bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibroblast Growth Factor Receptor 4 Regulates Tumor Invasion by Coupling Fibroblast Growth Factor Signaling to Extracellular Matrix Degradation
Authors: Sugiyama Nami , Varjosalo Markku , Meller Pipsa , Lohi Jouko , Hyytiäinen Marko , Kilpinen Sami , Kallioniemi Olli , Ingvarsen Signe , Engelholm Lars H. , Taipale Jussi , Alitalo Kari , Keski-Oja Jorma , Lehti Kaisa
Published: September 2010

Aberrant expression and polymorphism of fibroblast growth factor receptor 4 (FGFR4) has been linked to tumor progression and anticancer drug resistance. We describe here a novel mechanism of tumor progression by matrix degradation involving epithelial-to-mesenchymal transition in response to membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14) induction at the edge of tumors expressing the FGFR4-R388 risk variant. Both FGFR4 and MT1-MMP were upregulated in tissue biopsies from several human cancer types including breast adenocarcinomas, where they were partially coexpressed at the tumor/stroma border and tumor invasion front. The strongest overall coexpression was found in prostate carcinoma. Studies with cultured prostate carcinoma cell lines showed that the FGFR4-R388 variant, which has previously been associated with poor cancer prognosis, increased MT1-MMP–dependent collagen invasion. In this experimental model, knockdown of FGFR4-R388 or MT1-MMP by RNA interference blocked tumor cell invasion and growth in collagen. This was coupled with impaired phosphorylation of FGFR substrate 2 and Src, upregulation of E-cadherin, and suppression of cadherin-11 and N-cadherin. These in vitro results were substantiated by reduced MT1-MMP content and in vivo growth of prostate carcinoma cells after the FGFR4-R388 gene silencing. In contrast, knockdown of the alternative FGFR4-G388 allele enhanced MT1-MMP and invasive tumor cell growth in vivo and within three-dimensional collagen. These results will help to explain the reported association of the FGFR4-R388 variant with the progression and poor prognosis of certain types of tumors. Cancer Res; 70(20); 7851–61. ©2010 AACR.
Activation-Induced Cytidine Deaminase Accelerates Clonal Evolution in BCR-ABL1–Driven B-Cell Lineage Acute Lymphoblastic Leukemia
Authors: Gruber Tanja Andrea , Chang Mi Sook , Sposto Richard , Müschen Markus
Published: September 2010

Activation-induced cytidine deaminase (AID) is required for somatic hypermutation and immunoglobulin (Ig) class switch recombination in germinal center (GC) B cells. Occasionally, AID can target non-Ig genes and thereby promote GC B-cell lymphomagenesis. We recently showed that the oncogenic BCR-ABL1 kinase induces aberrant expression of AID in pre-B acute lymphoblastic leukemia (ALL) and lymphoid chronic myelogenous leukemia blast crisis. To elucidate the biological significance of aberrant AID expression, we studied loss of AID function in a murine model of BCR-ABL1 ALL. Mice transplanted with BCR-ABL1–transduced AID−/− bone marrow had prolonged survival compared with mice transplanted with leukemia cells generated from AID+/+ bone marrow. Consistent with a causative role of AID in genetic instability, AID−/− leukemia had a lower frequency of amplifications and deletions and a lower frequency of mutations in non-Ig genes, including Pax5 and Rhoh compared with AID+/+ leukemias. AID−/− and AID+/+ ALL cells showed a markedly distinct gene expression pattern, and AID−/− ALL cells failed to downregulate a number of tumor-suppressor genes including Rhoh, Cdkn1a (p21), and Blnk (SLP65). We conclude that AID accelerates clonal evolution in BCR-ABL1 ALL by enhancing genetic instability and aberrant somatic hypermutation, and by negative regulation of tumor-suppressor genes. Cancer Res; 70(19); 7411–20. ©2010 AACR.
Inhibition of Autophagy Enhances Anticancer Effects of Atorvastatin in Digestive Malignancies
Authors: Yang Pei-Ming , Liu Yuan-Ling , Lin Yi-Chu , Shun Chia-Tung , Wu Ming-Shiang , Chen Ching-Chow
Published: September 2010

Preclinical and clinical studies have shown that statins, the 3-hydroxy-3-methylglutaryl–CoA reductase inhibitors with cholesterol-lowering properties, exhibited anticancer effects. However, the underlying mechanisms remain ill defined. In this study, we showed that atorvastatin could inhibit the growth of hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells via induction of apoptosis. Atorvastatin also induced autophagy that is a physiologic process involved in the turnover of intracellular organelles. Atorvastatin-induced autophagy was found to be inhibited by AMP-activated protein kinase (AMPK) small interfering RNA. Examination of HCC patients showed the positive correlation between AMPK activity and autophagic marker (beclin-1). Atorvastatin-induced AMPK activation could induce p21 expression, which was also positively correlated with beclin-1 expression in CRC patients. AMPK/p21 signaling caused endoplasmic reticulum (ER) stress response leading to the induction of autophagy. Inhibition of autophagy by an autophagic inhibitor bafilomycin A1 or genetic knockout of autophagy-related gene 5 enhanced atorvastatin-induced cytotoxicity and apoptosis. In summary, activation of AMPK by atorvastatin enhances p21 expression and ER stress response, leading to autophagy, which promotes survival of cancer cells. Combinations of atorvastatin with bafilomycin A1 provide a novel and promising strategy to improve the treatment of digestive malignancies. Cancer Res; 70(19); 7699–709. ©2010 AACR.
Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia
Authors: Chiarini Francesca , Grimaldi Cecilia , Ricci Francesca , Tazzari Pier Luigi , Evangelisti Camilla , Ognibene Andrea , Battistelli Michela , Falcieri Elisabetta , Melchionda Fraia , Pession Andrea , Pagliaro Pasqualepaolo , McCubrey James A. , Martelli Alberto M.
Published: September 2010

