bluuebunny/crossref_metadata_2025 huggingface dataset:
Suberoylanilide hydroxamic acid (Zolinza/vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice
Authors: Shankar Sharmila , Davis Rachel , Singh Karan P. , Kurzrock Razelle , Ross Douglas D. , Srivastava Rakesh K.
Published: June 2009

The purpose of this study was to examine whether histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; Zolinza/vorinostat) could sensitize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant breast carcinoma in vivo. BALB/c nude mice were orthotopically implanted with TRAIL-resistant MDA-MB-468 cells and treated i.v. with SAHA, TRAIL, or SAHA followed by TRAIL for four times during first 3 weeks. The effects of drugs on tumor growth and markers of apoptosis, metastasis, and angiogenesis were examined. SAHA sensitized TRAIL-resistant xenografts to undergo apoptosis through multiple mechanisms. Whereas TRAIL alone was ineffective, SAHA inhibited growth of MDA-MB-468 xenografts in nude mice by inhibiting markers of tumor cell proliferation, angiogenesis, and metastasis and inducing cell cycle arrest and apoptosis. The sequential treatment of nude mice with SAHA followed by TRAIL was more effective in inhibiting tumor growth, angiogenesis, and metastasis and inducing apoptosis than SAHA alone, without overt toxicity. Treatment of nude mice with SAHA resulted in down-regulation of nuclear factor-κB and its gene products (cyclin D1, Bcl-2, Bcl-XL, vascular endothelial growth factor, hypoxia-inducible factor-1α, interleukin-6, interleukin-8, matrix metalloproteinase-2, and matrix metalloproteinase-9) and up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa, PUMA, p21CIP1, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in tumor cells. Furthermore, control mice showing increased rate of tumor growth had increased numbers of CD31+ or von Willebrand factor-positive blood vessels and increased circulating vascular endothelial growth factor receptor 2-positive endothelial cells compared with SAHA-treated or SAHA plus TRAIL-treated mice. In conclusion, sequential treatment with SAHA followed by TRAIL may target multiple pathways in tumor progression, angiogenesis, and metastasis and represents a novel therapeutic approach to treat breast cancer. [Mol Cancer Ther 2009;8(6):1596–69]
Novel benzylidene-thiazolidine-2,4-diones inhibit Pim protein kinase activity and induce cell cycle arrest in leukemia and prostate cancer cells
Authors: Beharry Zanna , Zemskova Marina , Mahajan Sandeep , Zhang Fengxue , Ma Jian , Xia Zuping , Lilly Michael , Smith Charles D. , Kraft Andrew S.
Published: June 2009

The Pim protein kinases play important roles in cancer development and progression, including prostate tumors and hematologic malignancies. To investigate the potential role of these enzymes as anticancer drug targets, we have synthesized novel benzylidene-thiazolidine-2,4-diones that function as potent Pim protein kinase inhibitors. With IC50 values in the nanomolar range, these compounds block the ability of Pim to phosphorylate peptides and proteins in vitro and, when added to DU145 prostate cancer cells overexpressing Pim, inhibit the ability of this enzyme to phosphorylate a known substrate, the BH3 protein BAD. When added to prostate cancer cell lines, including PC3, DU145, and CWR22Rv1, and human leukemic cells, MV4;11, K562, and U937 cells, these compounds induce G1-S cell cycle arrest and block the antiapoptotic effect of the Pim protein kinase. The cell cycle arrest induced by these compounds is associated with an inhibition of cyclin-dependent kinase 2 and activity and translocation of the Pim-1 substrate p27Kip1, a cyclin-dependent kinase 2 inhibitory protein, to the nucleus. Furthermore, when added to leukemic cells, these compounds synergize with the mammalian target of rapamycin inhibitor rapamycin to decrease the phosphorylation level of the translational repressor 4E-BP1 at sites phosphorylated by mammalian target of rapamycin. Combinations of rapamycin and the benzylidene-thiazolidine-2,4-diones synergistically block the growth of leukemic cells. Thus, these agents represent novel Pim inhibitors and point to an important role for the Pim protein kinases in cell cycle control in multiple types of cancer cells. [Mol Cancer Ther 2009;8(6):1473–83]
Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines
Authors: Eguchi Tomohiro , Itadani Hiraku , Shimomura Toshiyasu , Kawanishi Nobuhiko , Hirai Hiroshi , Kotani Hidehito
Published: June 2009

Because cyclin-dependent kinases (CDK) play a pivotal role in cancer progression, the development of CDK inhibitors has attracted attention in antitumor therapy. However, despite significant preclinical and clinical developments, CDK inhibition biomarkers for predicting efficacy against certain cancers in individual patients have not been identified. Here, we characterized a macrocyclic quinoxalin-2-one CDK inhibitor, compound A, and identified a gene biomarker for predicting its efficacy. Compound A showed 100-fold selectivity for CDK family proteins over other kinases and inhibited both E2F transcriptional activity and RNA polymerase II phosphorylation. Compound A treatment resulted in decreased proliferation in various tumor cell lines; however, the apoptosis induction rate differed significantly among the cell lines examined, which was consistent with roscovitine. By comparing the mRNA expression profiles of sensitive and resistant cell lines, we found that expression levels of an endogenous CDK inhibitor, p18INK4C, showed a strong negative correlation to the sensitivity. In fact, p18 status was correlated with the response to CDK inhibitor in an independent data set of multiple myeloma cell lines and silencing p18 expression increased the susceptibility of resistant cells to CDK inhibitors. The analysis of molecular mechanisms revealed that cells with lowered p18 had aberrant CDK6 and E2F activities, which resulted in a transcriptional down-regulation of Mcl-1, a key molecule associated with flavopiridol-induced apoptosis, thereby leading to susceptibility to therapeutic intervention with CDK inhibitors. These results identified a molecular basis for CDK inhibitors to exert an antitumor effect in p18-deficient cancers and support the clinical use of CDK inhibitors. [Mol Cancer Ther 2009;8(6):1460–72]
Roles of DNA repair and reductase activity in the cytotoxicity of the hypoxia-activated dinitrobenzamide mustard PR-104A
Authors: Gu Yongchuan , Patterson Adam V. , Atwell Graham J. , Chernikova Sophia B. , Brown J. Martin , Thompson Larry H. , Wilson William R.
Published: June 2009

