bluuebunny/crossref_metadata_2025 huggingface dataset:
Intratumoral Estrogen Disposition in Breast Cancer
Authors: Haynes Ben P. , Straume Anne Hege , Geisler Jürgen , A'Hern Roger , Helle Hildegunn , Smith Ian E. , Lønning Per E. , Dowsett Mitch
Published: March 2010

Purpose: The concentration of estradiol (E2) in breast tumors is significantly higher than that in plasma, particularly in postmenopausal women. The contribution of local E2 synthesis versus uptake of E2 from the circulation is controversial. Our aim was to identify possible determinants of intratumoral E2 levels in breast cancer patients.

Experimental Design: The expression of genes involved in estrogen synthesis, metabolism, and signaling was measured in 34 matched samples of breast tumor and normal breast tissue, and their correlation with estrogen concentrations assessed.

Results: ESR1 (9.1-fold; P < 0.001) and HSD17B7 (3.5-fold; P < 0.001) were upregulated in ER+ tumors compared with normal tissues, whereas STS (0.34-fold; P < 0.001) and HSD17B5 (0.23-fold; P < 0.001) were downregulated. Intratumoral E2 levels showed a strong positive correlation with ESR1 expression in all patients (Spearman r = 0.55, P < 0.001) and among the subgroups of postmenopausal (r = 0.76, P < 0.001; n = 23) and postmenopausal ER+ patients (r = 0.59, P = 0.013; n = 17). HSD17B7 expression showed a significant positive correlation (r = 0.59, P < 0.001) whereas HSD17B2 (r = −0.46, P = 0.0057) and HSD17B12 (r = −0.45, P = 0.0076) showed significant negative correlations with intratumoral E2 in all patients. Intratumoral E2 revealed no correlation to CYP19, STS, and HSD17B1 expression. Multivariate models comprising ESR1 and plasma E2 predicted between 50% and 70% of intratumoral E2 variability.

Conclusion: Uptake due to binding to the ER, rather than intratumoral estrogen synthesis by aromatase or sulfatase, is the single most important correlate and a probable determinant of intratumoral E2. An increased expression of HSD17B7 may explain the increased ratio of E2 to estrone (E1) in breast tumors compared with normal tissue. Clin Cancer Res; 16(6); 1790–801
Cetuximab-Based Immunotherapy and Radioimmunotherapy of Head and Neck Squamous Cell Carcinoma
Authors: Niu Gang , Sun Xilin , Cao Qizhen , Courter Donald , Koong Albert , Le Quynh-Thu , Gambhir Sanjiv Sam , Chen Xiaoyuan
Published: March 2010

Purpose: To show the relationship between antibody delivery and therapeutic efficacy in head and neck cancers, in this study we evaluated the pharmacokinetics and pharmacodynamics of epidermal growth factor receptor (EGFR)–targeted immunotherapy and radioimmunotherapy by quantitative positron emission tomography (PET) imaging.

Experimental Design: EGFR expression on UM-SCC-22B and SCC1 human head and neck squamous cell cancer (HNSCC) cells were determined by flow cytometry and immunostaining. Tumor delivery and distribution of cetuximab in tumor-bearing nude mice were evaluated with small animal PET using 64Cu-DOTA-cetuximab. The in vitro toxicity of cetuximab to HNSCC cells was evaluated by MTT assay. The tumor-bearing mice were then treated with four doses of cetuximab at 10 mg/kg per dose, and tumor growth was evaluated by caliper measurement. FDG PET was done after the third dose of antibody administration to evaluate tumor response. Apoptosis and tumor cell proliferation after cetuximab treatment were analyzed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Ki-67 staining. Radioimmunotherapy was done with 90Y-DOTA-cetuximab.

Results: EGFR expression on UM-SCC-22B cells is lower than that on SCC1 cells. However, the UM-SCC-22B tumors showed much higher 64Cu-DOTA-cetuximab accumulation than the SCC1 tumors. Cetuximab-induced apoptosis in SCC1 tumors and tumor growth was significantly inhibited, whereas an agonistic effect of cetuximab on UM-SCC-22B tumor growth was observed. After cetuximab treatment, the SCC1 tumors showed decreased FDG uptake, and the UM-SCC-22B tumors had increased FDG uptake. UM-SCC-22B tumors are more responsive to 90Y-DOTA-cetuximab treatment than SCC1 tumors, partially due to the high tumor accumulation of the injected antibody.