Recent findings have highlighted that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival, and drug resistance. These observations lend compelling weight to the application of PI3K/Akt/mTOR inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235, an orally bioavailable imidazoquinoline derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. NVP-BEZ235 was cytotoxic to a panel of T-ALL cell lines as determined by MTT assays. NVP-BEZ235 treatment resulted in cell cycle arrest and apoptosis. Western blots showed a dose- and time-dependent dephosphorylation of Akt and mTORC1 downstream targets in response to NVP-BEZ235. Remarkably, NVP-BEZ235 targeted the side population of both T-ALL cell lines and patient lymphoblasts, which might correspond to leukemia-initiating cells, and synergized with chemotherapeutic agents (cyclophosphamide, cytarabine, dexamethasone) currently used for treating T-ALL patients. NVP-BEZ235 reduced chemoresistance to vincristine induced in Jurkat cells by coculturing with MS-5 stromal cells, which mimic the bone marrow microenvironment. NVP-BEZ235 was cytotoxic to T-ALL patient lymphoblasts displaying pathway activation, where the drug dephosphorylated eukaryotic initiation factor 4E-binding protein 1, at variance with rapamycin. Taken together, our findings indicate that longitudinal inhibition at two nodes of the PI3K/Akt/mTOR network with NVP-BEZ235, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment of those T-ALLs that have aberrant upregulation of this signaling pathway for their proliferation and survival. Cancer Res; 70(20); 8097–107. ©2010 AACR.
Pancreatic Cancer Screening in a Prospective Cohort of High-Risk Patients: A Comprehensive Strategy of Imaging and Genetics
Authors: Verna Elizabeth C. , Hwang Caroline , Stevens Peter D. , Rotterdam Heidrun , Stavropoulos Stavros N. , Sy Carolyn D. , Prince Martin A. , Chung Wendy K. , Fine Robert L. , Chabot John A. , Frucht Harold
Published: September 2010

Purpose: Pancreatic cancer is a virtually uniformly fatal disease. We aimed to determine if screening to identify curable neoplasms is effective when offered to patients at high risk.

Experimental Design: Patients at high risk of pancreatic cancer were prospectively enrolled into a screening program. Endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and genetic testing were offered by a multidisciplinary team according to each patient's risk.

Results: Fifty-one patients in 43 families were enrolled, with mean age of 52 years, 35% of whom were male. Of these patients, 31 underwent EUS and 33 MRI. EUS revealed two patients with pancreatic cancer (one resectable, one metastatic), five with intraductal papillary mucinous neoplasms (IPMN), seven with cysts, and six with parenchymal changes. Five had pancreatic surgery (one total pancreatectomy for pancreatic cancer, three distal and one central pancreatectomy for pancreatic intraepithelial neoplasia 2 and IPMN). A total of 24 (47%) had genetic testing (19 for BRCA1/2 mutations, 4 for CDKN2A, 1 for MLH1/MSH2) and 7 were positive for BRCA1/2 mutations. Four extrapancreatic neoplasms were found: two ovarian cancers on prophylactic total abdominal hysterectomy and bilateral salpingo-oophorectomy, one carcinoid, and one papillary thyroid carcinoma. Overall, 6 (12%) of the 51 patients had neoplastic lesions in the pancreas and 9 (18%) had neoplasms in any location. All were on the initial round of screening. All patients remain alive and without complications of screening.

Conclusions: Pancreatic cancer screening for high-risk patients with a comprehensive strategy of imaging and genetics is effective and identifies curable neoplasms that can be resected. Ongoing study will better define who will benefit from screening and what screening strategy will be the most effective. Clin Cancer Res; 16(20); 5028–37. ©2010 AACR.
Pharmacologic Inactivation of Kinase Suppressor of Ras1 Sensitizes Epidermal Growth Factor Receptor and Oncogenic Ras-Dependent Tumors to Ionizing Radiation Treatment
Authors: Xiao Hongyan , Zhang Qingbei , Shen Jikun , Bindokas Vytas , Xing H. Rosie
Published: September 2010

Selective enhancement of tumor response to radiation therapy is a highly attractive objective, but it has not been met clinically. Gain-of-function Ras (gf) signaling via hyperactivation of receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR), or via oncogenic mutation of Ras is shown to confer radioresistance and requires the engagement of the Raf/MEK/ERK pathway. However, upstream mediators of such interaction in cancer cells that could be targeted for radiosensitization have not been identified and characterized. Here, we provide original observations both in vitro and in vivo that kinase suppressor of Ras1 (KSR1) is a new target for reversing gf Ras-mediated radioresistance. We employed EGFR-dependent A431 squamous cell carcinoma (SCC) and genetically defined the molecular function of KSR1 in irradiation-induced Raf/MEK/ERK activation. In vitro KSR1 inactivation via genetic inhibition of its expression or kinase function abrogated ionizing radiation–induced activation of the Raf/MEK/ERK2 cascade, enhanced the cytotoxic effect of radiation, and achieved radiosensitization associated with inhibition of DNA damage repair and enhancement of clonogenic death. In vivo pharmacologic inactivation of KSR1 by KSR1 AS-ODN infusion leads to radiosensitization in EGFR-dependent A431 SCC and in oncogenic K-Ras-driven A549 human non–small cell lung carcinoma. These observations collectively establish KSR1 as a novel target for radiosensitization and show the feasibility of using KSR1 AS-ODN as a radiosensitizer for treating gf Ras-dependent human malignancies. Identification of such mediators of gf Ras signaling in response to irradiation holds promises for improving the therapeutic efficacy of radiation therapy and our ability to eradicate tumor. Mol Cancer Ther; 9(10); 2724–36. ©2010 AACR.
Efficacy of the Multi-Kinase Inhibitor Enzastaurin Is Dependent on Cellular Signaling Context
Authors: Kuo Wen-Liang , Liu Jing , Mauceri Helena , Vokes Everett E. , Weichselbaum Ralph , Rosner Marsha Rich , Cohen Ezra Eddy Wyssam
Published: September 2010

