bluuebunny/crossref_metadata_2025 huggingface dataset:
Cetuximab/C225-Induced Intracellular Trafficking of Epidermal Growth Factor Receptor
Authors: Liao Hong-Jun , Carpenter Graham
Published: July 2009

The monoclonal antibody C225 interacts with the ectodomain of the epidermal growth factor (EGF) receptor (EGFR) to block ligand binding and initiates receptor endocytosis and intracellular trafficking. The data herein show that C225-dependent EGFR trafficking relocalizes the receptor to the endoplasmic reticulum (ER) and nucleus. This mechanism, which also involves interaction of the C225-internalized receptor with the Sec61 translocon within the ER, is, in most respects, analogous to the pathway previously described for EGF-induced trafficking to the ER and nucleus. However, although inhibition of receptor tyrosine kinase activity blocks EGF-induced nuclear localization of the receptor, the same kinase inhibitors stimulate C225-dependent nuclear localization of EGFR in the nucleus. In contrast, the kinase inhibitor Lapatinib fails to stimulate nuclear accumulation of the receptor in C225-treated cells and does not provoke receptor dimerization as do inhibitors that recognize the open conformation of the receptor kinase. This suggests that inhibitor-dependent receptor dimerization may facilitate C225-induced receptor trafficking. [Cancer Res 2009;69(15):6179–83]
Polycomb CBX7 Promotes Initiation of Heritable Repression of Genes Frequently Silenced with Cancer-Specific DNA Hypermethylation
Authors: Mohammad Helai P. , Cai Yi , McGarvey Kelly M. , Easwaran Hariharan , Van Neste Leander , Ohm Joyce E. , O'Hagan Heather M. , Baylin Stephen B.
Published: July 2009

Epigenetic silencing of genes in association with aberrant promoter DNA hypermethylation has emerged as a significant mechanism in the development of human cancers. Such genes are also often targets of the polycomb group repressive complexes in embryonic cells. The polycomb repressive complex 2 (PRC2) has been best studied in this regard. We now examine a link between PRC1 and cancer-specific gene silencing. Here, we show a novel and direct association between a constituent of the PRC1 complex, CBX7, with gene repression and promoter DNA hypermethylation of genes frequently silenced in cancer. CBX7 is able to complex with DNA methyltransferase (DNMT) enzymes, leading us to explore a role for CBX7 in maintenance and initiation of gene silencing. Knockdown of CBX7 was unable to relieve suppression of deeply silenced genes in cancer cells; however, in embryonal carcinoma (EC) cells, CBX7 can initiate stable repression of genes that are frequently silenced in adult cancers. Furthermore, we are able to observe assembly of DNMTs at CBX7 target gene promoters. Sustained expression of CBX7 in EC cells confers a growth advantage and resistance to retinoic acid–induced differentiation. In this setting, especially, there is increased promoter DNA hypermethylation for many genes by analysis of specific genes, as well as through epigenomic studies. Our results allow us to propose a potential mechanism through assembly of novel repressive complexes, by which the polycomb component of PRC1 can promote the initiation of epigenetic changes involving abnormal DNA hypermethylation of genes frequently silenced in adult cancers. [Cancer Res 2009;69(15):6322–30]
Tumor Repressive Functions of Estrogen Receptor β in SW480 Colon Cancer Cells
Authors: Hartman Johan , Edvardsson Karin , Lindberg Karolina , Zhao Chunyan , Williams Cecilia , Ström Anders , Gustafsson Jan-Åke
Published: July 2009

Estrogen receptor β (ERβ) is the predominant ER in the colorectal epithelium. Compared with normal colon tissue, ERβ expression is reduced in colorectal cancer. Our hypothesis is that ERβ inhibits proliferation of colon cancer cells. Hence, the aim of this study has been to investigate the molecular function of ERβ in colon cancer cells, focusing on cell cycle regulation. SW480 colon cancer cells have been lentivirus transduced with ERβ expression construct with or without mutated DNA-binding domain or an empty control vector. Expression of ERβ resulted in inhibition of proliferation and G1 phase cell cycle arrest and this effect was dependent on a functional DNA-binding region. c-Myc is overexpressed in an overwhelming majority of colorectal tumors. By Western blot and real-time PCR, we found c-Myc to be down-regulated in the ERβ-expressing cells. Furthermore, the c-Myc target gene p21(Waf1/Cip1) was induced and Cdc25A was reduced by ERβ at the transcriptional level. The second cdk2-inhibitor, p27Kip1, was induced by ERβ, but this regulation occurred at the posttranscriptional level, probably through ERβ-mediated repression of the F-box protein p45Skp2. Expression of the ERβ-variant with mutated DNA binding domain resulted in completely different cell cycle gene regulation. We performed in vivo studies with SW480 cells ± ERβ transplanted into severe combined immunodeficient/beige mice; after three weeks of ERβ-expression, a 70% reduction of tumor volume was seen. Our results show that ERβ inhibits proliferation as well as colon cancer xenograft growth, probably as a consequence of ERβ-mediated inhibition of cell-cycle pathways. Furthermore, this ERβ-mediated cell cycle repression is dependent on functional ERE binding. [Cancer Res 2009;69(15):6100–6]
Cucurbitacin B Induces Apoptosis by Inhibition of the JAK/STAT Pathway and Potentiates Antiproliferative Effects of Gemcitabine on Pancreatic Cancer Cells
Authors: Thoennissen Nils H. , Iwanski Gabriela B. , Doan Ngan B. , Okamoto Ryoko , Lin Patricia , Abbassi Sam , Song Jee Hoon , Yin Dong , Toh Melvin , Xie Wei Dong , Said Jonathan W. , Koeffler H. Phillip
Published: July 2009