Conclusion: Cetuximab has an agonistic effect on the growth of UM-SCC-22B tumors, indicating that tumor response to cetuximab treatment is not necessarily related to EGFR expression and antibody delivery efficiency, as determined by PET imaging. Although PET imaging with antibodies as tracers has limited function in patient screening, it can provide guidance for targeted therapy using antibodies as delivery vehicles. Clin Cancer Res; 16(7); 2095–105. ©2010 AACR.
Information Needed to Conduct First-in-Human Oncology Trials in the United States: A View from a Former FDA Medical Reviewer
Authors: Senderowicz Adrian M.
Published: March 2010

Any drug product not previously authorized for marketing in the United States requires the submission of an Investigational New Drug application (IND). Although the IND submission is regulated by law (21CFR 312), there are several issues that are not covered in the law or U.S. Food and Drug Administration (FDA) guidances that are important for a successful IND submission. For oncology products, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 guidance (still in draft) is the most relevant. The most difficult issues to solve in an IND are chemistry, manufacturing and control information, and pharmacology and toxicology. In the United States, pivotal toxicological studies are done in two species: one rodent (i.e., rats) and one nonrodent (i.e., dogs). The safe starting dose is based on toxicological findings observed in the most sensitive species. Most first-in-humans studies in oncology include patients with advanced and/or metastatic disease, as serious to severe side effects of anticancer therapies are often less threatening to advanced cancer patients than their disease, and acceptable levels of toxicity are higher. For other indications (adjuvant therapy, chemoprevention, or healthy volunteers), first-in-human studies need to follow ICH M3 guidelines as the risk to benefit ratio in those subjects and/or patients without evidence of tumor is different. The division welcomes submissions before the IND, also known as pre-INDs, particularly for products with “atypical issues.” Clin Cancer Res; 16(6); 1719–25
Anti-CD22 Immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-Positive Hematologic Malignancies of Childhood: Preclinical Studies and Phase I Clinical Trial
Authors: Wayne Alan S. , Kreitman Robert J. , Findley Harry W. , Lew Glen , Delbrook Cynthia , Steinberg Seth M. , Stetler-Stevenson Maryalice , FitzGerald David J. , Pastan Ira
Published: March 2010

Purpose: Although most children with B-lineage acute lymphoblastic leukemia (ALL) and non–Hodgkin lymphoma are cured, new agents are needed to overcome drug resistance and reduce toxicities of chemotherapy. We hypothesized that the novel anti-CD22 immunotoxin, RFB4(dsFv)-PE38 (BL22, CAT-3888), would be active and have limited nonspecific side effects in children with CD22-expressing hematologic malignancies. We conducted the first preclinical and phase I clinical studies of BL22 in that setting.

Experimental Design: Lymphoblasts from children with B-lineage ALL were assessed for CD22 expression by flow cytometry and for BL22 sensitivity by in vitro cytotoxicity assay. BL22 was evaluated in a human ALL murine xenograft model. A phase I clinical trial was conducted for pediatric subjects with CD22+ ALL and non–Hodgkin lymphoma.

Results: All samples screened were CD22+. BL22 was cytotoxic to blasts in vitro (median IC50, 9.8 ng/mL) and prolonged the leukemia-free survival of murine xenografts. Phase I trial cohorts were treated at escalating doses and schedules ranging from 10 to 40 μg/kg every other day for three or six doses repeated every 21 or 28 days. Treatment was associated with an acceptable safety profile, adverse events were rapidly reversible, and no maximum tolerated dose was defined. Pharmacokinetics were influenced by disease burden consistent with rapid drug binding by CD22+ blasts. Although no responses were observed, transient clinical activity was seen in most subjects.