PR-104 is a dinitrobenzamide mustard currently in clinical trial as a hypoxia-activated prodrug. Its major metabolite, PR-104A, is metabolized to the corresponding hydroxylamine (PR-104H) and amine (PR-104M), resulting in activation of the nitrogen mustard moiety. We characterize DNA damage responsible for cytotoxicity of PR-104A by comparing sensitivity of repair-defective hamster Chinese hamster ovary cell lines with their repair-competent counterparts. PR-104H showed a repair profile similar to the reference DNA cross-linking agents chlorambucil and mitomycin C, with marked hypersensitivity of XPF−/−, ERCC1−/−, and Rad51D−/− cells but not of XPD−/− or DNA-PKCS−/− cells. This pattern confirmed the expected dependence on the ERCC1-XPF endonuclease, implicated in unhooking DNA interstrand cross-links at blocked replication forks, and homologous recombination repair (HRR) in restarting collapsed forks. However, even under anoxia, the hypersensitivity of XPF−/−, ERCC1−/−, and Rad51D−/− cells to PR-104A itself was lower than for chlorambucil. To test whether this reflects inefficient PR-104A reduction, a soluble form of human NADPH:cytochrome P450 oxidoreductase was stably expressed in Rad51D−/− cells and their HRR-restored counterpart. This expression increased hypoxic metabolism of PR-104A to PR-104H and PR-104M as well as hypoxia-selective cytotoxicity of PR-104A and its dependence on HRR. We conclude that PR-104A cytotoxicity is primarily due to DNA interstrand cross-linking by its reduced metabolites, although under conditions of inefficient PR-104A reduction (low reductase expression or aerobic cells), a second mechanism contributes to cell killing. This study shows that hypoxia, reductase activity, and DNA interstrand cross-link repair proficiency are key variables that interact to determine PR-104A sensitivity. [Mol Cancer Ther 2009;8(6):1714–23]
IKKβ-mediated nuclear factor-κB activation attenuates smac mimetic–induced apoptosis in cancer cells
Authors: Bai Lang , Chen Wenshu , Chen Wenjie , Wang Xia , Tang Hong , Lin Yong
Published: June 2009

Smac mimetics (SM) have been recently reported to kill cancer cells through the extrinsic apoptosis pathway mediated by autocrine tumor necrosis factor (TNF). SM also activates nuclear factor-κB (NF-κB). However, how SM induces NF-κB and the role of NF-κB in SM-induced cancer cell death has not been well elucidated. We found that effective blockage of NF-κB had no detectable effect on SM compound 3 (SMC3)–induced TNF secretion, suggesting that the induction of TNF by SMC3 is independent of NF-κB. Conversely, SMC3-induced NF-κB activation was found to be mediated by autocrine TNF because this effect of SMC3 was effectively inhibited when TNF was blocked with either a TNF neutralizing antibody or TNF small interfering RNA. In addition, although SMC3 dramatically reduced c-IAP1 level, it had marginal effect on c-IAP2 expression, TNF-induced RIP modification, NF-κB activation, and downstream antiapoptosis NF-κB target expression. Furthermore, blocking NF-κB by targeting IKKβ or RelA substantially potentiated SMC3-induced cytotoxicity, suggesting that the NF-κB pathway inhibits SMC3-induced apoptosis in cancer cells. Our results show that through TNF autocrine, SM induces an IKKβ-mediated NF-κB activation pathway that protects cancer cells against SM-induced apoptosis, and thus, NF-κB blockage could be an effective approach for improving the anticancer value of SM. [Mol Cancer Ther 2009;8(6):1636–45]
Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts
Authors: Messersmith Wells A. , Rajeshkumar N.V. , Tan Aik Choon , Wang Xiao Fei , Diesl Veronica , Choe Sung E. , Follettie Max , Coughlin Christina , Boschelli Frank , Garcia-Garcia Elena , Lopez-Rios Fernando , Jimeno Antonio , Hidalgo Manuel
Published: June 2009