The number of targeted small molecules being developed in oncology is increasing rapidly. Many of these are designed to inhibit multiple kinases, and thus the mechanisms of responsiveness and predictive biomarkers can be difficult to discern. In fact, with few exceptions, multi-kinase inhibitors are developed with limited mechanism-based patient selection. Enzastaurin is a multi-kinase inhibitor being studied in several malignancies that we hypothesized would be active in squamous cell carcinoma of the head and neck, because it inhibits classic and novel protein kinase C isoforms. Indeed, enzastaurin reduced the growth of SQ-20B and CAL27 tumor xenografts, decreased proliferation in these cell lines, inhibited putative target phosphorylation, and induced cell cycle arrest. Gene expression arrays confirmed that expression of cell cycle genes, including cyclins D and E, were significantly altered by exposure to enzastaurin. However, testing a panel of squamous cell carcinoma of the head and neck cell lines revealed variable sensitivity to enzastaurin, which correlated significantly with baseline cyclin D1 protein expression. Moreover, sensitivity and resistance could be reversed, respectively, by expression or depletion of cyclin D1. Furthermore, analysis of sensitive and resistant cell lines revealed distinct differences in cyclin D1 regulation. Enzastaurin modulated cyclin D1 synthesis through an Akt-regulated pathway in the former, whereas high-level CCND1 gene amplification was present in the latter. These results underscore the critical relevance of cellular signaling context in developing cancer therapies in general and suggest that enzastaurin in particular would be most effective in tumors where baseline cyclin D1 expression is low to moderate and physiologically regulated. Mol Cancer Ther; 9(10); 2814–24. ©2010 AACR.
Colon Tumor Cell Growth–Inhibitory Activity of Sulindac Sulfide and Other Nonsteroidal Anti-Inflammatory Drugs Is Associated with Phosphodiesterase 5 Inhibition
Authors: Tinsley Heather N. , Gary Bernard D. , Thaiparambil Jose , Li Nan , Lu Wenyan , Li Yonghe , Maxuitenko Yulia Y. , Keeton Adam B. , Piazza Gary A.
Published: September 2010

Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity, but toxicity resulting from cyclooxygenase (COX) inhibition limits their clinical use for chemoprevention. Studies suggest that the mechanism may be COX independent, although alternative targets have not been well defined. Here, we show that the NSAID sulindac sulfide (SS) inhibits cyclic guanosine 3′,5′-monophosphate (cGMP) phosphodiesterase (PDE) activity in colon tumor cell lysates at concentrations that inhibit colon tumor cell growth in vitro and in vivo. A series of chemically diverse NSAIDs also inhibited cGMP hydrolysis at concentrations that correlate with their potency to inhibit colon tumor cell growth, whereas no correlation was observed with COX-2 inhibition. Consistent with its selectivity for inhibiting cGMP hydrolysis compared with cyclic AMP hydrolysis, SS inhibited the cGMP-specific PDE5 isozyme and increased cGMP levels in colon tumor cells. Of numerous PDE isozyme–specific inhibitors evaluated, only the PDE5-selective inhibitor MY5445 inhibited colon tumor cell growth. The effects of SS and MY5445 on cell growth were associated with inhibition of β-catenin–mediated transcriptional activity to suppress the synthesis of cyclin D and survivin, which regulate tumor cell proliferation and apoptosis, respectively. SS had minimal effects on cGMP PDE activity in normal colonocytes, which displayed reduced sensitivity to SS and did not express PDE5. PDE5 was found to be overexpressed in colon tumor cell lines as well as in colon adenomas and adenocarcinomas compared with normal colonic mucosa. These results suggest that PDE5 inhibition, cGMP elevation, and inhibition of β-catenin transcriptional activity may contribute to the chemopreventive properties of certain NSAIDs. Cancer Prev Res; 3(10); 1303–13. ©2010 AACR.
Prevention of Murine Acute Graft-versus-Host Disease by Recipient-Derived Paired Immunoglobulin-Like Receptor B Lentivirus-Transfected Dendritic Cells
Authors: Zhao Juan , Luo Yi , Wang Xiaochong , Zhou Hao , Li Qiubai , You Yong , Zou Ping
Published: September 2010