Pancreatic cancer is an aggressive malignancy that is generally refractory to chemotherapy, thus posing experimental and clinical challenges. In this study, the antiproliferative effect of the triterpenoid compound cucurbitacin B was tested in vitro and in vivo against human pancreatic cancer cells. Dose-response studies showed that the drug inhibited 50% growth of seven pancreatic cancer cell lines at 10−7 mol/L, whereas clonogenic growth was significantly inhibited at 5 × 10−8 mol/L. Cucurbitacin B caused dose- and time-dependent G2-M-phase arrest and apoptosis of pancreatic cancer cells. This was associated with inhibition of activated JAK2, STAT3, and STAT5, increased level of p21WAF1 even in cells with nonfunctional p53, and decrease of expression of cyclin A, cyclin B1, and Bcl-XL with subsequent activation of the caspase cascade. Interestingly, the combination of cucurbitacin B and gemcitabine synergistically potentiated the antiproliferative effects of gemcitabine on pancreatic cancer cells. Moreover, cucurbitacin B decreased the volume of pancreatic tumor xenografts in athymic nude mice by 69.2% (P < 0.01) compared with controls without noticeable drug toxicities. In vivo activation of JAK2/STAT3 was inhibited and expression of Bcl-XL was decreased, whereas caspase-3 and caspase-9 were up-regulated in tumors of drug-treated mice. In conclusion, we showed for the first time that cucurbitacin B has profound in vitro and in vivo antiproliferative effects against human pancreatic cancer cells, and the compound may potentate the antiproliferative effect of the chemotherapeutic agent gemcitabine. Further clinical studies are necessary to confirm our findings in patients with pancreatic cancer. [Cancer Res 2009;69(14):5876–84]
Helicobacter pylori Infection and Gastric Cancer Risk: Evaluation of 15 H. pylori Proteins Determined by Novel Multiplex Serology
Authors: Gao Lei , Michel Angelika , Weck Melanie N. , Arndt Volker , Pawlita Michael , Brenner Hermann
Published: July 2009

Infection with Helicobacter pylori is a major cause of gastric cancer (GC). The association likely has been underestimated in the past due to disease-related clearance of the infection. On the other hand, only a minority of the infected individuals develop GC, and better risk stratification is therefore highly desirable. We aimed to assess the association of GC with antibodies to 15 individual H. pylori proteins, determined by novel multiplex serology, to identify potentially relevant risk markers. This analysis was based on 123 GC cases aged 50 to 74 years and 492 age-matched and sex-matched controls from Saarland, Germany. Eight of the antibodies were significantly associated with noncardia GC and seven of them were significantly related to GC at any site. More pronounced associations were observed for noncardia GC; adjusted odds ratios (95% confidence intervals) ranged from 1.60 (1.01–2.54) for HyuA to 5.63 (3.20–9.91) for cytotoxin-associated antigen A (CagA). A dose-response relationship was found between the number of seropositivities and GC (P < 0.001). The seropositivities of CagA and GroEL were found to be independent predictors of GC, which were strongly related to GC risk in a dose-response manner (P < 0.001). In conclusion, GroEL was identified as a new independent risk marker that may contribute to enhanced quantification of H. pylori–related GC risk. [Cancer Res 2009;69(15):6164–70]
3-Phosphoinositide–Dependent Kinase 1 Potentiates Upstream Lesions on the Phosphatidylinositol 3-Kinase Pathway in Breast Carcinoma
Authors: Maurer Matthew , Su Tao , Saal Lao H. , Koujak Susan , Hopkins Benjamin D. , Barkley Christina R. , Wu Jiaping , Nandula Subhadra , Dutta Bhaskar , Xie Yuli , Chin Y. Rebecca , Kim Da-In , Ferris Jennifer S. , Gruvberger-Saal Sofia K. , Laakso Mervi , Wang Xiaomei , Memeo Lorenzo , Rojtman Albert , Matos Tulio , Yu Jennifer S. , Cordon-Cardo Carlos , Isola Jorma , Terry Mary Beth , Toker Alex , Mills Gordon B. , Zhao Jean J. , Murty Vundavalli V.V.S. , Hibshoosh Hanina , Parsons Ramon
Published: July 2009

Lesions of ERBB2, PTEN, and PIK3CA activate the phosphatidylinositol 3-kinase (PI3K) pathway during cancer development by increasing levels of phosphatidylinositol-3,4,5-triphosphate (PIP3). 3-Phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP3 recruits PDK1 and AKT to the cell membrane through interactions with their pleckstrin homology domains, allowing PDK1 to activate AKT by phosphorylating it at residue threonine-308. We show that total PDK1 protein and mRNA were overexpressed in a majority of human breast cancers and that 21% of tumors had five or more copies of the gene encoding PDK1, PDPK1. We found that increased PDPK1 copy number was associated with upstream pathway lesions (ERBB2 amplification, PTEN loss, or PIK3CA mutation), as well as patient survival. Examination of an independent set of breast cancers and tumor cell lines derived from multiple forms of human cancers also found increased PDK1 protein levels associated with such upstream pathway lesions. In human mammary cells, PDK1 enhanced the ability of upstream lesions to signal to AKT, stimulate cell growth and migration, and rendered cells more resistant to PDK1 and PI3K inhibition. After orthotopic transplantation, PDK1 overexpression was not oncogenic but dramatically enhanced the ability of ERBB2 to form tumors. Our studies argue that PDK1 overexpression and increased PDPK1 copy number are common occurrences in cancer that potentiate the oncogenic effect of upstream lesions on the PI3K pathway. Therefore, we conclude that alteration of PDK1 is a critical component of oncogenic PI3K signaling in breast cancer. [Cancer Res 2009;69(15):6299–306]
Functional Unresponsiveness and Replicative Senescence of Myeloid Leukemia Antigen–specific CD8+ T Cells After Allogeneic Stem Cell Transplantation
Authors: Beatty Gregory L. , Smith Jasmine S. , Reshef Ran , Patel Kunal P. , Colligon Theresa A. , Vance Barbara A. , Frey Noelle V. , Johnson F. Brad , Porter David L. , Vonderheide Robert H.
Published: July 2009