Recently, Src tyrosine kinase has emerged as an attractive target for anticancer therapy, and Src is overexpressed in pancreatic cancer. The purpose of the study was to investigate the in vivo efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, using a panel of human pancreatic tumor xenografts. Surgically resected human pancreatic tumors were implanted into female nude mice and randomized to bosutinib versus control. Src and other pathways were analyzed by Western Blot, IHC, and Affymetrix U133 Plus 2.0 gene arrays. Of 15 patient tumors, 3 patient tumors were found to be sensitive to bosutinib, defined as tumor growth of <45% than that of control tumors. There were no definite differences between sensitive and resistant tumors in the baseline Src kinase pathway protein expression assessed by Western Blot. Caveolin-1 expression, as assessed by reverse transcription-PCR and immunohistochemistry, was frequently higher in sensitive cases. In sensitive tumors, bosutinib resulted in increased apoptosis. Phosphorylation of key signaling molecules downstream of Src, signal transducers and activators of transcription 3, and signal transducers and activators of transcription 3, were significantly inhibited by bosutinib. K-Top Scoring Pairs analysis of gene arrays gave a six-gene classifier that predicted resistance versus sensitivity in six validation cases. These results may aid the clinical development of bosutinib and other Src inhibitors in pancreas cancer. [Mol Cancer Ther 2009;8(6):1484–93]
Mutation-associated fusion cancer genes in solid tumors
Authors: Kaye Frederic J.
Published: June 2009

Chromosomal translocations and fusion oncogenes serve as the ultimate biomarker for clinicians as they show specificity for distinct histopathologic malignancies while simultaneously encoding an etiologic mutation and a therapeutic target. Previously considered a minor mutational event in epithelial solid tumors, new methodologies that do not rely on the detection of macroscopic cytogenetic alterations, as well as access to large series of annotated clinical material, are expanding the inventory of recurrent fusion oncogenes in both common and rare solid epithelial tumors. Unexpectedly, related assays are also revealing a high number of tandem or chimeric transcripts in normal tissues including, in one provocative case, a template for a known fusion oncogene. These observations may force us to reassess long-held views on the definition of a gene. They also raise the possibility that some rearrangements might represent constitutive forms of a physiological chimeric transcript. Defining the chimeric transcriptome in both health (transcription-induced chimerism and intergenic splicing) and disease (mutation-associated fusion oncogenes) will play an increasingly important role in the diagnosis, prognosis, and therapy of patients with cancer. [Mol Cancer Ther 2009;8(6):1399–408]
Luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin
Authors: Zhou Qiong , Yan Bing , Hu Xiaowen , Li Xue-Bing , Zhang Jie , Fang Jing
Published: June 2009

Luteolin, a common dietary flavonoid, has been found to have antitumor properties and therefore poses special interest for the development of preventive and/or therapeutic agent for cancers. E-cadherin, a marker of epithelial cells, mediates cell-cell adhesion. Decreased expression of E-cadherin results in a loss of cell-cell adhesion and an increased cell invasion. Many studies have shown the antiproliferative activities of luteolin on cancer cells. However, the effects of luteolin on invasion of cancer cells remain unclear. In this article, we show that luteolin inhibits invasion of prostate cancer PC3 cells through E-cadherin. We found that Luteolin induced expression of E-cadherin through mdm2. Overexpression of mdm2 or knockdown of E-cadherin could restore invasion of PC3 cells after luteolin treatment. Luteolin inhibits mdm2 through AKT and overexpression of active AKT attenuated luteolin-induced expression of E-cadherin, suggesting that luteolin regulates E-cadherin through AKT/mdm2 pathway. The in vivo experiments showed that luteolin inhibited spontaneous lung metastasis of PC3 cells implanted onto the nude mice. These findings provide a new sight into the mechanisms that luteolin is against cancer cells, and suggest that molecular targeting of E-cadherin by luteolin may be a useful strategy for treatment of invasive prostate cancers. [Mol Cancer Ther 2009;8(6):1684–91]
Ghrelin Plasma Levels Are Not Altered in Major Depression
Authors: Kluge Michael , Schüssler Petra , Schmid Dagmar , Uhr Manfred , Kleyer Sara , Yassouridis Alexander , Steiger Axel
Published: June 2009

Background: In patients with major depression, the function of most endocrine axes is altered compared to healthy subjects. The orexigenic hormone ghrelin, which shows higher plasma levels in females than males, interacts with several of these endocrine axes. In addition, ghrelin levels in depressed patients decrease with psychopathological improvement. Therefore, we hypothesized that ghrelin levels in patients with major depression would be higher than in healthy subjects. Methods: Nocturnal (20:00–07:00 h) secretion patterns of ghrelin in 20 patients with major depression [11 females, age 39.4 ± 10.2 years (mean ± standard deviation); 9 males, age 38.3 ± 10.4 years] with a total score on the Hamilton Depression Rating Scale, 21-item version, of 24.8 ± 5.2 and 20 healthy subjects [11 females, age 38.7 ± 10.8 years; 9 males, age 39.1 ± 11.2 years] were determined following an adaptation night. Results: Ghrelin plasma levels of depressed patients and matched healthy subjects did not differ at any point in time when stratified for sex. Accordingly, the area under the curve was comparable: depressed females, 423.3 ± 103.4; healthy females, 398.0 ± 94.6; depressed males, 266.3 ± 56.9, and healthy males, 228.4 ± 41.3. Conclusion: This is the first comparison of ghrelin secretion patterns in patients with major depression and healthy controls. Surprisingly, no relevant differences were ascertained between the two groups.
Stress Type Dependence of Expression and Cytoplasmic-Nuclear Partitioning of Glucocorticoid Receptor, Hsp90 and Hsp70 in Wistar Rat Brain
Authors: Djordjevic Ana , Adzic Miroslav , Djordjevic Jelena , Radojcic Marija B.
Published: June 2009