Direct interaction between T-suppressor and dendritic cells (DCs) results in DC tolerance by inducing upregulation of immunoglobulin-like transcript (ILT) 3 and ILT4. DCs were treated with a lentiviral vector containing paired immunoglobulin-like B gene (PIR-B) DCs and the effect of PIR-B-DCs on graft-versus-host disease (GVHD) was analyzed after allogeneic bone marrow (BM) transplantation (BMT). Therefore, 1 × 106 recipient-derived PIR-B-DCs were injected into BALB/c (H-2kd) mice using BM-splenocyte grafts from major histocompatibility complex-disparate C57BL/6 (H-2kb). Our results showed that PIR-B-DCs deficient in surface costimulatory molecules had higher PIR-B protein expression than immature DCs and interleukin 10-treated DCs. Survival analysis showed PIR-B-DC cotransplantation resulted in significant prolongation of allograft survival (mean survival time: 46.0 ± 13.6 vs. 17.4 ± 3.6 days in untreated MST; p < 0.01). Furthermore, samples from the liver and skin of a mouse did not show clinical or histological signs of GVHD following the injection of PIR-B-DCs. These results demonstrated that PIR-B-DC cotransplantation may attenuate the severity of GVHD after BMT.
Carina Angle Measurements for Diagnosis of Patent Ductus Arteriosus in Preterm Infants
Authors: Strauss Tzipora , Pessach Itai , Jacoby Elad , Schushan-Eisen Irit , Mazkereth Ram , Kuint Jacob
Published: September 2010

Background: Bedside diagnosis of patent ductus arteriosus (PDA) continues to be important, especially when echocardiography is not readily available. Objective: The aim of our study was to evaluate whether measurement of left main bronchus displacement portrayed on a chest X-ray as a widened carina angle (CA) may support the presumptive diagnosis of PDA. Methods: Displacement of the left bronchus was assessed by measuring the angle between the two main bronchi at the level of the carina in 47 infants with PDA and 73 with no evidence of ductus, all born before 32 weeks of gestation. Results: The PDA group had a significantly wider CA (99.9 ± 12.1°) compared to the no-ductus group (72.9 ±15.7°; p < 0.001). Resolution of the PDA resulted in closure of the CA (62.3 ± 10.8°). We observed a significant and positive association between an increased CA measurement and PDA occurrence (OR = 1.7, 95% CI = 1.4–2.1). A CA cutoff point of 90° had the highest sensitivity (85%) and specificity (85%) for indicating the presence of PDA. Conclusions: Measurement of the CA is an easily accessible and reliable tool that may assist in establishing the diagnosis of PDA.
Clinical Relevance of Carotid Atherosclerosis among Egyptians: A 5-Year Retrospective Analysis of 4,733 Subjects
Authors: Abd Allah Foad , Baligh Essam , Ibrahim Magdy
Published: September 2010

Background and Purpose: The prevalence of carotid artery stenosis has been studied in several cohorts and groups of populations. Prevalence estimates were mostly based on ultrasound studies, because duplex ultrasound is accurate, reproducible and inexpensive to diagnose and follow up patients with arterial disorders. The purpose of our study was to describe the pattern of carotid artery disease in a large sample of Egyptians. Methods: We analyzed the data of 4,733 Egyptian subjects, who underwent extracranial carotid duplex scanning at the vascular laboratories of Cairo University Hospitals from January 1, 2003, to January 1, 2008. Demographic, clinical data and causes of referral were correlated with ultrasound findings. Results: Atherosclerotic carotid artery disease was present in 41% of the study population in the form of intimal thickening in 835 (17.6%), <50% stenosis in 983 (20.8%), 50–69% stenosis in 81 (1.7%), ≧70% stenosis in 38 (0.8%) and occlusion of internal carotid artery in 3 (0.06%) patients. Nonatherosclerotic disease was detected in 9 (0.2%) patients only. Significant and clinically relevant stenosis ≧50% was detected in 19 (2.5%) of the atherosclerotic symptomatic subjects. Multivariate stepwise logistic regression analysis selected age, diabetes mellitus, hypertension, smoking and dyslipidemia as independent predictors of the presence of carotid atherosclerotic disease. Conclusion: Hemodynamically significant and clinically relevant extracranial atherosclerotic carotid disease is rare among Egyptians. Risk factors for carotid atherosclerosis are the same as in societies where carotid disease is more prevalent.
Haptoglobin Gene Polymorphisms in Sickle Cell Disease Patients with Different βS-Globin Gene Haplotypes
Authors: Adekile A.D. , Haider M.Z.
Published: September 2010

Objective: To investigate the prevalence of haptoglobin (Hp) gene alleles in Kuwaiti sickle cell disease (SCD) patients, who generally have a mild phenotype, and compare the pattern to Nigerian SCD patients whose SCD phenotype is more severe. Subjects and Methods: Hp genotyping was carried out in a group of 82 and 54 SCD patients from Kuwait and Nigeria, respectively, and appropriate Hb AA controls. The Hp genotyping was done using a PCR technique followed by agarose gel electrophoresis. Results: The frequency of the Hp-2 allele was 73.8% among Kuwaiti SCD patients, while the Hp-1 allele predominated among Nigerian patients (60.7%). However, the differences were not significant (p > 0.05) when the allele distributions were compared between Kuwaiti SCD and their AA counterparts or between Nigerian SCD and their AA controls. There was no association of Hp-2 allele with frequent vaso-occlusive crisis among the Kuwaiti SCD patients. Conclusion: The distribution of Hp alleles appears to follow ethnic and geographical trends. Their role in the pathophysiology of pain crisis is not clear.
A Comparative Analysis of Tuberculosis Treatment Success between Hunan Province of China and Eastern Ghana
Authors: Abuaku Benjamin K. , Tan Hongzhuan , Li Xingli , Chen Mengshi , Huang Xin
Published: September 2010

