bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship among tumor architecture, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in mouse xenograft models
Authors: Williamson Mark J. , Silva Matthew D. , Terkelsen Jennifer , Robertson Robbie , Yu Li , Xia Cindy , Hatsis Panos , Bannerman Bret , Babcock Trisha , Cao Yueying , Kupperman Erik
Published: November 2009

Understanding a compound's preclinical pharmacokinetic, pharmacodynamic, and efficacy relationship can greatly facilitate its clinical development. Bortezomib is a first-in-class proteasome inhibitor whose pharmacokinetic/pharmacodynamic parameters are poorly understood in terms of their relationship with efficacy. Here we characterized the bortezomib pharmacokinetic/pharmacodynamic/efficacy relationship in the CWR22 and H460 xenograft models. These studies allowed us to specifically address the question of whether the lack of broad bortezomib activity in solid tumor xenografts was due to insufficient tumor penetration. In vivo studies showed that bortezomib treatment resulted in tumor growth inhibition in CWR22 xenografts, but not in H460 xenografts. Using 20S proteasome inhibition as a pharmacodynamic marker and analyzing bortezomib tumor exposures, we show that efficacy was achieved only when suitable drug exposures drove proteasome inhibition that was sustained over time. This suggested that both the magnitude and duration of proteasome inhibition were important drivers of efficacy. Using dynamic contrast-enhanced magnetic resonance imaging and high-resolution computed tomographic imaging of vascular casts, we characterized the vasculature of CWR22 and H460 xenograft tumors and identified prominent differences in vessel perfusion, permeability, and architecture that ultimately resulted in variations in bortezomib tumor exposure. Comparing and contrasting the differences between a bortezomib-responsive and a bortezomib-resistant model with these techniques allowed us to establish a relationship among tumor perfusion, drug exposure, pharmacodynamic response and efficacy, and provided an explanation for why some solid tumor models do not respond to bortezomib treatment. [Mol Cancer Ther 2009;8(12):3234–43]
SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo
Authors: Buchanan Sean G. , Hendle Jorg , Lee Patrick S. , Smith Christopher R. , Bounaud Pierre-Yves , Jessen Katti A. , Tang Crystal M. , Huser Nanni H. , Felce Jeremy D. , Froning Karen J. , Peterman Marshall C. , Aubol Brandon E. , Gessert Steve F. , Sauder J. Michael , Schwinn Kenneth D. , Russell Marijane , Rooney Isabelle A. , Adams Jason , Leon Barbara C. , Do Tuan H. , Blaney Jeff M. , Sprengeler Paul A. , Thompson Devon A. , Smyth Lydia , Pelletier Laura A. , Atwell Shane , Holme Kevin , Wasserman Stephen R. , Emtage Spencer , Burley Stephen K. , Reich Siegfried H.
Published: November 2009

The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition. [Mol Cancer Ther 2009;8(12):3181–90]
Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells
Authors: Sun Feng , Chan Eli , Wu Zhenlong , Yang Xiaojing , Marquez Victor E. , Yu Qiang
Published: November 2009

Polycomb protein EZH2-mediated gene silencing is implicated in breast tumorigenesis through methylation of histone H3 on Lysine 27 (H3K27). We have previously shown that S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A can modulate histone methylation and disrupt EZH2 complex. Here, we used 3-deazaneplanocin A, together with other chromatin remodeling agents, as well as RNA interference–mediated EZH2 depletion, to probe the role of EZH2 in coordination with other epigenetic components in gene regulation in breast cancer cells. Through genome-wide gene expression analysis, coupled with extensive chromatin immunoprecipitation analysis of histone modifications, we have identified a variety of gene sets that are regulated either by EZH2 alone or through the coordinated action of EZH2 with HDAC and/or DNA methylation. We further found that tumor antigen GAGEs were regulated by distinct epigenetic mechanisms in a cell context–dependent manner, possibly reflecting mechanistic heterogeneity in breast cancer. Intriguingly, we found that EZH2 regulates a remarkable cohort of genes whose functions are highly enriched in immunoresponse and autocrine inflammation network, and that their transcriptional activation upon EZH2 perturbation is cancer specific, revealing a potential novel role of EZH2 in regulating cancer immunity. These findings show the complexity and diversity of epigenetic regulation in human cancer and underscore the importance for developing combinatorial pharmacologic approaches for effective epigenetic gene reactivation. [Mol Cancer Ther 2009;8(12):3191–202]
Bim-targeted cancer therapy: A link between drug action and underlying molecular changes
Authors: Akiyama Toru , Dass Crispin R. , Choong Peter F.M.
Published: November 2009