Chronic exposure to stress is associated with different behavioral and neurological syndromes including impaired excitability of nerve cells in hippocampus (HIPPO) and prefrontal cortex (PFC), regions of the brain that are important for adaptation. The successful adaptation to stress involves negative feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis provided by the glucocorticoid receptor (GR), which is a steroid-dependent transcription factor found in a heterocomplex with heat shock proteins Hsp90 and Hsp70. In Wistar rats, chronic social isolation leads to a significant decrease in serum corticosterone (CORT), probably due to alterations in the GR signaling pathway. We exploited this type of stress, alone or in combination with acute immobilization, to define changes in the expression level and compartmental distribution of GR, Hsp90 and Hsp70 in HIPPO and PFC. The results indicated that in acute and combined stress, when CORT was increased, GR was translocated to the nucleus in both brain structures. Under chronic stress, when CORT was below the control level, GR was retained in the cytoplasm of PFC, and evenly distributed between compartments in HIPPO. Simultaneously, heat shock proteins partitioning in HIPPO seemed to be mainly stress type-independent, while that of PFC was dependent on stress type. Thus, the stress type-specific responses of GR and heat shock proteins were mainly detected in PFC rather than in HIPPO of Wistar rats. The observed alterations in protein expression and cytoplasmic-nuclear partitioning of the GR, Hsp90 and Hsp70 proteins may be related to maladaptive response of the HPA axis under chronic stress.
CYP2D6 Genotype Predicts Antipsychotic Side Effects in Schizophrenia Inpatients: A Retrospective Matched Case-Control Study
Authors: Kobylecki Camilla J. , Jakobsen Klaus D. , Hansen Thomas , Jakobsen Ida V. , Rasmussen Henrik B. , Werge Thomas
Published: June 2009

Objective: The aim of the present retrospective pilot study was to examine the clinical impact of the cytochrome P450 (CYP) enzyme CYP2D6 poor metabolizer (PM) genotype in patients taking antipsychotic medication. The impaired metabolic capacity of the PM genotype results in higher steady-state plasma concentrations at a given dose, thus increasing the risk of toxic effects from medication. Methods: We identified 18 PM patients with a schizophrenia spectrum diagnosis from a clinical database covering all patients who have been analyzed in an ongoing standardized CYP2D6 screening program. Each PM patient was carefully matched on age, gender and diagnosis with an intermediate metabolizer (IM) and an extensive metabolizer (EM) from the same database to generate 18 triplets. Clinical data, primarily on side effects of treatment, were obtained from medical records by an experienced research and consultant psychiatrist, who was blinded to the results of the genotyping. Results: We found that extrapyramidal syndrome or tardive dyskinesia (EPS/TD) was significantly more frequent among PM patients than among the matched IM and EM control subjects. This finding was further supported by the significantly higher prevalence of noncompliance among the same PM patients. Importantly, this association was not due to differences in the use of CYP2D6-dependent or EPS/TD-causing medication across the 3 matched patient groups. Conclusions: This leads us to conclude that genetically encoded differences in the rate of drug metabolism through CYP2D6 can predict antipsychotic side effects and prompts the question of whether genotyping early in the course of illness to facilitate adjustment of pharmacotherapy will improve treatment outcomes and reduce side effects.
Poor Reliability of Vaginal and Endocervical Cultures for Evaluating Microbiology of Endometrial Cavity in Women with Chronic Endometritis
Authors: Cicinelli Ettore , De Ziegler Dominique , Nicoletti Roberto , Tinelli Raffaele , Saliani Nicola , Resta Leonardo , Bellavia Marina , De Vito Danila
Published: June 2009

Background: Chronic endometritis (CE) is a subtle pathology causing infertility and abnormal uterine bleeding. We evaluated the reliability of vaginal and cervical cultures for detecting infectious agents at the endometrial level. Methods: In a prospective diagnostic study, 181 women diagnosed with CE and 100 controls underwent vaginal, endocervical and endometrial sampling. Cultures for common bacteria, Neisseria gonorrhoeae, yeast and Ureaplasma urealyticum and PCR for Chlamydia trachomatis were performed. Results: The prevalent infectious agents at the endometrial level were common bacteria(59.7% of cases); U. urealyticum was detected in 11.0% and C. trachomatis in only 2.8%. The concordance rate between endocervical and endometrial specimens for common bacteria was 48.3%; 100% for C. trachomatis and 58.3% for U. urealyticum. The concordance rate between vaginal and endometrial cultures for common bacteria was 50.2%, only 16.7% for C. trachomatis and 48.8% for U. urealyticum. For common bacteria both vaginal and cervical cultures showed low sensitivities of 0.30 and 0.19, respectively. Conclusion: Common bacteria and U. urealyticum were the prevalent infectious agents in the uterine cavity of women diagnosed with CE. Both vaginal and endocervical cultures had low concordance with endometrial cultures. Only C. trachomatis test at cervical level had high concordance with endometrial findings.
Dehydroepiandrosterone Pretreatment Alters the Ischaemia/Reperfusion-Induced VEGF, IL-1 and IL-6 Gene Expression in Acute Renal Failure
Authors: Vannay Ádám , Fekete Andrea , Langer Róbert , Tóth Tibor , Sziksz Erna , Vásárhelyi Barna , Szabó Attila J. , Losonczy György , Ádori Csaba , Gál Anikó , Tulassay Tivadar , Szabó András
Published: June 2009