Objective: To assess the differences in tuberculosis (TB) treatment success between Hunan and Eastern Ghana. Subjects and Methods: The study was a retrospective comparative study using 2005–2006 surveillance data from the Hunan province of China and the Eastern region of Ghana. Data analyzed were from the provincial/regional capital and a randomly selected city of lower economic status. χ2 test and Fisher’s exact test were used to do general and stratified comparison of treatment success rates within/between the two areas. Multivariate logistic regression was used to analyze the independent effect of explanatory variables on treatment success. Results: Generally, the treatment success rate was significantly higher in Hunan (93.1 vs. 60.7%, p = 0.000). Stratified analyses showed a similar pattern for almost all the group-specific rates. Key predictors of TB treatment success in Hunan were gender, age group, and type of city of residence whilst in Eastern Ghana treatment success was associated with only age group. Odds ratios for treatment success in Hunan were significantly lower for males (OR = 0.78; 95% CI = 0.63, 0.97), and higher for patients resident in the provincial capital (OR = 1.35; 95% CI = 1.12, 1.62). In both countries treatment success rates decreased with increasing age. Conclusion: TB treatment success in Hunan was comparatively better than that in Eastern Ghana. Gender, age group, and type of city of residence were the key predictors of treatment success in Hunan whilst in Eastern Ghana age group was the key predictor.
Knowledge and Attitude towards Stroke Risk Factors, Warning Symptoms and Treatment in an Iranian Population
Authors: Borhani Haghighi Afshin , Karimi Ali Asghar , Amiri Ali , Ghaffarpasand Fariborz
Published: September 2010

Objectives: To assess the baseline knowledge regarding stroke risk factors, symptoms, treatment and information resources in an Iranian urban population. Subjects and Methods: A community-based face-to-face interview survey was conducted in the Shiraz urban area in Iran. A total of 385 potential participants between the ages of 15 and 83 years were randomly selected from people referred to Motahari Clinic, Shiraz University of Medical Sciences, Shiraz. All the participants answered the 63 questions about different aspects of stroke. SPSS software version 15 was used to analyze the data. Results: The 385 participants completed the face-to-face interview. The most common risk factors for stroke identified by respondents were hypertension (342; 88.8%) and smoking (338; 87.8%). The most common warning signs of stroke were abdominal pain (370; 96.1%) and chest pain (338; 88.7%). Conclusion: This study shows that the knowledge of and attitude towards stroke risk factors in the general population of Shiraz are adequate. By using the public media and school education, it is possible to promote the level of the population’s knowledge of and attitude towards stroke.
Role of Neopterin, C-Reactive Protein and Myeloperoxidase in Patients Undergoing Cardiopulmonary Bypass
Authors: Ayaz Lokman , Unlu Ali , Sucu Nehir , Tamer Lulufer , Atik Ugur , Sungur Mehmet Ali
Published: September 2010

Objective: The aim of the present study was to investigate the role of neopterin (NP), C-reactive protein (CRP) and myeloperoxidase (MPO) in patients undergoing coronary artery bypass grafting with or without cardiopulmonary bypass (CPB). Patients and Methods: Forty patients submitted for elective coronary artery bypass grafting were included in this prospective study. Patients were divided into two groups of 20 individuals, those who did not undergo CPB (group 1), aged 54.1 ± 13.5 years, and those who did (group 2), aged 60.2 ± 11.7 years. In group 1, there were 17 males and 3 females, while in group 2, there were 16 males and 4 females. Serum CRP, serum and urine NP and leukocyte MPO activity were measured preoperatively, at the end of surgery, and 4, 24 and 72 h after surgery using high-performance liquid chromatography, immunoturbidimetry and the reduction in o-dianizidine, respectively. Results: The level of serum NP was higher preoperatively and at the end of surgery (0 h), 4, 24, and 72 h after the operation in those who underwent CPB compared to those who did not. However, there was no significant difference in NP concentrations between the two groups at any time except 24 h after surgery (p = 0.002). Urine NP concentrations showed similar values preoperatively but increased postoperatively in both groups of patients. The only significant difference in urine NP concentration between the two groups occurred at 0 and 24 h after surgery (p = 0.001, p = 0.000). Serum CRP concentrations showed similar values preoperatively, at the end of surgery and 72 h after the operation and increased at 4 and 24 h postoperatively in both groups. The only significant difference in CRP concentration between the two groups occurred 4 and 24 h after surgery (p = 0.024 and p = 0.000, respectively). MPO levels were found to be increased in the CPB patients when compared to those patients who did not undergo CPB. However, the difference between the groups was not statistically significant. Conclusion: Our data show that CPB induced a rise in NP and CRP levels.
Brugada Syndrome with Aborted Sudden Cardiac Death Related to Liquorice-Induced Hypokalemia
Authors: Yorgun Hikmet , Aksoy Hakan , Şendur Mehmet Ali , Ateş Ahmet Hakan , Kaya Ergün Barış , Aytemir Kudret , Oto Ali
Published: September 2010

Objective: It was the aim of this study to report an aborted cardiac arrest due to ventricular fibrillation and electrocardiographic changes consistent with Brugada syndrome due to liquorice-induced hypokalemia. Clinical Presentation and Intervention: Ventricular fibrillation was witnessed in a 50-year-old woman who was admitted to our emergency department with a history of liquorice ingestion, a herbal product. After stopping liquorice ingestion, the Brugada-like electrocardiographic pattern changed progressively with potassium replacement. A diagnosis of Brugada syndrome was made after the ajmaline challenge test. The patient was discharged with an implantable cardioverter defibrillator and had an uneventfull follow-up. Conclusion: This report illustrates the importance of the investigation for herbal medications in the detailed history of a patient in the cases of electrolyte disturbances and the potential role of hypokalemia in the induction of malignant arrhythmia in Brugada syndrome.
Bilateral Stress Fracture of the Fibulae and Periostitis of the Tibiae
Authors: Tsuchie Hiroyuki , Okada Kyoji , Nagasawa Hiroyuki , Chida Shuichi , Shimada Yoichi
Published: September 2010