Purpose: The therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myeloid malignancies has been attributed in part to a graft-versus-leukemia effect that is dependent on donor T lymphocytes. CD8+ T-cell responses to MHC class I–restricted tumor epitopes, not just allogeneic antigens, may help mediate antileukemia effects after HSCT, but the specificity and function of such cells are not completely understood.

Experimental Design: We examined the diversity, phenotype, and functional potential of leukemia-associated antigen-specific CD8+ T cells in patients with myeloid leukemia following allogeneic HSCT. Screening for antigen-specific T cells was accomplished with a peptide/MHC tetramer library.

Results: Patients with acute myelogenous leukemia or chronic myelogenous leukemia in remission following HSCT exhibited significant numbers of peripheral blood CD8+ T cells that recognized varying combinations of epitopes derived from leukemia-associated antigens. However, these cells failed to proliferate, release cytokines, or degranulate in response to antigen-specific stimuli. As early as 2 months after HSCT, CD8+ T cells from patients were predominantly CD28− CD57+ and had relatively short telomeres, consistent with cellular senescence.

Conclusions: Circulating leukemia-specific CD8+ T cells are prominent in myeloid leukemia patients after HSCT, but such cells are largely functionally unresponsive, most likely due to replicative senescence. These findings carry important implications for the understanding of the graft-versus-leukemia effect and for the rational design of immunotherapeutic strategies for patients with myeloid leukemias.
Identification of the Chromatin Regions Coated by Non-coding Xist RNA
Authors: Murakami K. , Ohhira T. , Oshiro E. , Qi D. , Oshimura M. , Kugoh H.
Published: July 2009

Xist non-coding RNA (ncRNA) is essential for X chromosome inactivation (XCI). Some genes can escape from XCI, but how this occurs is unknown. We developed a modified RNA tagging and recovery of associated proteins (TRAP) method to study the association between Xist RNA and its target genes. In mouse cells, Xist RNA was detected on the Uba1 gene, but not on Jarid1c and Utx genes, which escape from XCI. Using this technique we were able to show that the Xist RNA molecule is not present on active genes that escape from XCI, but is present on genes inactivated by XCI, suggesting that this method is a powerful tool for functional analysis of ncRNA.
High-Resolution Genomic Profiling of Carboplatin Resistance in Early-Stage Epithelial Ovarian Carcinoma
Authors: Österberg L. , Levan K. , Partheen K. , Staaf J. , Sundfeldt K. , Horvath G.
Published: July 2009

Chemotherapy resistance remains a major obstacle to successful treatment of ovarian cancer patients. Therefore, increased knowledge of underlying mechanisms and identification of predictive factors are of great importance. Standard treatment for ovarian carcinoma is surgery followed by platinum-based chemotherapy. In this study, we aimed to search for genes or genomic regions involved in platinum resistance in ovarian carcinoma. Array-based comparative genomic hybridization (CGH) was used to identify genetic alterations in 32 early-stage epithelial ovarian carcinomas homogeneously treated with single-agent carboplatin. The arrays contain 33,370 bacterial artificial chromosome (BAC) clones and form a contiguous and tiling coverage of the human genome with an average resolution of ∼100 kb. We found certain genetic changes associated with carboplatin response. Gains in 1q25.1–q41 were significantly more frequent in carboplatin-resistant tumours. In this region, we further detected two smallest regions of overlap (SRO) at 1q25.2 and 1q32.2 (∼690 and ∼830 kb in size, respectively). Interestingly, we found some regions that were lost exclusively in the sensitive tumours 17q24.1, Xq21.33–q22.1, and 6 regions in 15q. We also detected genetic differences with regard to histologic subtype. Gain in 8q was found highly associated with serous and clear cell subtypes, and an SRO was identified at 8q24.22–q24.23. The genomic regions found altered in this study confirm some of our previous metaphase CGH results. The alteration found in chromosome arm 1q was verified and specified, and is therefore of great interest as a candidate for predictive markers. Identifying predictive markers of chemosensitive and chemoresistant disease would greatly help in the choice of chemotherapy in the clinic, and thus improve treatment of women with ovarian cancer.
The Effect of Intravitreal Ranibizumab on the Fellow Untreated Eye with Subfoveal Scarring due to Exudative Age-Related Macular Degeneration
Authors: Rouvas Alexandros , Liarakos Vasilios S. , Theodossiadis Panagiotis , Papathanassiou Miltiadis , Petrou Petros , Ladas Ioannis , Vergados Ioannis
Published: July 2009