In the past few years, the pro-apoptotic molecule Bim has attracted increasing attention as a plausible target for tumor therapy. A variety of normal and pathological systems regulated by Bim, dependent on cell type, apoptotic stimulation, and chemotherapeutic agents, have been documented. Bim promotes anoikis of many tumor cells, such as lung cancer, breast cancer, osteosarcoma, and melanoma. Various chemotherapeutic agents use Bim as a mediating executioner of cell death. Hence, Bim suppression supports metastasis and chemoresistance. Imatinib, gefitinib, bortezomib, and Bim protein itself are spotlighted as current and future Bim-targeting therapeutic agents. The potential benefits of Bim-targeted therapies are selectivity of treatment for tumor cells and reduction in tumor-associated phenomena such as chemoresistance and metastasis. Thus, Bim-targeting therapies may provide more effective and unique tumor management modalities in future. This review article discusses all these issues. [Mol Cancer Ther 2009;8(12):3173–80]
The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma
Authors: Ohno Masasuke , Natsume Atsushi , Kondo Yutaka , Iwamizu Hidetaka , Motomura Kazuya , Toda Hiroshi , Ito Motokazu , Kato Takenori , Wakabayashi Toshihiko
Published: November 2009

Type I IFNs are involved in double-stranded RNA responses. Here, we investigated the possibility that IFN-β may induce or downregulate cellular microRNAs (miRNA) in human neoplasms and thereby use the RNA interference system to show antitumor effects. Because of its known connection to glioma biology, we focused on miR-21 among seven miRNAs influenced by IFN-β. We analyzed the effect of IFN-β treatment on miR-21 expression in glioma cells and intracranial glioma xenografts. IFN-β treatment reduced miR-21 expression in glioma cells markedly, and IFN-β administration suppressed the growth of glioma-initiating cell–derived intracranial tumors. The levels of primary miR-21 gene transcripts, precursor miR-21, and mature miR-21 decreased 6 hours after the addition of IFN-β, indicating that the reduction in miR-21 levels was due to transcriptional suppression. We did reporter assays to elucidate the IFN-β–mediated suppression of miR-21; the addition of signal transducers and activators of transcription 3 (STAT3)–expressing vectors induced the IFN-β–mediated suppression of miR-21, whereas STAT3-inhibiting agents inhibited the miR-21 suppression. Thus, the results of our study show that the downregulation of miR-21 contributes to the antitumor effects of IFN-β and that miR-21 expression is negatively regulated by STAT3 activation. These results highlight the importance of understanding the transcriptional regulation of the miRNAs involved in oncogenesis. (Mol Cancer Res 2009;7(12):2022–30)
Bmi1 Functions as an Oncogene Independent of Ink4A/Arf Repression in Hepatic Carcinogenesis
Authors: Xu Chuan-Rui , Lee Susie , Ho Coral , Bommi Prashant , Huang Shi-Ang , Cheung Siu Tim , Dimri Goberdhan P. , Chen Xin
Published: November 2009

Bmi1 is a polycomb group proto-oncogene that has been implicated in multiple tumor types. However, its role in hepatocellular carcinoma (HCC) development has not been well studied. In this article, we report that Bmi1 is overexpressed in human HCC samples. When Bmi1 expression is knocked down in human HCC cell lines, it significantly inhibits cell proliferation and perturbs cell cycle regulation. To investigate the role of Bmi1 in promoting liver cancer development in vivo, we stably expressed Bmi1 and/or an activated form of Ras (RasV12) in mouse liver. We found that while Bmi1 or RasV12 alone is not sufficient to promote liver cancer development, coexpression of Bmi1 and RasV12 promotes HCC formation in mice. Tumors induced by Bmi1/RasV12 resemble human HCC by deregulation of genes involved in cell proliferation, apoptosis, and angiogenesis. Intriguingly, we found no evidence that Bmi1 regulates Ink4A/Arf expression in both in vitro and in vivo systems of liver tumor development. In summary, our study shows that Bmi1 can cooperate with other oncogenic signals to promote hepatic carcinogenesis in vivo. Yet Bmi1 functions independent of Ink4A/Arf repression in liver cancer development. (Mol Cancer Res 2009;7(12):1937–45)
A Proposed Unified Mechanism for the Reduction of Human Breast Cancer Risk by the Hormones of Pregnancy
Authors: Jacobson Herbert I. , Lemanski Nicole , Agarwal Anu , Narendran Amithi , Turner Kelvin E. , Bennett James A. , Andersen Thomas T.
Published: November 2009

Parity in women is associated with reduced lifetime risk of breast cancer, and hormones of pregnancy [estrogen (E), progesterone (P), human chorionic gonadotropin (hCG)] are implicated. Parity also reduces mammary cancer risk in carcinogen-exposed rats, and administering pregnancy hormones to these animals is similarly effective. Because pregnancy hormones are also able to stimulate cancer growth, we proposed to resolve this dichotomy by determining whether administered pregnancy hormones elicit the cancer-inhibiting agent α-fetoprotein (AFP) from the liver, which would implicate AFP as a proximal effector of hormonal anticancer activity. Accordingly, we treated groups of nitrosomethylurea-exposed rats with saline, E3, E2 + P, E3 + P, hCG, or allowed them to experience pregnancy, and then monitored mammary cancer incidence and serum levels of AFP over time. Each hormone treatment reduced mammary cancer incidence and elevated serum AFP levels. To challenge human tissues, human HepG2 liver cells in culture were treated with the same hormonal agents. Each hormone regimen increased the levels of AFP in the culture medium. Medium containing AFP elicited by hCG inhibited the E2-stimulated proliferation of cultured human MCF7 breast cancer cells, whereas hCG alone did not inhibit their growth. Furthermore, antibodies to AFP neutralized the growth-inhibiting effect of AFP-containing HepG2 medium. We conclude that in the treatment of carcinogen-exposed rats with the hormones of pregnancy, and by inference in women who have experienced pregnancy, that AFP is a proximal agent that inhibits mammary gland cancer. Cancer Prev Res; 3(2); 212–20
The Cyclooxygenase Inhibitor Sulindac Sulfide Inhibits EP4 Expression and Suppresses the Growth of Glioblastoma Cells
Authors: Kambe Atsushi , Yoshioka Hiroki , Kamitani Hideki , Watanabe Takashi , Baek Seung Joon , Eling Thomas E.
Published: November 2009