Background: Beneficial effects of dehydroepiandrosterone (DHEA) pretreatment were reported in ischaemia/reperfusion (I/R)-induced kidney damage. Methods: To investigate the mechanism of DHEA pretreatment during renal I/R injury, the left renal pedicles of DHEA- [GDHEA; 4.0 mg/kg/day DHEA dissolved in propylene glycol (PG)] and PG-pretreated male Wistar rats (GPG) were clamped for 55 min followed by 2 (T2) and 24 h (T24) of reperfusion. Sham-operated, non-clamped animals (T₀) served as controls in both groups. Renal function, kidney morphology and interleukin 1β (IL-1β), interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) expression were determined in the kidneys of both groups. Results: Renal functional parameters and kidney structure did not differ in GDHEA versus GPG at any time point. Renal mRNA expression of IL-1β was lower at T₀, while IL-6 at T2 was lower in GDHEA than in GPG.While renal VEGF mRNA expression remained unchanged, protein levels were increased at T2 and T24 compared to T₀ kidneys in both groups. VEGF protein levels were lower at T2 and T24 in GDHEA than in GPG. Conclusion: We found that DHEA pretreatment alters renal IL-1β, IL-6 and VEGF synthesis. Moreover, contrary changes in VEGF mRNA and protein levels suggest that VEGF synthesis – distinct from other organs – might be primarily posttranscriptionally regulated in postischaemic rat kidneys.
Plasma Exchange Therapy in Steroid-Unresponsive Relapses in Patients with Multiple Sclerosis
Authors: Trebst Corinna , Reising Ansgar , Kielstein Jan T. , Hafer Carsten , Stangel Martin
Published: June 2009

Background:Plasma exchange (PE) is well established for conditions such as rapid progressive vasculitis associated with autoantibodies against neutrophil cytoplasmic antigens (ANCA), anti-glomerular basement membrane (GBM) antibody disease, or thrombotic thrombocytopenic purpura (TTP). Also, several neurological disorders, such as acute worsening in myasthenia gravis, Guillan-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), can successfully be treated with PE. Only small case series have previously shown that PE is also effective in relapses in patients with multiple sclerosis (MS). Methods:We report our experiences of PE therapy in a series of 20 patients with 21 steroid unresponsive MS relapses. Results:A marked-to-moderate clinical response with clear gain of function in 76% of patients with uni- or bilateral optic neuritis and in 87.5% of patients with relapses other than optic neuritis was observed. Conclusions:PE is an effective and well tolerated therapeutic option for steroid-unresponsive MS relapses.
The Impact of Gene-Environment Dependence and Misclassification in Genetic Association Studies Incorporating Gene-Environment Interactions
Authors: Lindström Sara , Yen Yu-Chun , Spiegelman Donna , Kraft Peter
Published: June 2009

The possibility of gene-environment interaction can be exploited to identify genetic variants associated with disease using a joint test of genetic main effect and gene-environment interaction. We consider how exposure misclassification and dependence between the true exposure E and the tested genetic variant G affect this joint test in absolute terms and relative to three other tests: the marginal test (G), the standard test for multiplicative gene-environment interaction (GE), and the case-only test for interaction (GE-CO). All tests can have inflated Type I error rate when E and G are correlated in the underlying population. For the GE and G-GE tests this inflation is only noticeable when the gene-environment dependence is unusually strong; the inflation can be large for the GE-CO test even for modest correlation. The joint G-GE test has greater power than the GE test generally, and greater power than the G test when there is no genetic main effect and the measurement error is small to moderate. The joint G-GE test is an attractive test for assessing genetic association when there is limited knowledge about casual mechanisms a priori, even in the presence of misclassification in environmental exposure measurement and correlation between exposure and genetic variants.
Using Allele Sharing Distance for Detecting Human Population Stratification
Authors: Gao Xiaoyi , Martin Eden R.
Published: June 2009

There is a long history of using allele sharing distance (ASD) and closely related metrics for population stratification analysis. However, the theory for this practical usage has not been reported. In this paper, we describe the theoretical background for using ASD on single nucleotide polymorphism (SNP) genetic data for human population stratification analysis. In showing the proof, we lay the ground work for a general distance-based method for classifying subpopulations using SNPs and ASD. We also show its relation to other closely related distance metrics using HapMap Phase I SNP data.
A New Sex-Specific Genetic Map of the Human Pseudoautosomal Regions (PAR1 and PAR2)
Authors: Flaquer Antònia , Fischer Christine , Wienker Thomas F.
Published: June 2009

Objectives: Accurate sex-specific genetic maps are essential for gene mapping projects when using multipoint methods, especially for the pseudoautosomal regions (PARs). This paper describes a new sex-specific genetic map for the human PARs. Methods: We used multipoint linkage analysis, three-generation pedigrees and to date, the largest set of genetic markers to estimate recombination events in the PARs. The new map combines genotype data from 28 CEPH pedigrees and 29 genetic markers. All genetic markers have been physically mapped, thus providing the opportunity to compare genetic to physical distance through all the intervals. Results: Recombination activity in PAR1 is on average 7-fold higher in male than in female meiosis, resulting in a much larger genetic map for males. This new map shows how genetically different in size is the X chromosome between males and females. Conclusions: Genetic distances vary extremely between males and females in the PARs. These differences should be considered in genetic studies using accurate sex-specific maps instead of sex-averaged maps. The new map provides a significantly different length compared to some previously published maps, since a much higher number of genetic markers is used. Therefore, we conclude that our map is the most accurate resource for obtaining genetic map information for the PARs.
Lactate Dehydrogenase Leakage as a Marker for Apoptotic Cell Degradation Induced by Influenza Virus Infection in Human Fetal Membrane Cells
Authors: Uchide Noboru , Ohyama Kunio , Bessho Toshio , Toyoda Hiroo
Published: June 2009