Objective: This study describes a unique case of bilateral stress fractures of the fibulae and provides a literature review. Clinical Presentation and Intervention: A 16-year-old female badminton player presented with pain around the bilateral distal lateral legs. She had mild bilateral varus deformity at the knee joint, and the bilateral ankles showed valgus deformity in standing posture. Radiographs and computed tomography showed periosteal reactions on the bilateral distal fibulae. Technetium-99m bone scintigraphy demonstrated increased uptake in the bilateral distal fibulae and the bilateral middle third of the tibiae. A diagnosis of bilateral distal fibular stress fractures was made. She was advised to stop playing badminton until the symptoms disappeared. Conclusion: Varus deformity of the knee and valgus deformity of the ankle may have influenced the mechanism underlying bilateral symmetric stress fractures.
Upper Gastrointestinal Hemorrhage from Hepatic Artery Pseudoaneurysm Secondary to Trauma: A Case Report
Authors: Luo Xiaofang , Tan Shiyun , Wang Junyu , Qian Cuijuan
Published: September 2010

Objective: We report a rare but serious case of upper gastrointestinal hemorrhage from hepatic artery pseudoaneurysm. Clinical Presentation and Intervention: An 11-year-old child with a history of hepatic trauma 6 months before was admitted for hematemesis and melena. Repeat ultrasound examination showed a 3.6 × 2.8 cm anechoic area with clear border in the right hepatic lobe. Selective angiography confirmed the presence of a pseudoaneurysm of the right hepatic artery. Transcatheter arterial embolization was used to successfully treat the pseudoaneurysm. Conclusion: This report shows that hepatic artery pseudoaneurysm should be considered as a possible cause of upper gastrointestinal hemorrhagefollowing known hepatic injury. A high index of suspicion, repeated Doppler ultrasound and timely selective angiography are required for diagnosis. Embolotherapy is the treatment of choice.
Ancestry as a Determinant of Mean Population C-Reactive Protein Values
Authors: Shah Tina , Newcombe Paul , Smeeth Liam , Addo Juliet , Casas Juan P. , Whittaker John , Miller Michelle A. , Tinworth Lorna , Jeffery Steve , Strazzullo Pasquale , Cappuccio Francesco P. , Hingorani Aroon D.
Published: September 2010

Background—

Eligibility for rosuvastatin treatment for cardiovascular disease prevention includes a C-reactive protein (CRP) concentration >2 mg/L. Most observational studies of CRP and cardiovascular disease have been in Europeans. We evaluated the influence of ancestry on population CRP concentration to assess the implications for statin targeting in non-Europeans.

Methods and Results—

In a systematic review and meta-analysis among 221 287 people from 89 studies, geometric mean CRP was 2.6 mg/L (95% credible interval, 2.27 to 2.96) in blacks resident in the United States (n=18 585); 2.51 mg/L (95% CI, 1.18 to 2.86) in Hispanics (n=5049); 2.34 mg/L (95% CI, 1.99 to 2.8) in South Asians (n=1053); 2.03 mg/L (95% CI, 1.77 to 2.3) in whites (n=104 949); and 1.01 mg/L (95% CI, 0.88 to 1.18) in East Asians (n=39 521). Differences were not explained by study design or CRP assay and were preserved after adjustment for age and body mass index. At age 60 years, fewer than half of East Asians but more than two thirds of Hispanics were estimated to have CRP values exceeding 2 mg/L. HapMap frequencies of CRP polymorphisms known to associate with CRP concentration but not coronary heart disease events differed by ancestry. In participant data from the Wandsworth Heart and Stroke Study including European, South Asian and African, and Caribbean-descent subjects, body mass index, systolic blood pressure, and smoking contributed to between-group differences in CRP, but the majority of the difference in CRP was unexplained.

Conclusions—

Differences in CRP concentration in populations of diverse ancestry are sufficiently large to affect statin eligibility, based on a single CRP threshold of 2 mg/L, and only partially influenced by differences in variables related to cardiovascular risk. A single threshold value of CRP for cardiovascular risk prediction could lead to inequalities in statin eligibility that may not accurately reflect underlying levels of cardiovascular risk.
Classification as Clustering: A Pareto Cooperative-Competitive GP Approach
Authors: McIntyre Andrew R. , Heywood Malcolm I.
Published: September 2010

Intuitively population based algorithms such as genetic programming provide a natural environment for supporting solutions that learn to decompose the overall task between multiple individuals, or a team. This work presents a framework for evolving teams without recourse to prespecifying the number of cooperating individuals. To do so, each individual evolves a mapping to a distribution of outcomes that, following clustering, establishes the parameterization of a (Gaussian) local membership function. This gives individuals the opportunity to represent subsets of tasks, where the overall task is that of classification under the supervised learning domain. Thus, rather than each team member representing an entire class, individuals are free to identify unique subsets of the overall classification task. The framework is supported by techniques from evolutionary multiobjective optimization (EMO) and Pareto competitive coevolution. EMO establishes the basis for encouraging individuals to provide accurate yet nonoverlaping behaviors; whereas competitive coevolution provides the mechanism for scaling to potentially large unbalanced datasets. Benchmarking is performed against recent examples of nonlinear SVM classifiers over 12 UCI datasets with between 150 and 200,000 training instances. Solutions from the proposed coevolutionary multiobjective GP framework appear to provide a good balance between classification performance and model complexity, especially as the dataset instance count increases.
The Potential Impact of Not Being Able to Create Parallel Tests on Expected Classification Accuracy
Authors: Wyse Adam E.
Published: September 2010