Conclusions: CD22 represents an excellent target and anti-CD22 immunotoxins offer therapeutic promise in B-lineage hematologic malignancies of childhood. Clin Cancer Res; 16(6); 1894–903
Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry
Authors: Walsh Michael D. , Buchanan Daniel D. , Cummings Margaret C. , Pearson Sally-Ann , Arnold Sven T. , Clendenning Mark , Walters Rhiannon , McKeone Diane M. , Spurdle Amanda B. , Hopper John L. , Jenkins Mark A. , Phillips Kerry D. , Suthers Graeme K. , George Jill , Goldblatt Jack , Muir Amanda , Tucker Kathy , Pelzer Elise , Gattas Michael R. , Woodall Sonja , Parry Susan , Macrae Finlay A. , Haile Robert W. , Baron John A. , Potter John D. , Le Marchand Loic , Bapat Bharati , Thibodeau Stephen N. , Lindor Noralane M. , McGuckin Michael A. , Young Joanne P.
Published: March 2010

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families.

Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing.

Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups.

Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking. Clin Cancer Res; 16(7); 2214–24. ©2010 AACR.
Wireless Capsules for Esophageal pH Monitoring: Are We Placing Them Correctly?
Authors: Doma Siva , Paladugu Susmita , Parkman Henry P. , Friedenberg Frank K.
Published: March 2010

Background: Recommended Bravo™ capsule placement is 6 cm proximal to the squamocolumnar junction. This is because the junction resides 1 cm distal to the lower esophageal sphincter. Aim: To determine the positional accuracy of capsule placement compared with the ideal location in symptomatic patients. Methods: Retrospective analysis of consecutive symptomatic outpatients undergoing both capsule placement and esophageal manometry on the same day. Error in capsule placement (ECP) was calculated as the actual capsule position (ACP) minus the ideal capsule position (ICP) based on manometry results. An error in positioning ≤3 cm was deemed an accurate placement. Results: Accurate placement of the capsule occurred in 91/147 (62%) patients. In patients with inaccurate placement, 92.9% were placed >3 cm proximal to the ICP. Only longer esophageal length correlated with the severity of proximal misplacement. There was no relationship between severity of ECP and whether the study demonstrated acid reflux. Conclusions: Our results suggest that endoscopic misplacement of Bravo capsules is common. Capsule misplacement proximally occurred far more frequently than distal misplacement. Capsule misplacement was not associated with pH study results.
Does the Histamine H4 Receptor Have a Pro- or Anti-Inflammatory Role in Murine Bronchial Asthma?
Authors: Neumann Detlef , Beermann Silke , Seifert Roland
Published: March 2010

The histamine H4 receptor is expressed preferentially on immune cells, indicating a possible role of the H4 receptor in inflammation. Studies of inflammation in several animal models point to a pro-inflammatory function of the H4 receptor. However, studies on experimental murine bronchial asthma yielded conflicting results, a fact which is neglected in most H4 receptor publications. Therefore, the present review critically analyzes available data on the role of the H4 receptor in the murine bronchial asthma model.
Stimulus Rate and Subcortical Auditory Processing of Speech
Authors: Krizman Jennifer , Skoe Erika , Kraus Nina
Published: March 2010

Many sounds in the environment, including speech, are temporally dynamic. The auditory brainstem is exquisitely sensitive to temporal features of the incoming acoustic stream, and by varying the speed of presentation of these auditory signals it is possible to investigate the precision with which temporal cues are represented at a subcortical level. Therefore, to determine the effects of stimulation rate on the auditory brainstem response (ABR), we recorded evoked responses to both a click and a consonant-vowel speech syllable (/da/) presented at three rates (15.4, 10.9 and 6.9 Hz). We hypothesized that stimulus rate affects the onset to speech-evoked responses to a greater extent than click-evoked responses and that subcomponents of the speech- ABR are distinctively affected. While the click response was invariant with changes in stimulus rate, timing of the onset response to /da/ varied systematically, increasing in peak latency as presentation rate increased. Contrasts between the click- and speech-evoked onset responses likely reflect acoustic differences, where the speech stimulus onset is more gradual, has more delineated spectral information, and is more susceptible to backward masking by the subsequent formant transition. The frequency-following response (FFR) was also rate dependent, with response magnitude of the higher frequencies (>400 Hz), but not the frequencies corresponding to the fundamental frequency, diminishing with increasing rate. The selective impact of rate on high-frequency components of the FFR implicates the involvement of distinct underlying neural mechanisms for high- versus low-frequency components of the response. Furthermore, the different rate sensitivities of the speech-evoked onset response and subcomponents of the FFR support the involvement of different neural streams for these two responses. Taken together, these differential effects of rate on the ABR components likely reflect distinct aspects of auditory function such that varying rate of presentation of complex stimuli may be expected to elicit unique patterns of abnormality, depending on the clinical population.
Multiple Myeloma with Monoclonal Free IgG3 Heavy Chains and Free Kappa Light Chains
Authors: Richter Alex G. , Harding Stephen , Huissoon Aarnoud , Drayson Mark , Pratt Guy
Published: March 2010