EP4 expression in human glioblastoma cells correlates with growth on soft agar. The cyclooxygenase inhibitor sulindac sulfide first altered specificity protein-1 (Sp-1) and early growth response gene-1 expression, then increased the expression of nonsteroidal anti-inflammatory drug-activated gene 1 and activating transcription factor 3, and then decreased EP4 expression. EP4 suppression was dependent on blocking the Sp-1 binding sites in the human EP4 promoter. Mutation in the Sp-1 sites in EP4 altered the promoter activity and abolished sulindac sulfide effects. The inhibitory effect of sulindac sulfide on EP4 expression was reversed by PD98059, a mitogen-activated protein/extracellular signal–regulated kinase kinase-1/extracellular signal–regulated kinase inhibitor. Sp-1 phosphorylation was dependent on sulindac sulfide–induced Erk activation. Chromatin immunoprecipitation assay confirmed that Sp-1 phosphorylation decreases Sp-1 binding to DNA and leads to the suppression of EP4. Inhibition of cell growth on soft agar assay was found to be a highly complex process and seems to require not only the inhibition of cyclooxygenase activity but also increased expression of nonsteroidal anti-inflammatory drug-activated gene 1 and activating transcription factor 3 and suppression of EP4 expression. Our data suggest that the suppression of EP4 expression by sulindac sulfide represents a new mechanism for understanding the tumor suppressor activity.
Does the Cranial Suspensory Ligament Have a Role in Cryptorchidism?
Authors: Kassim Normadiah M. , Russell D.A. , Payne A.P.
Published: November 2009

The cranial suspensory ligament (CSL) is a fibromuscular structure anchoring the embryonic gonad to the posterior abdominal wall in male and female mammals. Its persistence in females is believed to be responsible for retaining the ovaries within the abdomen, while its regression in males permits testis descent. Embryonic loss of the CSL in males is believed to be an androgen-dependent event, and failure of this process has been proposed as a cause of cryptorchidism. The present study demonstrates that the nuclei of mesenchymal cells in the caudal part of the CSL are immunoreactively positive for androgen receptor. We examined the effects of exposure of the non-steroidal antiandrogen flutamide during the period from gestational day 10 to birth on the development of the CSL and on testis descent. Exposure of male Albino Swiss rats to the antiandrogen flutamide during this period resulted in feminization of the external genitalia and the suppression of growth of the testes and male reproductive tracts. In adulthood, testes were found to be located in diverse positions including normal scrotal (50%), intra-abdominal (10%) and ectopic suprainguinal (40%). The CSL of the testis persisted into adulthood in all flutamide-treated males, regardless of testis location. In all cases, the ligament consisted of bundles of smooth muscle fibres in the retroperitoneal fat of the posterior abdominal wall. These findings suggest that androgen blockade during embryonic development interferes with testicular descent, but that maldescent cannot be correlated with either the persistence of the CSL of the testis or its structure.
Impact of Adalimumab on Symptoms of Psoriatic Arthritis in Patients with Moderate to Severe Psoriasis: A Pooled Analysis of Randomized Clinical Trials
Authors: Mease Philip J. , Signorovitch James , Yu Andrew P. , Wu Eric Q. , Gupta Shiraz R. , Bao Yanjun , Mulani Parvez M.
Published: November 2009

Background: Psoriatic arthritis often affects patients with psoriasis. Objective: To examine the effect of adalimumab on psoriatic arthritis in patients with moderate to severe psoriasis. Methods: Data from patients with psoriasis and a reported history of comorbid psoriatic arthritis in 3 randomized, placebo-controlled psoriasis trials of adalimumab were analyzed. Results: Adalimumab (n = 274) reduced the risk of psoriatic arthropathy adverse events by 75% versus placebo (1.1 vs. 4.8%; p = 0.025). Psoriasis/psoriatic arthritis-related pain was significantly reduced (–31.3 vs. –5.6 visual analog scale units; p < 0.0001). At week 16, adalimumab-treated patients were more likely to respond (56.9 vs. 4.5%; p < 0.001) and responded for a greater percentage of follow-up time (39.3 vs. 2.9%; p< 0.0001) than placebo-treated patients (regression model for PASI 75 and ACR 20 responses). Conclusion: Adalimumab treatment of moderate to severe psoriasis reduced symptoms of comorbid psoriatic arthritis.
Multiple Sclerosis, Lymphoma and Nasopharyngeal Carcinoma: The Central Role of Epstein-Barr Virus?
Authors: Rolls Alexander E.S. , Giovannoni Gavin , Constantinescu Cris S. , Boniface David , Hawkes Christopher H.
Published: November 2009