Aim: Our purpose was to evaluate the possible effect of intravitreal ranibizumab on the fellow untreated eye with choroidal neovascularization (CNV) and subfoveal scarring associated with age-related macular degeneration (AMD). Methods: A retrospective observational study was conducted. One hundred eighty-seven ranibizumab-treated patients diagnosed as having subfoveal CNV scarring in the untreated eye were compared with a control group of untreated unilateral subfoveal CNV scarring. Inclusion criteria concerning treated eyes in the ranibizumab group complied with the MARINA and ANCHOR studies. Demographic data, clinical course, visual acuity, fluorescein angiography and optical coherence tomography findings were evaluated. Results: Clinical improvement was confirmed in 24% of the patients in the ranibizumab group and in only 12.9% of the controls. Improvement was noted as early as 2–4 months (2.83 ± 0.75 months) after the initiation of treatment in the fellow eye compared with 33.25 ± 9.43 months in the control group (p = 0.01; Mann-Whitney U test). Kaplan-Meier curves demonstrate the positive impact of ranibizumab on the visual acuity of the fellow untreated eye (p = 0.016; Log-Rank test). Conclusions: Ranibizumab might induce some therapeutic effect in selected cases of end-stage CNV scarring, which needs to be further examined. The VEGF levels in the compartments of the fellow eye of patients with age-related macular degeneration treated with ranibizumab need to be further evaluated.
Future Screening for Incipient Alzheimer’s Disease – The Influence of Prevalence on Test Performance
Authors: Mattsson Niklas , Zetterberg Henrik
Published: July 2009

Much effort has been made to identify and verify diagnostic biomarkers for early stage Alzheimer’s disease (AD). The need for this is often advocated by possible future disease-modifying treatments, likely to be most effective if initiated early in the disease process. Since the neurodegenerative process probably starts many years before the first onset of symptoms, such future drugs are likely to invoke a need for screening presymptomatic individuals. Here, we speculate on the performance of currently available AD biomarkers in hypothetical screening programs of different designs. We note that many diagnostic tests will have an excellent ability to exclude upcoming AD. However, even the best tests will suffer from poor positive predictive values given the relatively low disease prevalence in populations with no or very few symptomatic individuals, also when taking future converters to AD into account. The magnitude of this problem, which is common among most screening programs, will depend on the efficacy, safety and cost of the future anti-AD drugs. A number of tentative solutions to the problem, apart from better tests, are discussed.
Arrhythmia Susceptibility in Mice after Therapy with β-Catenin-Transduced Hematopoietic Progenitor Cells after Myocardial Ischemia/Reperfusion
Authors: Gardiwal Ajmal , Reissmann Lara-Marie , Kotlarz Daniel , Oswald Hanno , Korte Thomas , Landmesser Ulf , Klein Gunnar , Templin Christian
Published: July 2009

Background: Hematopoietic progenitor cells (HPCs) can improve cardiac function after myocardial infarction. However, occurrence of arrhythmias is a potential limitation of cell therapy. In this study, we investigated the cardiac electrophysiological properties of ex vivo expanded HPCs, generated by β-catenin gene transfer, after transcoronary delivery in a murine model of ischemia/reperfusion (I/R) injury. Methods and Results: To assess arrhythmia inducibility of ex vivo expanded HPCs, mice were subjected to I/R and assigned to sham operation (n = 8), I/R (n = 21) and HPC (n = 15) treatment. Six weeks later, mice were subjected to long-term electrocardiogram recording and in vivo transvenous electrophysiological study. After I/R, mice showed a significant prolongation of conduction and repolarization compared with sham-operated mice. There was a marked increase in ventricular ectopic activity in infarcted mice as compared with sham-operated mice. Cardiac electrophysiological parameters and ventricular ectopic activity were not altered in mice treated with HPCs in comparison with control I/R mice. Conclusion: Transcoronary delivery of genetically ex vivoexpanded HPCs did not alter the electrophysiological properties in mice after I/R. Therefore, ex vivo β-catenin-mediated HPC expansion may represent an attractive therapeutic option for cell transplantation treatment of myocardial infarction without electrophysiological side effects.
High-Dose Lovastatin for Acute Ischemic Stroke: Results of the Phase I Dose Escalation Neuroprotection with Statin Therapy for Acute Recovery Trial (NeuSTART)
Authors: Elkind Mitchell S.V. , Sacco Ralph L. , MacArthur Robert B. , Peerschke Ellinor , Neils Greg , Andrews Howard , Stillman Joshua , Corporan Tania , Leifer Dana , Liu Rui , Cheung Ken
Published: July 2009

Background: Hydroxymethylglutaryl coenzyme A reductase inhibitors (‘statins’) reduce the neuronal injury in dose-dependent fashion in rodent stroke models. We sought to determine whether lovastatin at doses above those currently approved can be administered safely within 24 h after an acute ischemic stroke. Methods: We conducted a phase 1B dose-finding study using an adaptive design novel to stroke trials, the continual reassessment method, to find the highest tolerated dose of lovastatin. Planned doses were 1, 3, 6, 8 and 10 mg/kg/day for 3 days. The primary safety outcomes were myotoxicity and hepatotoxicity. The model was calibrated to select a dose causing 7–13% toxicity. Results: We enrolled 33 patients (16 men/17 women, age range 23–82 years). Three patients were treated at 1 mg/kg, 10 at 3 mg/kg, 12 at 6 mg/kg, and 8 at 8 mg/kg. Thirty of the 33 patients (90.9%) completed at least 11 of 12 doses. Two patients at the 6-mg/kg dose level experienced transient mild elevations in transaminases without clinical sequelae. After an initial dose reduction, the dose was re-escalated to 8 mg/kg, and no further patients reached safety outcomes. No clinical liver disease, myopathy, or creatine phosphokinase elevations occurred. The final model-based toxicity at 8 mg/kg was 13%; no patient was treated at 10 mg/kg. Conclusions: Lovastatin at doses above those currently approved by the Food and Drug Administration is feasible for 3 days after an acute ischemic stroke and the maximum tolerated dose is estimated to be 8 mg/kg/day. Further randomized studies are warranted to confirm its safety and to demonstrate its efficacy in improving functional outcomes after stroke.
Leukocyte-Platelet Aggregates in Acute and Subacute Ischemic Stroke
Authors: Marquardt L. , Anders C. , Buggle F. , Palm F. , Hellstern P. , Grau A.J.
Published: July 2009

