvToPrnt.top, cnvsRltvToPrnt.left)=0A= //console.info("cnvsRltvToViewPort {top:%s, left: = %s}", cnvsRltvToViewPort.top, cnvsRltvToViewPort.left)=0A= =0A= // adjust relative position of canvas to the window = if calculated values=0A= // are forcing canvas go out of view port=0A= // next order should be preserved to keep left top = corner visible always=0A= =0A= // adjust right side and move a bit to the left=0A= if (cnvsRltvToViewPort.left + c_c.width > = viewp_c.width)=0A= {=0A= var horAdj =3D c_c.width - (viewp_c.width - = cnvsRltvToViewPort.left)=0A= cnvsRltvToPrnt.left -=3D horAdj=0A= cnvsRltvToViewPort.left -=3D horAdj=0A= //console.log('adjust right side and move to = the left %spx', horizontalAdjustment)=0A= }=0A= =0A= // adjust below side and move to the top=0A= if (cnvsRltvToViewPort.top + c_c.height > = viewp_c.height)=0A= {=0A= var vertAdj =3D c_c.height - (viewp_c.height - = cnvsRltvToViewPort.top)=0A= cnvsRltvToPrnt.top -=3D vertAdj=0A= cnvsRltvToViewPort.top -=3D vertAdj=0A= // console.log('adjust below side and move to = the top %spx', verticalAdjustment)=0A= }=0A= =0A= // adjust left side and move to the right=0A= if (cnvsRltvToViewPort.left < 0)=0A= {=0A= // console.log('adjust left side and move to the = right %spx', -(cnvsLeftRelativeToWindowPort))=0A= cnvsRltvToPrnt.left -=3D = cnvsRltvToViewPort.left=0A= cnvsRltvToViewPort.left =3D 0=0A= }=0A= // adjust above side and move to the bottom=0A= if (cnvsRltvToViewPort.top < 0)=0A= {=0A= // console.log('adjust above side and move to = the bottom %spx', -(cnvsTopRelativeToWindowPort))=0A= cnvsRltvToPrnt.top -=3D = cnvsRltvToViewPort.top=0A= cnvsRltvToViewPort.top =3D 0=0A= }=0A= // console.info("cnvsRltvToPrnt adjusted {top: %s, = left: %s}", cnvsRltvToPrnt.top, cnvsRltvToPrnt.left)=0A= // console.info("cnvsRltvToViewPort adjusted {top: = %s, left: %s}", cnvsRltvToViewPort.top, cnvsRltvToViewPort.left)=0A= return cnvsRltvToPrnt=0A= }=0A= })=0A= // = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D end of hoverHandlers = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=0A= =0A= =0A= // = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D $j.fn.figPopup = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D=3D=3D=3D=3D=0A= function hoverOverHandler () {=0A= var h =3D new hoverHandlers();=0A= h.over(this)=0A= }=0A= =0A= function hoverOutHandler () {=0A= var h =3D new hoverHandlers();=0A= h.out(this)=0A= }=0A= =0A= $j.fn.figPopup =3D function(opts){=0A= var config =3D {=0A= interval: 500,=0A= timeout: 0,=0A= over: hoverOverHandler, // handler onMouseOver=0A= out: hoverOutHandler // handler onMouseOut=0A= }=0A= $j.extend(config, opts)=0A= return config=0A= }=0A= =0A= // = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D= =3D end of $j.fn.figPopup = =3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=0A= =0A= }) (jQuery) // end of extention of jQuery with figPopup=0A= =0A= =0A= =0A= jQuery(document).ready( function () {=0A= var fp_cfg =3D new jQuery.fn.figPopup()=0A= jQuery('a.figpopup').hoverIntent(fp_cfg)=0A= });=0A= }=0A= =0A= // end of hoverIntent routines for figures' popups=0A= // = *************************************************************************= ***=0A= // implementation of ....=0A= // = *************************************************************************= ***=0A= ------=_NextPart_000_0000_01CAE911.5CDEEDB0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.ncbi.nlm.nih.gov/corehtml/pmc/js/noext.menu.js if (typeof(noext) =3D=3D=3D 'undefined') { noext =3D {};=20 } if (typeof jQuery =3D=3D=3D 'undefined') { throw new Error('noext.Menu: jQuery must be present'); } // Constructor noext.Menu =3D function (n, subMenuStyle) { this.n =3D n; this.subMenuStyle =3D (subMenuStyle =3D=3D=3D 'ext') ? 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