In many practical testing situations, alternate test forms from the same testing program are not strictly parallel to each other and instead the test forms exhibit small psychometric differences. This article investigates the potential practical impact that these small psychometric differences can have on expected classification accuracy. Ten different sets of tests were assembled by minimizing the differences in test information at five θ locations. The impact of the psychometric differences between the assembled test forms was quantified for two different groups of simulated examinees across a range of possible cut scores. Results indicated that using sequential or simultaneous test assembly is preferred to random test assembly. Analyses also implied that the small differences in the psychometric properties between tests produced differences in overall classification accuracy that were less than 1.5%. The biggest differences in classification accuracy were found when the test information functions were not as well matched in regions where there were more examinees. Although these differences were fairly small, they may have the potential to have a practically significant impact on decision making. It is suggested that classification accuracy critically depends on the differences in test information, the location of the cut score, and the groups of examinees considered.
A Test-Length Correction to the Estimation of Extreme Proficiency Levels
Authors: Magis David , Béland Sébastien , Raîche Gilles
Published: September 2010

In this study, the estimation of extremely large or extremely small proficiency levels, given the item parameters of a logistic item response model, is investigated. On one hand, the estimation of proficiency levels by maximum likelihood (ML), despite being asymptotically unbiased, may yield infinite estimates. On the other hand, with an appropriate prior distribution, the Bayesian approach of maximum a posteriori (MAP) yields finite estimates, but it suffers from severe estimation bias at the extremes of the proficiency scale. As a first step, a simple correction to the MAP estimator is proposed to reduce this estimation bias. The correction factor is determined through a simulation study and depends only on the length of the test. In a second step, some additional simulations emphasize that the corrected estimator behaves like the ML estimator and outperforms the standard MAP method for extremely small or extremely large abilities. Although based on the Rasch model, the method could be adapted to other logistic item response models.
Construing Organizational Identity: The Role of Embodied Cognition
Authors: Harquail Celia V. , Wilcox King Adelaide
Published: September 2010

This paper presents a theory of organizational identity based on embodied cognition. Embodied cognitive science focuses on developing theories that reveal how humans’ capacities to process information and gain knowledge are functions of bodily experiences. What members come to know about an organization is a function of what they physically experience, as well as what is in their heads. We propose and examine four embodied capacities that members use to construe what they believe is central, distinctive, and enduring about their organizations. We suggest this approach reveals an important fourth dimension of OI: that an individual’s construal of organizational identity must also be ‘substantiated’ or verified by a member’s embodied experiences. We consider how an embodied construal of OI might add to three dominant perspectives on OI, and discuss how it might expand our understanding of six OI-related topics, ranging from individual organizational identification to large-scale organizational change. We close with suggestions for future research, including new empirical methods and perhaps a reexamination of organizational cognition as a whole.
Use of the Internet and Ratings of Information Sources for Medical Decisions: Results from the DECISIONS Survey
Authors: Couper Mick P. , Singer Eleanor , Levin Carrie A. , Fowler Floyd J. , Fagerlin Angela , Zikmund-Fisher Brian J.
Published: September 2010

Background

The rise in Internet use for seeking health information raises questions about the role the Internet may play in how patients make medical decisions.

Objective

To examine Internet use and perceived importance of different sources of information by patients making 9 specific medical decisions covering prescription medication initiation, cancer screening, and elective surgery.

Setting

National sample of US adults identified by random-digit dialing.

Design

Cross-sectional survey conducted between November 2006 and May 2007.

Participants

The final sample comprised 2575 English-speaking US adults aged 40 y and older who had either undergone 1 of 9 medical procedures or tests or talked with a health care provider about doing so during the previous 2 y.

Measurements

Participants indicated if they or other family members used the Internet to seek information related to each of the specific medical decisions and rated how important the health care provider, the Internet (if used), family and friends, and the media (newspapers, magazines, and television) were in providing information to help make the medical decision.

Results

Use of the Internet for information related to specific decisions among adults 40 y and older was generally low (28%) but varied across decisions, from 17% for breast cancer screening to 48% for hip/knee replacement. Internet use was higher at younger ages, rising from 14% among those aged 70 y and older to 38% for those aged 40 to 49 y. Internet users consistently rated health care providers as the most influential source of information for medical decisions, followed by the Internet, family and friends, and media.

Limitations

Telephone surveys are limited by coverage and nonresponse. The authors excluded health-related Internet use not associated with the 9 target decisions.

Conclusions

A minority of patients reported using the Internet to make specific common medical decisions, but use varied widely by type of decision. Perhaps reflecting perceived risk and uncertainty, use was lowest for screening decisions and highest for surgical decisions.
Decision-Making Processes for Breast, Colorectal, and Prostate Cancer Screening: The DECISIONS Survey
Authors: Hoffman Richard M. , Lewis Carmen L. , Pignone Michael P. , Couper Mick P. , Barry Michael J. , Elmore Joann G. , Levin Carrie A. , Van Hoewyk John , Zikmund-Fisher Brian J.
Published: September 2010

Background

Patients should understand the risks and benefits of cancer screening in order to make informed screening decisions.