Background: Leukocyte-platelet aggregates appear to be a stable and sensitive marker of platelet activation as suggested by studies in coronary heart disease. We tested the hypothesis that leukocyte-platelet aggregates are increased after ischemic stroke and investigated the contribution of different leukocyte subtypes to such increase. Methods: We serially determined granulocyte-, lymphocyte- and monocyte-platelet aggregates, using flow cytometry at days 1, 2, 3, 5, 7, 10, and 90 in patients with ischemic stroke (n = 45) and in age- and sex-matched healthy control subjects (n = 30). Results: Granulocyte-platelet aggregates (granulocytes with ≥1 platelet/μl) were more common in patients than control subjects from day 1 through day 10 (p < 0.04, respectively), but not on day 90 after stroke. The percentage of granulocytes forming aggregates was increased on days 1–3 after stroke but not at other time points. Lymphocyte-platelet aggregates were not more common at any time point after stroke. Total numbers and percentages of monocytes forming platelet aggregates were significantly increased on day 2 (p = 0.003), but not at other time points after stroke. Conclusion: The 3 leukocyte subtypes showed different kinetics regarding aggregate formation with platelets after ischemic stroke. Increase of monocyte-platelet aggregates is short-lived and may reflect an acute reaction to cerebral ischemia, whereas granulocyte-platelet aggregate formation persists into the subacute phase, suggesting that they are a particularly sensitive parameter reflecting both prothrombotic and inflammatory processes after stroke.
Cognitive Function in Japanese Centenarians according to the Mini-Mental State Examination
Authors: Inagaki Hiroki , Gondo Yasuyuki , Hirose Nobuyoshi , Masui Yukie , Kitagawa Koji , Arai Yasumichi , Ebihara Yoshinori , Yamamura Ken , Takayama Michiyo , Nakazawa Susumu , Shimizu Ken-ichiro , Homma Akira
Published: July 2009

Background/Aims: We examined the effect of aging on cognitive function at the limit of human life expectancy by characterizing state of cognition in centenarians without clinical cognitive impairment. Methods: Participants were 68 centenarians without cognitive impairment (Clinical Dementia Rating (CDR) 0), 96 controls 60 to 74 years old, and 46 controls 75 to 89 years old. We visited the places where centenarians were living and administered the Mini-Mental State Examination (MMSE) individually. Control subjects came to the assembly hall within their dwelling area, to be administered the MMSE. Results: Mean total scores of centenarians (22.3) were lower than for either 60–74 (27.2) or 75–89 (26.2). Comparison of scores in each of five cognitive domains measured by MMSE showed a significant age-group effect upon orientation, memory, and attention. Centenarians’ scores were lower than for younger groups in every domain except for the language and praxis, concentration, and for repetition. Conclusion: The centenarians’ scores in memory and orientation declined as in earlier studies of normal aging. Centenarians’ scores for attention and concentration differed from those in previous studies. The present result suggests that even primary memory is influenced by advanced age in centenarians, while ability to store information declines, ability to process is maintained.
Combination Effects of Enalapril and Losartan on Lipid Peroxidation in the Kidneys of KK-Ay/Ta Mice
Authors: Yamazaki Takahiko , Tanimoto Mitsuo , Gohda Tomohito , Ohara Ikko , Hagiwara Shinji , Murakoshi Maki , Matsumoto Masakazu , Kaneko Shigeru , Aoki Tatsuya , Toyoda Hitoe , Ishikawa Yuji , Funabiki Kazuhiko , Horikoshi Satoshi , Tomino Yasuhiko
Published: July 2009

Background: Adenosine monophosphate activated protein kinase (AMPK) has a protective effect on lipid peroxidation. Adiponectin and AMPK might have a role in the pathogenesis of diabetic nephropathy. Blockade of the renin-angiotensin system (RAS) increases adiponectin levels and reduces oxidative stress. The objective of the present study was to examine lipid peroxidation via adiponectin and AMPK activation in the kidneys of KK-Ay/Ta mice by RAS inhibitors, such as enalapril and/or losartan. Methods: KK-Ay/Ta mice were given enalapril (2.5 mg/kg/day) and/or losartan (25 mg/kg/day), or hydralazine (25 mg/kg/day) in the drinking water for 8 weeks starting at 8 weeks of age. They were divided into 5 groups as follows: enalapril 2.5 mg/kg/day treatment group (n = 5), losartan 25 mg/kg/day treatment group (n = 5), enalapril 2.5 mg/kg/day + losartan 25 mg/kg/day combination treatment group (n = 5), hydralazine 25 mg/kg/day treatment group (n = 5) and tap water group as the untreated group (n = 5). The urinary albumin/creatinine ratio (ACR), serum adiponectin and systemic blood pressure were measured as test parameters. Expressions of adiponectin, phospho-AMPKα (p-AMPKα) and phospho-acetyl CoA carboxylaseβ (p-ACCβ) in the kidneys were evaluated by Western blot analyses. Pathological changes of glomeruli were evaluated by light microscopy. Accumulations of Nε-(carboxymethyl) lysine (CML), malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) in glomeruli were evaluated by immunohistochemical analyses. Results: Enalapril and/or losartan improved levels of urinary ACR with activation of adiponectin, p-AMPKα and p-ACCβ in the kidneys. CML, MDA and 4-HNE expressions in glomeruli were significantly suppressed by enalapril and/or losartan, especially in the combination treatment group. Conclusions: It appears that enalapril and/or losartan, especially in combination, inhibited accumulation of CML/MDA/4-HNE in diabetic renal tissues. These effects might be related to lipid peroxidation via tissue-specific activation of adiponectin and AMPK.
Effect of Mometasone Furoate on Nasal Congestion Model in Rats
Authors: Ogawa Masami , Tsumuro Tae , Takubo Miho , Ueda Yuhki , Yatsuzuka Rie , Kishi Yuko , Kamei Chiaki
Published: July 2009