Objective: In order to elucidate the implication of apoptosis in lactate dehydrogenase (LDH) leakage from influenza virus-infected cells, the effects of a general caspase inhibitor, N-t-Boc-Asp(OMe)-fluoromethylketone (Boc-D-fmk), on LDH leakage, apoptosis induction and virus proliferation were examined. Methods: Cultured human fetal membrane chorion and amnion cells were incubated with or without Boc-D-fmk after influenza virus infection. LDH leakage was estimated by measuring LDH activities in the culture supernatants and cell lysates. The extent of apoptosis was determined by caspase-3 protein cleavage and DNA fragmentation. Virus proliferation was determined by a plaque-forming assay. Results: While virus proliferation was observed in both chorion and amnion cells, the virus infection resulted in LDH leakage, caspase-3 protein cleavage, and oligonucleosomal DNA fragmentation, all of which were observed only in the chorion cells and inhibited by the presence of Boc-D-fmk except for the virus proliferation. Conclusion: LDH level in amniotic fluid is known to be one of markers for predicting fetal membrane damage. Therefore, this study provides a possible diagnostic application of LDH level to predict the extent of tissue damage of fetal membranes via apoptosis induced by influenza virus infection.
Intravitreal Bevacizumab to Treat Acute Central Serous Chorioretinopathy: Short-Term Effect
Authors: Seong Hyun Kyung , Bae Ji Hyun , Kim Eung Suk , Han Jae Ryong , Nam Woo Ho , Kim Ha Kyoung
Published: June 2009

Aims: To report the beneficial effect of intravitreal bevacizumab (Avastin) injection in patients with acute central serous chorioretinopathy. Methods: Ten eyes of 10 patients with acute central serous chorioretinopathy received an intravitreal bevacizumab (1.25 mg/0.05 ml) injection. At baseline and follow-up visits patients had best corrected visual acuity (BCVA), IOP assessment, dilated fundus examination and OCT imaging. Main outcome measures were the resolution of neurosensory detachment, improvement in visual symptoms and visual acuity. Results: All patients showed resolution of neurosensory detachment promptly, and improvement in visual acuity and symptoms within 1 month. In 1 case, fluorescein leakage resolved and neurosensory detachment nearly resolved at 2 weeks after treatment. At 6 months the mean BCVA (LogMAR) had improved from 0.32 to 0.04, which was statistically significant (p = 0.007, Wilcoxon signed ranks test). No recurrence was observed during a 6-month follow-up. Conclusions: Intravitreal bevacizumab injection for acute central serous chorioretinopathy may result in prompt resolution of neurosensory detachment and reduction of angiographic leakage. These short-term results suggest that intravitreal bevacizumab injection may constitute a promising therapeutic option in acute central serous chorioretinopathy.
Translating Fall Incidence Data into Fall-Preventive Measures in Geriatric Wards – A Survey in Belgian Hospitals
Authors: Coussement Joke , Dejaeger Eddy , Lambert Margareta , Van Den Noortgate Nele , De Paepe Leen , Boonen Steven , Schoevaerdts Didier , Milisen Koen
Published: June 2009

Background: Fall incidents and their negative outcomes represent a considerable problem in hospitals, especially in geriatric wards, and require implementation of strategies to prevent these undesirable events. For this reason, the College of Geriatrics, a body funded by the Belgian Government to set up quality improvement initiatives in geriatric wards, selected ‘Fall prevention in Belgian hospitals’ as a quality project for the year 2006. Objectives: Before developing and implementing a practice guideline specifically adapted to the clinical context in Belgian geriatric wards, this study was set up to gain insight into fall prevention measures currently implemented in geriatric wards of Belgian hospitals. Methods: In this study, we used a cross-sectional survey design. The study involved 113 hospitals with a geriatric department. Participants were geriatricians, head nurses, medical directors, care coordinators and occupational therapists. Measurements were carried out using a survey questionnaire (response rate: 56.6%). Results: Less than one third (32.8%) of Belgian geriatric wards had a formal fall prevention policy. However, more than 90.0% systematically registered falls, but less than a quarter used these data to improve preventive measures. Although the majority used screening (78.1%), comprehensive assessment (92.2%), and preventive strategies (98.4%) when patients are admitted, only about 10% used a standard plan to direct these efforts. Furthermore, 93.8% acknowledged using physical restraints as a fall prevention strategy. Conclusion: Given the high rates and complexity of falls in geriatric wards, hospitals need to further implement evidence-based assessment and standard intervention care plans to maintain uniformity and quality of care.
Association of Socioeconomic Position and Medical Insurance With Fetal Diagnosis of Critical Congenital Heart Disease
Authors: Peiris Vasum , Singh Tajinder P. , Tworetzky Wayne , Chong Erin C. , Gauvreau Kimberlee , Brown David W.
Published: June 2009

Background—

Access to beneficial novel healthcare technology has been inequitable in the United States. Fetal echocardiography, used with increasing frequency for prenatal diagnosis (PD) of congenital heart disease, allows for optimal neonatal management and possible improved outcomes. We sought to evaluate whether PD of critical congenital heart disease is related to socioeconomic (SE) position, medical insurance, and race.