Background: Multiple sclerosis (MS) and Hodgkin lymphoma (HL) share epidemiologic characteristics suggesting a possible common etiology. Epstein-Barr virus (EBV) is associated with HL, Burkitt lymphoma, some varieties of non-Hodgkin lymphoma (NHL) and nasopharyngeal carcinoma (NPC).Method:Patients were located through MS databases for (a) Barking and Havering, NE London; catchment ∼400,000; MS patient number 751, and (b) Nottingham, catchment ∼2,000,000; MS patient number 1,236. Search was undertaken for lymphoma or NPC and diagnosis of MS verified by McDonald criteria. Results: We identified five UK-born and resident patients of interest: (1) male with onset HL aged 20 years developing relapsing-remitting MS 11 years later; (2) female with severe relapsing-remitting MS whose partner developed NHL, 5 years after MS diagnosis; (3) female with secondary progressive MS beginning at age 38 years who developed NHL 25 years later; (4) female diagnosed with MS aged 19 years who developed HL 4 years later, and (5) female with hereditary motor and sensory neuropathy developing cervical cancer at the age of 32 years, NPC at 33 years, and RR MS at 36 years. Conclusion: Our study supports a possible association between MS, HL, NHL, and perhaps NPC all of which are associated with EBV infection.
Granulomatous Pneumocystis jiroveci Pneumonia in a Patient with Diffuse Large B-Cell Lymphoma: Case Report and Review of the Literature
Authors: Chang Hung , Shih Lee-Yung , Wang Chi-Wei , Chuang Wen-Yu , Chen Chien-Cheng
Published: November 2009

Here we report a case of diffuse large B-cell lymphoma who developed granulomatous Pneumocystis jiroveci pneumonia (PJP) after rituximab and combination chemotherapy. The infection presented as a solitary pulmonary nodule (SPN) instead of the commonly seen diffuse ground-glass infiltrates. The diagnosis was made by wedge resection of the nodule. Both the CD4+ lymphocyte count and immunoglobulin level were low. A literature search revealed 14 granulomatous PJP patients with hematological neoplasms, including the present case, which was the first with diffuse large B-cell lymphoma and the only patient receiving rituximab before PJP development. In addition to our report, only one case had previously presented with an SPN. Our experience suggests that granulomatous PJP should be considered a possible etiology when immunocompromised patients develop fever and SPNs.
Expression of Genes for Appetite-Regulating Peptides in the Hypothalamus of Genetically Selected Lean and Fat Sheep
Authors: Anukulkitch Chantacha , Rao Alexandra , Pereira Alda , McEwan John , Clarke Iain J.
Published: November 2009

Background/Aims: The aim was to determine whether genetic selection of sheep for body composition could be accounted for by changes in the level of expression of genes for appetite-regulating peptides in the hypothalamus. We examined gene expression in the hypothalamus of genetically lean, normal and fat ewes (n = 5/group). Methods: Plasma growth hormone (GH) and metabolic indicators were measured and gene expression in brains was quantified by in situ hybridization. Results: Body weight and voluntary food intake (VFI) were similar between groups, but lean and fat animals respectively had low and high indices of adiposity. GH levels were higher in lean and fat animals than in controls. In the arcuate nucleus (ARC), neuropeptide Y (NPY) expression/cell was higher in the lean animals than in normal animals, but overall NPY expression was similar in fat and normal animals. Pro-opiomelanocortin (POMC) and leptin receptor (ObRb) expression in the ARC was similar across groups. Orexin (ORX) and melanin-concentrating hormone (MCH) expression was inversely correlated to adiposity, being higher in lean and lower in fat animals. Conclusion: Expression of genes for orexigenic neuropeptides is altered in a consistent way. Energy expenditure is reduced by MCH but increased by ORX, so increased expression of the latter may cause increased energy expenditure in the lean animals and vice versa in the fat animals.
Procalcitonin: Inflammatory Biomarker for Assessing the Severity of Community-Acquired Pneumonia – A Clinical Observation in Geriatric Patients
Authors: Heppner H.J. , Bertsch T. , Alber B. , Esslinger A.S. , Dragonas C. , Bauer J.M. , Sieber C.C.
Published: November 2009

Community-acquired pneumonia is a common disease of the elderly and involves a high mortality risk. Demographic developments are creating new challenges for acute medical treatment strategies in geriatric patients with their underlying multimorbidity. In addition to the diagnostic parameters recorded on hospital admission, such as white cell count and C-reactive protein, procalcitonin, more than the risk scores CRB- and CURB-65 evaluated to date, appears to be a promising parameter for assessing the severity of pneumonia in elderly patients to allow early detection of severe courses and initiation of suitable treatment. The decisive factor is the dynamic course of the procalcitonin values over 3 consecutive days, as demonstrated in this case series.
Gastroschisis: Prenatal Diagnosis and Management
Authors: Grundy Howard , Anderson Robert L. , Filly Roy A. , Callen Peter , Goldberg James D. , Slotnick Nathan , Golbus Mitchell S.
Published: November 2009