Aims: The present study was performed to evaluate the effect of mometasone furoate on a nasal congestion model in Brown Norway rats. Methods: Nasal congestion in rats sensitized with toluene-2,4-diisocyanate (TDI) was measured using whole-body plethysmography which allowed animals to move freely. Results: Penh (enhanced pause), an index of nasal congestion, was significantly increased after 5% TDI challenge in sensitized rats compared with that in non-sensitized rats. The peak of the increase in Penh appeared at 1 and 5 h after TDI challenge. A single topical administration of mometasone furoate (0.05%) at 1 h before TDI challenge suppressed the increase of Penh in sensitized rats. A significant effect was observed 5–6 h after nasal administration. Almost the same results were obtained with fluticasone propionate (0.05%). Conclusion: Mometasone furoate may therefore be effective and have a rapid onset of action in nasal congestion when used clinically as with fluticasone propionate.
Patients’ Satisfaction with Flexible Bronchoscopy in a Hospital-Based Community Practice
Authors: Bernasconi Maurizio , Chhajed Prashant N. , Müller Patrick , Borer Heinz
Published: July 2009

Background: There are no data about patients’ satisfaction with a first bronchoscopy in community practice. Objectives: The aim of this study was to assess the satisfaction with flexible bronchoscopy and the willingness to return for the procedure if needed in hospital-based community practice. Methods: Prospective administration of a questionnaire before and after flexible bronchoscopy with inclusion of 126 patients in the analysis. Results: The reliability analysis demonstrated a good internal consistency of the questionnaire with a mean Cronbach α of 0.7 (range 0.63–0.76). Health status and overall satisfaction with bronchoscopy were reported as poor by 31 (25%) and 0 (0%) patients, fair by 34 (27%) and 3 (2%) patients, good by 47 (37%) and 51 (40%) patients and very good by 9 (7%) and 70 (56%) patients, respectively. Overall willingness to return for a flexible bronchoscopy if necessary was 98% (123/126). Transbronchial needle aspiration (TBNA) was the most often performed diagnostic procedure (74/126, 59%). Mean duration of the bronchoscopy in patients with and without TBNA was 30 and 19 min, respectively (p < 0.001). However, TBNA did not influence patient’s satisfaction. Preprocedure anxiety was reported by 26 of 51 patients (51%) and 24 of these patients (92%) rated their anxiety as unjustified after the procedure. Conclusions: Overall satisfaction and willingness to return for a flexible bronchoscopy in community practice are extremely high and these are independent of whether TBNA is undertaken or not.
Development and Implementation of an Audit Tool for Quality Control of Parenteral Nutrition
Authors: García‐Rodicio Sonsoles , Abajo Celia , Godoy Mercedes , Catalá Miguel Angel
Published: July 2009

Background: The aim of this article is to describe the development of a quality control methodology applied to patients receiving parenteral nutrition (PN) and to present the results obtained over the past 10 years. Development of the audit tool: In 1995, a total of 13 PN quality criteria and their standards were defined based on literature and past experiences. They were applied during 5 different 6‐month audits carried out in subsequent years. According to the results of each audit, the criteria with lower validity were eliminated, while others were optimized and new criteria were introduced to complete the monitoring of other areas not previously examined. Currently, the quality control process includes 22 quality criteria and their standards that examine the following 4 different areas: (1) indication and duration of PN; (2) nutrition assessment, adequacy of the nutrition support, and monitoring; (3) metabolic and infectious complications; and (4) global efficacy of the nutrition support regimen. The authors describe the current definition of each criterion and present the results obtained in the 5 audits performed. In the past year, 9 of the 22 criteria reached the predefined standards. The areas detected for further improvements were: indication for PN, nutrition assessment, and management of catheter infections. Conclusions: The definition of quality criteria and their standards is an efficient method of providing a qualitative and quantitative analysis of the clinical care of patients receiving PN. It detects areas for improvement and assists in developing a methodology to work efficiently.
Nutrition Support in Surgical Oncology
Authors: Huhmann Maureen B. , August David A.
Published: July 2009

This review article, the second in a series of articles to examine the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Pediatric Patients, evaluates the evidence related to the use of nutrition support in surgical oncology patients. Cancer patients develop complex nutrition issues. Nutrition support may be indicated in malnourished cancer patients undergoing surgery, depending on individual patient characteristics. As with the first article in this series, this article provides background concerning nutrition issues in cancer patients, as well as discusses the role of nutrition support in the care of surgical cancer patients. The goal of this review is to enrich the discussion contained in the clinical guidelines as they relate to recommendations made for surgical patients, cite the primary literature more completely, and suggest updates to the guideline statements in light of subsequently published studies.
Conflict Between Nursing Home Staff and Residents’ Families
Authors: Abrahamson Kathleen , Jill Suitor J. , Pillemer Karl
Published: July 2009