Methods and Results—

In a retrospective review of infants with critical congenital heart disease who underwent surgical or catheter intervention at age <30 days in our institution during 2003 to 2006, we extracted 6 SE variables for the block groups of patient residence from 2000 US Census and calculated a previously validated composite SE score for each patient. PD occurred in 222 (50%) infants. Race was not significantly associated with PD. Private insurance patients were much more likely to have PD (odds ratio, 3.7 versus public insurance; 95% CI, 2.4 to 5.7;
P
<0.001), as were patients of higher SE position (PD, 62% in highest quartile versus 35% in lowest quartile;
P
=0.001). Odds of PD increased with increasing SE score (odds ratio, 1.7, 2.3, and 2.9 for each quartile of higher SE score versus those in lowest SE quartile;
P
<0.001). Patients from economically poor neighborhoods were less likely to have PD (odds ratio, 1.2 for each 10% increase in prevalence of poverty;
P
=0.04). Private medical insurance (odds ratio, 3.4; 95% CI, 2.1 to 5.5;
P
<0.001) was the strongest predictor of PD in the logistic regression model.

Conclusion—

Patients with public insurance and lower SE position are less likely to have a PD of critical congenital heart disease.
Cross-Cultural Comparison of Student Attitudes toward Snakes
Authors: Özel Murat , Prokop Pavol , Uşak Muhammet
Published: June 2009

There is an increasing amount of research focusing on the origin of the human fear of animals. However, other dimensions of human views of frightening animals have been largely neglected. This study investigated attitudes toward snakes. The Snake Attitude Questionnaire (SAQ), which consisted of 58 Likert-type items (Cronbach's α = 0.91), was administered in a sample of students from two countries (Turkey and Slovakia). Students showed negative attitudes toward snakes, especially within the Negativistic and Naturalistic dimensions. Turkish students showed more positive Scientistic and Naturalistic attitudes than Slovakian students, and females showed more negative attitudes toward snakes than males. Although biology majors had more positive attitudes, compared with nonbiology majors, knowledge of snakes and beliefs about untrue myths were similar between these two subgroups. Our research indicates that fear of snakes negatively influences other attitudinal dimensions (especially naturalistic and scientific attitudes) although no students had been injured by a snake. Keeping various pets at home was associated with less fear of snakes. Nature protection actions should combine direct contact with these controversial animals with interventions against belief in untrue myths about snakes.
Oryx and Crake and the New Nostalgia for Meat
Authors: Parry Jovian
Published: June 2009

Recent years have seen the development of a new trend in gastronomic discourse toward acknowledging and even valorizing the role of animal slaughter in meat production. This development problematizes some of the ideas of influential theorists of meat such as Fiddes (1990) and Adams (1991): namely, that the animal in (post)modernity has been rendered invisible in the process of meat production and consumption (Adams, 1991), and that meat itself is a commodity with a declining reputation (Fiddes, 1990). This paper analyzes the role of nostalgia in this trend toward do-it-yourself (or at least witness-it-yourself) slaughter, and takes these developments in cultural tastes and feelings as a context within which to analyze the special significance of meat in Margaret Atwood's Oryx and Crake. In identifying this burgeoning nostalgia for meat and contextualizing it within a risk-reflexive, consumer-driven, dystopian near-future society of the author's own devising, Oryx and Crake foregrounds and illuminates these real-world developments in the meanings of meat.
Interrupting a History of Tolerance: Anti-Semitism and the Arabs
Authors: Hassan Riaz
Published: June 2009

The anti-Semitic rhetoric of many Islamist groups is qualitatively different from the reflective jurisprudence associated with the treatises of classical Islam. There is little evidence of any deep rooted anti-Semitism in the classical Islamic world. Jews have lived under Islamic rule for 14 centuries and in many lands, they were never free from discrimination but were rarely subjected to persecution as in Christian Europe. Most of the characteristic features of European-Christian anti-Semitism were absent from the Jewish-Muslim relations. This paper examines the growth of anti-Semitism in Arab-Muslim world and identifies some of the historical events which have contributed to this development.
The spatial genetic structure of bank vole (Myodes glareolus) and yellow-necked mouse (Apodemus flavicollis) populations: The effect of distance and habitat barriers
Authors: Kozakiewicz Michal , Gortat Tomasz , Panagiotopoulou Hanna , Gryczyńska–Siemiątkowska Alicja , Rutkowski Robert , Kozakiewicz Anna , Abramowicz Katarzyna
Published: June 2009

Habitat barriers are considered to be an important factor causing the local reduction of genetic diversity by dividing a population into smaller sections and preventing gene flow between them. However, the “barrier effect” might be different in the case of different species. The effect of geographic distance and water barriers on the genetic structure of populations of two common rodent species – the yellow-necked mouse (Apodemus flavicollis) and the bank vole (Myodes glareolus) living in the area of a lake (on its islands and on two opposite shores) was investigated with the use of microsatellite fragment analysis. The two studied species are characterised by similar habitat requirements, but differ with regard to the socio-spatial structure of the population, individual mobility, capability to cross environmental barriers, and other factors. Trapping was performed for two years in spring and autumn in north-eastern Poland (21°E, 53°N). A total of 160 yellow-necked mouse individuals (7 microsatellite loci) and 346 bank vole individuals (9 microsatellite loci) were analysed. The results of the differentiation analyses (FST and RST) have shown that both the barrier which is formed by a ca. 300 m wide belt of water (between the island and the mainland) and the actual distance of approximately 10 km in continuous populations are sufficient to create genetic differentiation within both species. The differences between local populations living on opposite lake shores are the smallest; differences between any one of them and the island populations are more distinct. All of the genetic diversity indices (the mean number of alleles, mean allelic richness, as well as the observed and expected heterozygosity) of the local populations from the lakeshores were significantly higher than of the small island populations of these two species separated by the water barrier. The more profound “isolation effect” in the case of the island populations of the bank vole, in comparison to the yellow-necked mouse populations, seems to result not only from the lower mobility of the bank vole species, but may also be attributed to other differences in the animals' behaviour.
Diet of the pulmonate gastropod Onchidella nigricans in the intertidal rocky shore, New Zealand
Authors: Alfaro Andrea
Published: June 2009