Ten fetuses with gastroschisis on whom a prenatal sonographic diagnosis and evaluation were available and who delivered at the University of California, San Francisco, were evaluated retrospectively. Six fetuses were delivered vaginally without mortality and minimal or absent morbidity. Four were delivered abdominally, 2 for unrelated obstetrical indications. A 3rd fetus had a suspected prenatal bowel perforation and was the sole mortality. Only 1 mother underwent primary cesarean section, specifically due to the fetal gastroschisis. Umbilical cord pH values were normal in those delivered vaginally. With careful ultrasound examination and immediate neonatal surgical capability in a level III perinatal center, vaginal delivery of fetuses with gastroschisis can be associated with excellent outcome. A multinational randomized study of the delivery mode of fetuses with gastroschisis is necessary and appropriate at this time.
Fetal Urinary Electrolytes in Bladder Outlet Obstruction
Authors: Reuss A. , Wladimiroff J.W. , Pijpers L. , Provoost A.P.
Published: November 2009

Ultrasound findings and urinary electrolytes in the fetus were correlated with fetal outcome and postmortem findings in 8 cases of fetal bladder outlet obstructions. One of the two fetuses, suggesting normal renal function according to urinary electrolytes, displayed renal dysplasia at birth. Six fetuses were predicted to have poor renal function, 5 of these were found to have renal dysplasia at autopsy. The interpretation of fetal urinary electrolytes as a prognostic indication for the presence or absence of renal dysplasia needs to be clarified.
Twin-Twin Transfusion Syndrome: The Surgical Removal of One Twin as a Treatment Option
Authors: Urig Michael A. , Simpson Gary F. , Elliott John P. , Clewell William H.
Published: November 2009

The twin-twin transfusion syndrome, associated with acute polyhydramnios in the 18th to 28th week of gestation, has a high perinatal mortality rate. Patients managed without intervention have essentially a 100% mortality rate for the involved twins. Different methods of intervention have been described, including therapeutic amniocentesis, selective feticide, and placental vessel puncture. In this case report we describe selective removal of one twin at 21 weeks of gestation by hysterotomy in a patient with the twin-twin transfusion syndrome.
Does
Ginkgo biloba
Reduce the Risk of Cardiovascular Events?
Authors: Kuller Lewis H. , Ives Diane G. , Fitzpatrick Annette L. , Carlson Michelle C. , Mercado Carla , Lopez Oscar L. , Burke Gregory L. , Furberg Curt D. , DeKosky Steven T.
Published: November 2009

Background—

Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory Study. The trial previously reported that
Ginkgo biloba
had no effect on the primary outcome, incident dementia.

Methods and Results—

The double-blind trial randomly assigned 3069 participants over 75 years of age to 120 mg of
G biloba
EGb 761 twice daily or placebo. Mean follow-up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between
G biloba
and placebo were evaluated using Cox proportional hazards regression adjusted for age and sex. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between
G biloba
and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207), or stroke (151) between
G biloba
and placebo. There were 24 hemorrhagic strokes, 16 on
G biloba
and 8 on placebo (not significant). There were only 35 peripheral vascular disease events, 12 (0.8%) on
G biloba
and 23 (1.5%) on placebo (
P
=0.04, exact test). Most of the peripheral vascular disease cases had either vascular surgery or amputation.

Conclusions—

There was no evidence that
G biloba
reduced total or CVD mortality or CVD events. There were more peripheral vascular disease events in the placebo arm.
G biloba
cannot be recommended for preventing CVD. Further clinical trials of peripheral vascular disease outcomes might be indicated.

Clinical Trial Registration—

clinicaltrials.gov Identifier: NCT00010803
Age and Sex Differences in Duration of Prehospital Delay in Patients With Acute Myocardial Infarction
Authors: Nguyen Hoa L. , Saczynski Jane S. , Gore Joel M. , Goldberg Robert J.
Published: November 2009

Background—

Coronary heart disease is the leading cause of morbidity and mortality in American men and women. Although there have been dramatic changes in the management of patients hospitalized with acute myocardial infarction (AMI) over the past several decades, a considerable proportion of patients with AMI continue to delay seeking medical care in a timely manner. This review provides an overview of the published literature that has examined age and sex differences in extent of prehospital delay in patients hospitalized with AMI.

Methods and Results—

A systematic review of the literature from 1960 to 2008, including publications that provided data on duration of prehospital delay in patients hospitalized with AMI, was conducted. A total of 44 articles (42 studies) were included in the present analysis. The majority of studies showed that in patients hospitalized with AMI, women and older persons were more likely to arrive at the hospital later than men and younger persons. Several factors associated with duration of prehospital delay, including sociodemographic, medical history, clinical, and contextual characteristics differed according to sex.