Objective: In this study, the authors examine the influence of conflict between nursing home staff and family members of residents on staff burnout. Method: Data were collected from interviews with a representative sample of 655 nursing home nurses and nursing assistants. Hypotheses were tested using structural equation modeling. Results: Results indicate that conflict with family members increases staff burnout and decreases staff satisfaction. Staff and family conflict increases when staff members feel they do not have enough time to complete required tasks. Level of conflict decreases when staff perceive that family members have care expectations that are similar to their own. Interestingly, staff who have personal experience as family caregivers are more likely to report conflict with family members of residents, a result that necessitates further study. Discussion: Staff burnout and dissatisfaction affects both individuals and organizations. Policy that addresses staff and family interaction can have an important place in the design and delivery of long-term care.
Abrupt forest ecosystem change in SW Sweden during the late Holocene
Authors: Gustavsson Gunnar , Lemdahl Geoffrey , Gaillard Marie-José
Published: July 2009

A peat profile from a small raised bog, situated in SW Sweden, was studied for insect, pollen and charcoal analyses in order to reconstruct the late-Holocene forest history of the area. The palaeoecological records cover the last 3700 cal. years. The results were compared with archaeological data, historical documents and palaeoclimate reconstructions from the region. From 1650 cal. yr BC to AD 1310 cal. yr, the study area was characterized by deciduous woodland with a diverse invertebrate fauna. The recorded insects indicate a relatively open or mosaic forest environment with abundance of dead wood. This forest environment was probably maintained by disturbances such as cattle grazing, fire, wood coppicing and small-scale cultivation. At around AD 1310, a major and rapid change in the forest ecosystem occurred, ie, species-rich deciduous woodland was replaced by a species-poor beech forest. The data indicate that a change in land use was the likely reason for the shift in forest type. Grazing and fire ceased, while tree cutting increased. The shift in land use correlates well with political—societal changes in the region during Mediaeval time. Climate changes seem to have influenced the wetland environment, but there is no obvious correlation between major or minor shifts in forest ecosystem and reconstructed climate changes. Today, nature conservationists regard the beech forests of Halland as remains of primeval forests hosting a unique flora and fauna. Our results give new insights and challenge that view.
High-resolution, well-preserved tritium record in the ice of Bortig Ice Cave, Bihor Mountains, Romania
Authors: Kern Zoltán , Molnár Mihály , Svingor Éva , Perşoiu Aurel , Nagy Balázs
Published: July 2009

Two 2 m long ice cores (BA and BB) were extracted from the floor ice of Borştig Ice Cave in December 2005. Below a co-existing dust horizon (~13 cm underneath the 10 December 2005 ice surface) neither core presented any sign of hiatus, so the ice deposition is considered to be continuous. Tritium concentration of 94 samples from a 1.85 m long ice section were analysed by liquid scintillation counting technique. Samples from the lower 0.33 m of the sequence did not contain tritium above the critical level (7.2 TU). The highest value of tritium content (166.4±4.0 TU) was found at ~96 cm below the surface. This salient value is considered to be synchronous with the climax of tritium concentration in the Northern Hemisphere's atmospheric precipitation (1963). Beside this characteristic global radiochemical marker event, minor events were also detected, and dated (ie, 1954, 1958 and 1975) by corresponding peaks in the tritium concentration record of BB ice core to peaks of an estimation of tritium activity of past precipitation at Borştig Ice Cave location. The estimation was based on a data set from four nearby stations of the Global Network of Isotopes in Precipitation. The highest annual accumulation rate (6.74 cm/yr) was between 1958 and 1963 and gradually decreased to 0.54 cm/yr for the recent decades. The mean ice accumulation rate was 4.34 cm/yr over the 1954—1986 period. The estimated age at the bottom of the 21 m thick ice block assuming constant accumulation is roughly 500 years.
Isotopic analysis of wetland development in the American Southwest
Authors: Minckley Thomas A. , Clementz Mark T. , Brunelle Andrea , Klopfenstein Grace A.
Published: July 2009

The analysis of stable isotope and elemental fractions of organic material collected from San Bernardino Ciénega was used to understand the history of vegetation composition and climate change within this desert wetland. A 4000-yr record of sediment buildup, based on four 14C measurements, provides unique opportunities for the study of environmental conditions within an arid landscape and documents climate shifts from drier to wetter conditions in the late Holocene. δ13C, δ15N, and C:N values were measured from a 3.8 m deep sedimentary section to understand the dynamics of vegetation and hydrology in desert wetlands. Through this section we observe δ 13C and C:N values indicating a shift in the dominant source of organic matter within the section: prior to 850 cal. yr BP (below 60 cm), aquatic vascular plants and occasionally terrestrial vegetation were the primary organic sources, whereas freshwater algae were the dominant organic matter source above this level. These values indicate that while conditions remained arid at this locality, the amount of standing water on the ciénega has increased over time. These results document both climate change and vegetation evolution on the ecotone of the Sonoran and Chihuahuan deserts and demonstrate how the study of local sediment accumulation in ciénegas can provide critical information on changing conditions within arid environments.
Sea ice and marine climate variability for NW Iceland/Denmark Strait over the last 2000 cal. yr BP
Authors: Andrews J.T. , Belt S.T. , Olafsdottir S. , Massé G. , Vare L.L.
Published: July 2009