Gut content analyses and stable isotopes (δ13C and δ15N) were used to investigate the food consumption and assimilation of the pulmonate, Onchidella nigricans, within a rocky intertidal platform at Waiwera, northern New Zealand. Analyses of gut contents indicate that this species is a generalist herbivore, which may consume a variety of micro- and macro-algae, although small zooplankton may be ingested, when present. Gut contents of individuals collected from different intertidal habitats (bare rock, Hormosira banksii, green filaments, and coralline algae) reflected the dominant algal species within each habitat, suggesting that food availability does not restrict the grazer's distribution across its range. The radular morphology and small size of this gastropod also support the notion that O. nigricans is a non-selective microphagous feeder. However, stable isotopes on O. nigricans from the four habitats and the dominant algal food types indicate a strong assimilation preference for microalgae. The δ13C values (-15 to -13‰) of O. nigricans were consistent with signatures for intertidal grazers, but δ15N values (8 to 9‰) were relatively high, which may indicate the presence of bacteria and microfaunal detritus in the diet. Clusters of isotopic signatures of individuals from different habitats suggest feeding preferences, which also may be attributed to differences in detrital and bacterial consumption. This study illustrates the importance of using parallel techniques in diet studies.
Ultrastructural analysis of the fat body in workers of Attini ants (Hymenoptera: Formicidae)
Authors: Roma Gislaine , Bueno Odair , Camargo-Mathias Maria
Published: June 2009

In the present study a comparative morphological analysis of the fat body cells of ant workers of the basal Attini species Cyphomyrmex rimosus and Mycetarotes parallelus, and the derived species Acromyrmex disciger and Atta laevigata was conducted. The results revealed that the fat body is located mainly in the abdomen around organs (perivisceral) and near the integument (parietal). The main cells observed are spherical or polygonal trophocytes with a slightly rough surface. The oenocytes, another cell type found, are closely associated with trophocytes, and present a spherical or polygonal shape and a smoother surface. The morphometric analysis showed that the area of trophocytes and oenocytes of C. rimosus and M. parallelus is significantly smaller when compared to those of A. disciger and A. laevigata. In the cytoplasm of parietal and perivisceral trophocytes and oenocytes, electronlucent droplets (probably lipids) and electrondense granules (probably proteins) indicate the participation of these cells in the storage of these elements, while digestive vacuoles, residual bodies, and multivesicular bodies suggest a role in intracellular digestion. In perivisceral trophocytes and oenocytes of C. rimosus, the presence of mitochondria, lamellar rough endoplasmic reticulum, and Golgi complex suggests that these cells synthesize proteins. Based on these data, no significant differences were observed between the fat body cells of basal and derived ants, except regarding the larger size of trophocytes and oenocytes of the derived species A. disciger and A. laevigata.
The Depth Dependence of Shear Finestructure off Point Arena and near Pioneer Seamount
Authors: Kunze Eric , Kennelly Maureen A. , Sanford Thomas B.
Published: June 2009

High-resolution velocity profiles to depths of 1600 m were collected off Point Arena and near Pioneer Seamount, California. They reveal shear increasing with depth relative to the GM76 model spectrum. Using an empirical parameterization found to collapse microstructure data the “dissipation rate” and “eddy diffusivity” are estimated from these shears. Away from the seamount, dissipation rates are depth invariant at 3–6(×10−10 W kg−1). As a result, the eddy diffusivity increases with depth, approaching 0.2–0.3(×10−4 m2 s−1) below 1200-m depth. This may be a result of the proximity of the continental rise and sloping topography, but there is evidence that it is a general result for the abyssal ocean. Immediately above the seamount, there is a 300–400-m thick layer of elevated shear, corresponding to an eddy diffusivity of ∼ 10−4 m2 s−1. If this localized enhancement is typical of seamounts, topographically induced mixing is insufficient to significantly modify global average mixing.
The Ordinary and the Extraordinary Countertransference
Authors: Freedman Norbert , Lasky Richard , Webster Jamieson
Published: June 2009

This is both a clinical and an epistemological inquiry into the concept of countertransference. A distinction is made between the ordinary countertransference, a transitory disruption residing within the analyst's consciousness, and the extraordinary countertransference, an impasse intolerable to the analyst to such an extent that it remains outside awareness. This distinction, rooted in the history of psychoanalytic thought, is here traced in a recorded psychoanalysis. The clinical material is examined from three perspectives, including empirical evaluation by computer-assisted monitoring of spoken language and two modes of psychoanalytic interpretive listening. Analytic sessions designated as ordinary were readily identified by quantitative measures. However, the threshold between the ordinary and the extraordinary countertransference was reached at the point where empirical observations broke down. Detailed psychoanalytic observation of the four sessions that lie beyond empirical validation led to a formulation of the analyst's state of consciousness during these pivotal hours.