Conclusions—

The elderly and women were more likely to exhibit longer delays in seeking medical care after the development of symptoms suggestive of AMI compared with other groups. Further research is needed to more fully understand the reasons for delay in these vulnerable groups.
Neuroimaging Support for Discrete Neural Correlates of Basic Emotions: A Voxel-based Meta-analysis
Authors: Vytal Katherine , Hamann Stephan
Published: November 2009

What is the basic structure of emotional experience and how is it represented in the human brain? One highly influential theory, discrete basic emotions, proposes a limited set of basic emotions such as happiness and fear, which are characterized by unique physiological and neural profiles. Although many studies using diverse methods have linked particular brain structures with specific basic emotions, evidence from individual neuroimaging studies and from neuroimaging meta-analyses has been inconclusive regarding whether basic emotions are associated with both consistent and discriminable regional brain activations. We revisited this question, using activation likelihood estimation (ALE), which allows spatially sensitive, voxelwise statistical comparison of results from multiple studies. In addition, we examined substantially more studies than previous meta-analyses. The ALE meta-analysis yielded results consistent with basic emotion theory. Each of the emotions examined (fear, anger, disgust, sadness, and happiness) was characterized by consistent neural correlates across studies, as defined by reliable correlations with regional brain activations. In addition, the activation patterns associated with each emotion were discrete (discriminable from the other emotions in pairwise contrasts) and overlapped substantially with structure–function correspondences identified using other approaches, providing converging evidence that discrete basic emotions have consistent and discriminable neural correlates. Complementing prior studies that have demonstrated neural correlates for the affective dimensions of arousal and valence, the current meta-analysis results indicate that the key elements of basic emotion views are reflected in neural correlates identified by neuroimaging studies.
Functional Dissociations within the Ventral Object Processing Pathway: Cognitive Modules or a Hierarchical Continuum?
Authors: Cowell Rosemary A. , Bussey Timothy J. , Saksida Lisa M.
Published: November 2009

We examined the organization and function of the ventral object processing pathway. The prevailing theoretical approach in this field holds that the ventral object processing stream has a modular organization, in which visual perception is carried out in posterior regions and visual memory is carried out, independently, in the anterior temporal lobe. In contrast, recent work has argued against this modular framework, favoring instead a continuous, hierarchical account of cognitive processing in these regions. We join the latter group and illustrate our view with simulations from a computational model that extends the perceptual-mnemonic feature-conjunction model of visual discrimination proposed by Bussey and Saksida [Bussey, T. J., & Saksida, L. M. The organization of visual object representations: A connectionist model of effects of lesions in perirhinal cortex. European Journal of Neuroscience, 15, 355–364, 2002]. We use the extended model to revisit early data from Iwai and Mishkin [Iwai, E., & Mishkin, M. Two visual foci in the temporal lobe of monkeys. In N. Yoshii & N. Buchwald (Eds.), Neurophysiological basis of learning and behavior (pp. 1–11). Japan: Osaka University Press, 1968]; this seminal study was interpreted as evidence for the modularity of visual perception and visual memory. The model accounts for a double dissociation in monkeys' visual discrimination performance following lesions to different regions of the ventral visual stream. This double dissociation is frequently cited as evidence for separate systems for perception and memory. However, the model provides a parsimonious, mechanistic, single-system account of the double dissociation data. We propose that the effects of lesions in ventral visual stream on visual discrimination are due to compromised representations within a hierarchical representational continuum rather than impairment in a specific type of learning, memory, or perception. We argue that consideration of the nature of stimulus representations and their processing in cortex is a more fruitful approach than attempting to map cognition onto functional modules.
Minds Made for Sharing: Initiating Joint Attention Recruits Reward-related Neurocircuitry
Authors: Schilbach Leonhard , Wilms Marcus , Eickhoff Simon B. , Romanzetti Sandro , Tepest Ralf , Bente Gary , Shah N. Jon , Fink Gereon R. , Vogeley Kai
Published: November 2009

The ability and motivation to share attention is a unique aspect of human cognition. Despite its significance, the neural basis remains elusive. To investigate the neural correlates of joint attention, we developed a novel, interactive research paradigm in which participants' gaze behavior—as measured by an eye tracking device—was used to contingently control the gaze of a computer-animated character. Instructed that the character on screen was controlled by a real person outside the scanner, 21 participants interacted with the virtual other while undergoing fMRI. Experimental variations focused on leading versus following the gaze of the character when fixating one of three objects also shown on the screen. In concordance with our hypotheses, results demonstrate, firstly, that following someone else's gaze to engage in joint attention resulted in activation of anterior portion of medial prefrontal cortex (MPFC) known to be involved in the supramodal coordination of perceptual and cognitive processes. Secondly, directing someone else's gaze toward an object activated the ventral striatum which—in light of ratings obtained from participants—appears to underlie the hedonic aspects of sharing attention. The data, therefore, support the idea that other-initiated joint attention relies upon recruitment of MPFC previously related to the “meeting of minds.” In contrast, self-initiated joint attention leads to a differential increase of neural activity in reward-related brain areas, which might contribute to the uniquely human motivation to engage in the sharing of experiences.
N400-like Potentials and Reaction Times Index Semantic Relations between Highly Repeated Individual Words
Authors: Renoult Louis , Debruille J. Bruno
Published: November 2009