MD99-2263 is a 46 cm box core collected from Djupall, a trough that cuts across the NW Iceland Shelf and ends above Denmark Strait. We provide a multiproxy record that documents changes in the regional marine climate over the last ~1700 yr. The depth/age model is based on seven calibrated radiocarbon dates on mollusk shells and on 210Pb and 137Cs. Sediment accumulation rates were variable (0.2—0.8 mm/yr) but increased dramatically ~AD 1500. Grain-size, magnetic properties, quantitative mineral composition of the <2 mm sediment fraction, benthic foraminiferal composition, benthic and planktic Δ18O ratios, and abundances/fluxes of the sea ice biomarker IP25 were determined. To better compare the various proxies, 12 of the critical climate proxies were co-ordinated into 100-yr/sample time series, which were examined by Principal Component Analysis. The 1st axis explained 49% of the variance and the 2nd axis explained an additional 17%. The variables most strongly associated with the 1st axis were sediment properties (phi mean, clay%) and the sea ice biomarker. Mineralogical indicators of drift ice rafting, such as the presence of quartz and potassium- and sodium-feldspars, coincide with the IP25 biomarker data and show an increase after AD 1200, but high values of quartz and some feldspars also occurred between c. AD 300 and 900 with pronounced minima between AD 900 and 1100. Overall, our data suggest a simple two-fold division in climate conditions over the last 1700 yr, with the major change occurring c. AD 1200. In the last few decades, conditions have reverted towards those experienced prior to AD 1200.
Equifinality and uncertainty in the interpretation of pollen data: the Multiple Scenario Approach to reconstruction of past vegetation mosaics
Authors: Bunting M.J. , Middleton R.
Published: July 2009

The long-term goal of pollen analysis has always been the reconstruction of past vegetation mosaics. However, the pollen signal is spatially integrated, and ecologically distinct vegetation structures can produce identical pollen signals. This paper proposes an iterative approach to reconstruction, the Multiple Scenario Approach, which involves creating a large number of hypothetical landscapes using a combination of deterministic and probabilistic `rules' for plant placement coupled with environmental parameters such as topography, simulating the pollen assemblage produced by each, and comparing them statistically with a sedimentary pollen signal to identify possible reconstructions. The method expressly aims to find multiple possible reconstructions, and also gives some insight into the spatial aspects of the vegetation being reconstructed in addition to its composition.
A Longitudinal Investigation of Inattention and Preliteracy Development
Authors: Walcott Christy M. , Scheemaker Anastasia , Bielski Kerri
Published: July 2009

Objective: The link between significant attention problems and reading difficulties among school-age children is clear, but few have examined the impact of early inattention on preliteracy development. This longitudinal study examines this link. Method: A total of 47 children had repeated measures of teacher-rated attention problems and three key preliteracy skills (phonemic awareness, letter knowledge, and rapid naming) in both preschool and kindergarten. Results: Teacher-reported attention problems in preschool significantly and negatively predicted both phonemic awareness and letter naming scores 1 year later, even after controlling for initial language ability and preschool performance on these tasks. Levels of preschool inattention did not significantly predict rapid automatic naming 1 year later. Likewise, preschool preliteracy scores did not predict attention problems in kindergarten. Conclusion: Early attention problems may interfere with the acquisition of certain preliteracy skills. Implications of these findings and directions for future research are presented. (J. of Att. Dis. 2010; 14(1) 79-85)
Exploring and negotiating femininity
Authors: Elm Malin Sveningsson
Published: July 2009

Previous studies have pointed at the girls' room's importance for girls' identity work. Instead of working with identities in the street, as the boys, girls have instead mainly sought their free places in the home. It is in the girls' room that girls have gathered together to engage in identity work, such as experimenting with style. The ‘Internet generation’ is not different in this respect. The difference is rather that where it used to be done primarily in the girls' room at home, or in fitting rooms of clothes' shops, the act of experimenting with styles is now increasingly also found online. The aim of this article is to look at how teenage girls use their production of style in their identity work in the Swedish Internet community, Lunarstorm. Results show how girls use their experimentation with style in a way that lets them explore and negotiate the conflicting ideals of femininity. The mediation does not seem to change what aspects of femininity are displayed. However, it does change the conditions on which femininity is explored and negotiated.
A chronicle of chaos
Authors: Robinson Sue
Published: July 2009

The extraordinary breaking news story of Hurricane Katrina offered an opportunity to document how multimedia and interactive features interfere with the carefully crafted news story of a newspaper. Scholarship on news narratives and medium theory informed this case study, a textual analysis of the 2005 Hurricane Katrina coverage in The Times-Picayune and its web partner Nola.com. The main finding was that the New Orleans' newspaper tale of a mythic Flood in an American city transformed into a chronicle about people's personal experiences in cyberspace. In the process, audiences joined with journalists and reshaped the news narrative, which took on unique cyber-temporal and cyber-spatial qualities.
Examination of Stability of Boundary Conditions in Water Vapor Transmission Tests
Authors: Pazera Marcin , Salonvaara Mikael
Published: July 2009

The diffusion of water vapor through construction materials is driven by the gradient of partial water vapor pressure. Traditionally, water vapor transmission tests (WVT), the `dry cup', and the `wet cup' tests have been conducted with 0 to 50% RH, and from 50% to 100% RH, respectively. Often, desiccants, saturated salt solutions or distilled water are used to generate the required RH. The stability of vapor pressure in WVT tests is of paramount significance because these values are used in calculating permeance. Dry cup tests performed with high permeance materials (>25 Perms) indicated a transient behavior for the two types of adsorbing desiccants; calcium sulfate and silica gel. Monitoring RH inside the dry cup was performed to examine the effect of low and high WVT on the performance of moisture sinks. The results indicate that for highly permeable construction materials, the use of vapor pressures corresponding to 0% RH in calculation of permeance is not appropriate.