We describe the case of a 34-year-old gentleman investigated for persistent neutropaenia following two episodes of pneumonia. Specialist investigations led to the diagnosis of multiple myeloma (MM) producing a truncated monoclonal γ3 heavy chain (HC) immunoglobulin molecule unattached to a light chain (LC) with atypical features for both MM and HC disease. Western blot showed γ3HC was truncated with a large deletion (75 kDa). Flow cytometry of the bone marrow aspirate revealed an unusual staining pattern. This plasma cell dyscrasia was also unusual in that a subpopulation (30%) secreted large quantities of free LC (FLC) as well as truncated IgG HC. This is the first description, investigation and treatment of MM with a plasma cell population producing truncated γ3HC and ĸFLC M-proteins and illustrates a number of unique immunological and clinical features.
Effect of Heparin on APP Metabolism and Aβ Production in Cortical Neurons
Authors: Klaver David , Hung Amos C. , Gasperini Robert , Foa Lisa , Aguilar Marie-Isabel , Small David H.
Published: March 2010

Background: The β-site APP cleaving enzyme 1 (BACE1) is a major target for drug design in Alzheimer’s disease. BACE1 binds strongly to heparin and other glycosaminoglycans, and there is evidence that the enzyme may interact with proteoglycans in vivo. Several studies suggest that heparin or heparan sulfate analogues may have value as therapeutic agents for the treatment of AD. Objective: To determine whether heparin can inhibit Aβ production in cortical neurons by inhibiting BACE1. Methods: Cortical neurons from APP (SW) Tg2576 mice were incubated with heparin and the amount of APP processing and Aβ production were measured by enzyme-linked immunosorbent assay and Western blotting. Results: Treatment of cortical neurons with heparin inhibited Aβ secretion. However, this effect was not mediated via inhibition of BACE1. Conclusions: Heparin or other glycosaminoglycans may have value for the treatment of Alzheimer’s disease. However, the data do not support the view that a heparin-induced decrease in Aβ secretion is due to inhibition of BACE1.
Effects of Dopamine Agonists on Neuropsychiatric Symptoms of Parkinson’s Disease
Authors: Rektorová Irena
Published: March 2010

The efficacy of dopamine (DA) agonists in the treatment of motor symptoms of Parkinson’s disease (PD) has been clearly demonstrated. It has also been documented that DA agonists may have both a positive and a negative impact on neuropsychiatric symptoms in PD patients. This paper will focus on the effects of DA agonists on depressive and cognitive symptoms of PD.
Immature platelet values indicate impaired megakaryopoietic activity in neonatal early-onset thrombocytopenia
Authors: Hammer Hannes , Bührer Christoph , Dame Christof , Cremer Malte , Weimann Andreas
Published: March 2010