The N400 ERP is an electrophysiological index of semantic processing. Its amplitude varies with the semantic category of words, their concreteness, or whether their meaning matches that of a preceding context. The results of a number of studies suggest that these effects could be markedly reduced or suppressed for stimuli that are repeated. Nevertheless, we have recently shown that significant effects of semantic matching and category could be obtained on N400-like potentials elicited by massively repeated target words in a prime–target semantic categorization task. If such effects could be obtained when primes also are repeated, it would then be possible to study the semantic associations between individual words. The present study thus aimed to test this hypothesis while (1) controlling for a potential contribution of physical matching to the processing of repeated targets and (2) testing if the N400-like effects obtained in these conditions are modulated by task instruction, as are classic N400 effects. Two category words were used as primes and two exemplars as targets. In one block of trials, subjects had to respond according to the semantic relation between prime and target (semantic instruction) and, in another block, they had to report changes in letter case (physical instruction). Results showed that the amplitude of the N400-like ERP obtained was modulated by semantic matching and category but not by letter case. The effect of semantic matching was observed only in the semantic instruction block. Interestingly, the effect of category was not modulated by task instruction. An independent component analysis showed that the component that made the greatest contribution to the effect of semantic matching in the time window of the N400-like potential had a scalp distribution similar to that reported for the N400 and was best fit as a bilateral generator in the superior temporal gyrus. The use of repetition could thus allow, at least in explicit semantic tasks, a drastic simplification of N400 protocols. Highly repeated individual words could be used to study semantic relations between individual concepts.
Bistable Prestressed Symmetric Laminates
Authors: Daynes S. , Diaconu C.G. , Potter K.D. , Weaver P.M.
Published: November 2009

The bistability of unsymmetric cross-ply [0n/90n] T laminates has already been investigated in much detail. In this work a new type of bistable laminate is presented which has a symmetric lay-up. Bistability derives from an unsymmetric fiber prestress applied to the laminate. The experimental procedure used to apply this fiber prestress is presented in detail. Experimental results are compared with analytical and finite element models which have the ability to model fiber prestress accurately. As well as having minimal hygrothermal variability, it is noted that the snap-through loads for a prestressed symmetric laminate can be much higher than its unstressed [0n/90n]T equivalent.
Progressive Fatigue Damage Modeling of Cross-ply Laminates, I: Modeling Strategy
Authors: Shokrieh M.M. , Taheri-Behrooz F.
Published: November 2009

The main goal of this research is the fatigue simulation of cross-ply laminates under cyclic tension—tension loading conditions. For this purpose, a progressive fatigue damage model is developed based on two main assumptions. First, it is assumed that off-axis plies are responsible for stress redistribution into the laminate. Second, on-axis plies are responsible for strength reduction and control failure of the laminate. Developed model is capable of predicting the fatigue life and residual strength of cross-ply laminates with a limited experimental data and acceptable accuracy. The results of the model are compared with the experimental data provided in the second part of the present article.
The Arab Security Sector: A New Research Agenda for a Neglected Topic
Authors: Barak Oren , David Assaf
Published: November 2009

This article discusses the lack of adequate attention to the Arab Security Sector and its complex political and social roles in the Arab States and presents the contours of a new research agenda for this topic. First, the authors demonstrate the insufficient scholarly attention accorded to the Arab Security Sector in several academic publications in the fields of Middle East Studies and Security Studies in the period 1990 —2005. Second, they focus on three major areas where recent theoretical and comparative advances in the study of civil—military relations have not been paralleled in the study of the Arab Security Sector: (1) the role of the Arab Security Sector in the process of state formation; (2) informal connections between actors within the Arab Security Sector and actors operating in the political system; and (3) the role of the Arab Security Sector in reflecting and reinforcing patterns of intersectoral relations in the Arab States.
A Meta-Study of Black Male Mental Health and Well-Being
Authors: Watkins Daphne C. , Walker Rheeda L. , Griffith Derek M.
Published: November 2009

Aggregating and interpreting available qualitative data is a necessary next step to understanding the mental health needs and experiences of Black men. This study describes the findings from a meta-synthesis of qualitative research on Black men’s mental health and well-being using Paterson, Thorne, Canam, and Jillings’s qualitative meta-study approach. Though previous studies have reported various forms of racism as salient concerns for Black men’s mental health and well-being, findings from this meta-study revealed seven themes that present an initial step toward advancing the knowledge pertaining to how Black men perceive and express their mental health and well-being. For instance, male gender socialization and economic status were found to play as large a role in Black men’s mental health and well-being as racism. Additional theoretical perspectives are proposed, and implications for clinical practice and research are discussed.
When Might Peer Aggression, Victimization, and Conflict Have Its Largest Impact? Microcontextual Considerations
Authors: Nishina Adrienne , Bellmore Amy
Published: November 2009

Peer aggression, victimization, and conflict are common occurrences during early adolescence. In the collection of articles in this special issue, several themes emerged, including the use of social psychological theory, individual difference variables, and social context. This article briefly reviews these articles and presents original data that examine microcontextual characteristics (i.e., context of specific events) of sixth and ninth graders’ peer victimization. Students completed daily reports on 5 school days across 2 weeks. Adolescents’ experiences were mostly public (i.e., witnessed by another individual) and perpetrated by a single student from the same grade. Adolescents were unlikely to receive help from others (less than half the time when a witness was present). Ninth-grade data suggest that friends are the most likely witnesses to help the target. Strangers to the target never intervened or tried to help. These findings are discussed in light of implications for prevention and intervention.
Classic Balint Group Work and the Thinking of W.R. Bion: How Balint Work Increases the Ability to Think One’s Own Thoughts
Authors: Rüth Ulrich
Published: November 2009

Some of W.R. Bion’s specific ideas can further the understanding of the classic Balint group technique. The group leader supports a ‘container-contained’ process, preventing the group from attacking or criticizing the presenter.