Objectives

To evaluate the extent of informed decision making in patient-provider discussions for colorectal (CRC), breast (BrCa), and prostate (PCa) cancer screening.

Setting

National sample of US adults identified by random-digit dialing.

Design

Cross-sectional survey conducted between November 2006 and May 2007.

Participants

English-speaking US adults aged 50 y and older who had discussed cancer screening with a health care provider within the previous 2 y.

Measurements

Cancer screening survey modules that asked about demographic characteristics, cancer knowledge, the importance of various sources of information, and self-reported cancer screening decision-making processes.

Results

Overall, 1082 participants completed 1 or more of the 3 cancer modules. Although participants generally considered themselves well informed about screening tests, half or more could not correctly answer even 1 open-ended knowledge question for any given module. Participants consistently overestimated risks for being diagnosed with and dying from each cancer and overestimated the positive predictive values of prostate-specific antigen tests and mammography. Providers were the most highly rated information source, usually initiated screening discussions (64%–84%), and often recommended screening (73%–90%). However, participants reported that providers elicited their screening preferences in only 31% (CRC women) to 57% (PCa) of discussions. Although more than 90% of the discussions addressed the pros of screening, only 19% (BrCa) to 30% (PCa) addressed the cons of screening.

Limitations

Recall bias is possible because screening process reports were not independently validated.

Conclusions

Cancer screening decisions reported by patients who discussed screening with their health care providers consistently failed to meet criteria for being informed. Given the high ratings for provider information and frequent recommendations for screening, providers have important opportunities to ensure that informed decision making occurs for cancer screening decisions.
How Does Feeling Informed Relate to Being Informed? The DECISIONS Survey
Authors: Sepucha Karen R. , Fagerlin Angela , Couper Mick P. , Levin Carrie A. , Singer Eleanor , Zikmund-Fisher Brian J.
Published: September 2010

Background

An important part of delivering high-quality, patient-centered care is making sure patients are informed about decisions regarding their health care. The objective was to examine whether patients’ perceptions about how informed they were about common medical decisions are related to their ability to answer various knowledge questions.

Methods

A cross-sectional survey was conducted November 2006 to May 2007 of a national sample of US adults identified by random-digit dialing. Participants were 2575 English-speaking US adults aged 40 and older who had made 1 of 9 medication, cancer screening, or elective surgery decisions within the previous 2 years. Participants rated how informed they felt on a scale of 0 (not at all informed) to 10 (extremely well-informed), answered decision-specific knowledge questions, and completed standard demographic questions.

Results

Overall, 36% felt extremely well informed (10), 30% felt well informed (8–9), and 33% felt not at all to somewhat informed (0–7). Multivariate logistic regression analyses showed no overall relationship between knowledge scores and perceptions of being extremely well informed (odds ratio [OR] = 0.94, 95% confidence interval [CI] 0.63–1.42, P = 0.78). Three patterns emerged for decision types: a negative relationship for cancer screening decisions (OR = 0.58, CI 0.33–1.02, P = 0.06), no relationship for medication decisions (OR = 0.99, CI 0.54–1.83, P = 0.98), and a positive relationship for surgery decisions (OR = 3.07, 95% CI 0.90–10.54, P = 0.07). Trust in the doctor was associated with feeling extremely well-informed for all 3 types of decisions. Lower education and lower income were also associated with feeling extremely well informed for medication and screening decisions. Retrospective survey data are subject to recall bias, and participants may have had different perspectives or more factual knowledge closer to the time of the decision.

Conclusions

Patients facing common medical decisions are not able to accurately assess how well informed they are. Clinicians need to be proactive in providing adequate information to patients and testing patients’ understanding to ensure informed decisions.
Renal Lesions of Nondomestic Felids
Authors: Newkirk K. M. , Newman S. J. , White L. A. , Rohrbach B. W. , Ramsay E. C.
Published: September 2010

To comprehensively evaluate the occurrence of renal lesions in a variety of nondomestic felids, necropsy cases from 1978 to 2008 were reviewed from a municipal zoo and a large cat sanctuary for those in which the kidneys were examined histologically. Seventy exotic felids were identified (25 tigers, 18 lions, 6 cougars, 5 leopards, 3 snow leopards, 3 clouded leopards, 3 Canadian lynx, 2 ocelots, 2 bobcats, 2 cheetahs, 1 jaguar), and their histologic renal lesions were evaluated and compared. The most common lesion was tubulointerstitial nephritis (TIN); 36 of 70 (51%) cats were affected to some degree. Lymphocytic interstitial nephritis was the most common lesion in the tigers (9 of 25, 36%) and was rarely seen in other species. Although the renal pelvis was not available for all cats, 28 of 47 (60%) had some degree of lymphocytic pyelitis. There was no significant association between the presence of pyelitis and that of TIN. Only 1 cat had pyelonephritis. Renal papillary necrosis was present in 13 of 70 (19%) cats and was significantly associated with historical nonsteroidal anti-inflammatory drug treatment (odds ratio, 7.1; 95% confidence interval, 1.9 to 26.8). Only 1 cat (lion) had amyloid accumulation, and it was restricted to the corticomedullary junction. Primary glomerular lesions were absent in all cats. Intraepithelial pigment was identified in many of the cats but was not correlated with severity of TIN. Despite several previous reports describing primary glomerular disease or renal amyloidosis in exotic felids, these lesions were rare to absent in this population.