‘Projective identification’ helps the group to understand what has been presented. Meaningless impressions, feelings, emotions, and simple facts are transferred to the group, such as still unthinkable bizarre ‘beta-elements’ to be transformed by the ‘alpha-function’ to the now thinkable ‘alpha-elements’.

Abstaining from the group process, the presenter is protected from re-projections of feelings and emotions. The Balint group technique makes sense to promote the ‘digestion’ of bizarre beta-element-like aspects into alpha-elements, enabling the presenter to ‘think his or her own thoughts’ instead of projected one, giving the chance to change into a response model instead of a reacting one. ‘Mental growth’ occurs when feelings and thoughts can be tolerated at a higher level.
The Use of Substitutes—Continuity and the Group-as-a-Whole
Authors: Nielsen Jan , Luggin Randi , Thygesen Bente , Aagaard Søren
Published: November 2009

This article is based on experiences in two group analytic therapy groups during periods where substitutes were used in the absence of the regular therapists. The article’s aim is—by means of examples—to illustrate and discuss how this was experienced by group members, substitutes and therapists.

Considering the group-as-a-whole as the primary therapeutic medium, the article will illustrate how the groups used their substitutes and their regular therapists, how they experienced their roles and functions as well as their symbolic significance. The group-as-a-whole is also considered as the carrier of continuity, i.e. the self-sustaining power of the group and the limits of this is illustrated and discussed in connection with planned versus unplanned substitute periods, showing the importance of preparation when the therapist has to be away and a substitute is used.
Foulkesian Authority: Another View. Response to Lecture by Morris Nitsun
Authors: Hutchinson Sylvia
Published: November 2009

This article is inspired by the theme of the 2009 Foulkes lecture and these views on authority relations were presented at the Study Day that followed. Foulkes’ view of the ownership of power involves distinguishing the conductor’s executive powers that are retained versus those that are surrendered by being transferred to the group. Foulkes’ anti-authoritarianism is rationalized in his method. This is accompanied by a discussion of the relationships between group cultures, task and styles of leadership. The link between gender, authority and historical context and social unconscious is briefly explored. Questions are raised about theorizing that is based on the primal horde concept and the privileging of father figures.
Effect of the Exercise Dance for Seniors (EXDASE) Program on Lower-Body Functioning Among Institutionalized Older Adults
Authors: Holmerová Iva , Machácová Katerina , Vanková Hana , Veleta Petr , Jurasková Bozena , Hrnciariková Dana , Volicer Ladislav , Andel Ross
Published: November 2009

Objectives: The authors conducted a randomized control trial to examine the effect of the Exercise Dance for Seniors (EXDASE) program on lower-body functioning among older individuals from residential care facilities in the Czech Republic. Method: Participants were randomly assigned into an experimental or control group. The experimental group completed a 3-month EXDASE program. Lower-body functioning was assessed using four performance-based measures. A 2 (group) × 2 (test) general linear model for repeated measures was used to explore whether differences in performance could be attributed to the intervention. Results: The authors found Group × Test interactions for the chair stand test, F(1, 50) = 14.37, p < .001, the 2-minute step test, F(1, 50) = 7.33, p = .009, the chair sit-and-reach test, F(1, 50) = 5.28, p = .026, and the timed up-and-go test, F (1, 44) = 6.59, p = .014, indicating that the experimental group outperformed the control group from pretest to posttest. Discussion: A relatively simple dance-based exercise can support lower-body functioning in previously sedentary, frail older adults.
Cheerful prospects and tranquil restoration: the visual experience of landscape as part of the therapeutic regime of the British asylum, 1800—60
Authors: Hickman Clare
Published: November 2009

The early nineteenth-century asylum in Britain was generally sited upon a hill with wide-ranging rural views, surrounded by agricultural land, gardens and landscaped grounds. A number of historians have discussed the role of these features as places for patients to partake in recreation, exercise and work. This paper will add to this literature by exploring the possibility that, alongside this active participation and interaction, the passive experience of viewing the landscape and the location of the asylum within a rural setting were also expected to have a therapeutic role.
Lycanthropy in Byzantine times (AD 330—1453)
Authors: Poulakou-Rebelakou E. , Tsiamis C. , Panteleakos G. , Ploumpidis D.
Published: November 2009

In this paper, the original Greek language texts of the Byzantine medical literature about lycanthropy are reviewed. The transformation of a human being into a wolf and the adoption of animal-like behaviour, which were already known from mythology and had been presented in the scientific works of ancient Greek and Roman physicians, were examined by six Byzantine physicians and explained as a type of melancholic depression or mania. In spite of the influence of Byzantine medicine, its rationality in the interpretation of lycanthropy was forgotten in medieval and Renaissance times when it was replaced by explanations based on demonic possession and witchcraft. More recently psychiatry has treated the phenomenon as a subject of medical inquiry and has again explained the condition in terms of mental disorder.