Newly released platelets, referred to as immature platelets, can be reliably quantified based on their RNA content by flow cytometry in an automated blood analyser. The absolute number of immature platelets (IPF#) and the immature platelet fraction (IPF%) reflect megakaryopoietic activity. We aimed to analyse the implication of these parameters in analysing the pathomechanism of early-onset neonatal thrombocytopenia. Platelet counts and IPF were determined at day 1 to 3 (d1 to d3) in 857 neonates admitted to intensive care. In thrombocytopenic patients (platelet counts<150 x 109/l, n=129), IPF# was significantly lower (8.5 ± 2.7 x 109/l), than in non-thrombocytopenic neonates (9.5 ± 3.6 x 109/l, n=682, p<0.05). IPF% was significantly higher in thrombocytopenic (9.3 ± 7.9%) vs. non-thrombocytopenic neonates (4.1 ± 1.8%, p<0.001). While neonates with early-onset infection (n=134) had lower platelet counts (199 ± 75 x 109/l) compared to controls (230 ± 68 x 109/l, n=574, p<0.01), there were no differences in IPF# or IPF%. Likewise, “small for gestational age” infants (SGA, n=149) had lower platelet counts at d1 (199 ± 75 x 109/l, p<0.001) than controls, but no differences in IPF. A trend towards lower IPF# was detected if SGA infants with platelet counts <100 x 109/l (5.4 ± 3.9 x 109/l, n=11) and thrombocytopenic neonates with infection (9.9 ± 7.3 x 109/l, n=10, p=0.11) were compared. The evaluation of IPF# indicates that thrombocytopenia in neonates is likely due to a combination of increased platelet consumption and inadequate megakaryopoietic response by the neonatal bone marrow. Furthermore, SGA neonates with moderate and severe thrombocytopenia might have a pronounced suppression of megakaryopoiesis compared to neonates with infection.
The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis
Authors: Blombäck Margareta , Bark Niklas , Johnsson Hans , Wallen N. Hakan , He Shu
Published: March 2010

The present study aimed to assess whether the fibrin network structure is modified by the direct thrombin-inhibitors lepirudin, argatroban or bivalirudin and by the indirect Xa-inhibitor danaparoid. Using an in vitro assay that imitates the physiological process of coagulation from thrombin generation to fibrin formation, we examined a normal plasma pool spiked with one of the inhibitors. At concentrations considered to be the plasma levels observed during therapy, almost no influence was detected for lepirudin despite clear-cut effects on “clotting time”. However, argatroban, bivalirudin and danaparoid increased the fibrin gel permeability (Ks) to a similar extent. At concentrations higher than the “therapeutic” levels, the dose-response curve in the Ks assay became very steep for lepirudin while those were shallow for the others. In parallel with the drug-induced increases of Ks, larger network pores in 3D-microscopic images and significant shortenings in “clot lysis time” induced by addition of rtPA were observed. Recombinant factor VIII (rFVIII) added to danaparoid-treated samples profoundly counteracted the increase of Ks but had only a slight or no effect on the other drugs. Thus, in vitro, argatroban, bivalirudin and danaparoid have comparable anticoagulating effects, rendering the fibrin network more permeable and less resistant to fibrinolysis. For lepirudin, the steep dose-response curve supports previous clinical findings, i.e. this thrombin inhibitor has a narrow therapeutic window. Furthermore, our data suggest that the haemostatic agent, rFVIII, might be effective in treatment of bleeding complications induced by danaparoid.
Total homocysteine in patients with angiographic coronary artery disease correlates with inflammation markers
Authors: Schroecksnadel Katharina , Grammer Tanja , Boehm Bernhard , März Winfried , Fuchs Dietmar
Published: March 2010

Moderate hyperhomocysteinaemia is considered as an independent risk marker for cardiovascular disease and stroke. Earlier, increased homocysteine production was detected in stimulated immunocompetent cells in vitro, and several markers of inflammation like neopterin or C-reactive protein (CRP) were demonstrated as significant indicators of cardiovascular risk. The relationship between coronary artery disease (CAD), homocysteine metabolism and markers of immune activation and inflammation was investigated in a population of 1717 patients undergoing coronary angiography, recruited as participants of the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. 1325 patients (77.2%) suffered from coronary artery disease (CAD), which was was defined as the occurrence of a visible luminal narrowing (≥20% stenosis) in at least 1 of 15 coronary segments according to the classification of the American Heart Association, the remaining 392 individuals of the study population served as controls. Significant differences regarding systolic blood pressure, homocysteine, neopterin and folic acid concentrations were observed between patients and controls. Older age, decreased creatinine-clearance and higher concentrations of homocysteine and CRP were indicative for CAD. Low B-vitamin availability, therapy and the extent of immune activation strongly influenced homocysteine concentrations. Homocysteine concentrations were correlated with neopterin levels (rs =0.325, p<0.001), and hyperhomocysteinaemic patients also presented with significantly higher CRP concentrations. Homocysteine accumulation coincided with impaired renal and heart function (as reflected by ProBNP[Brain natriuretic peptide]-concentrations). We conclude that homocysteine accumulation could result from B-vitamin deficiency which is related to chronic immune activation.
Different therapy options protecting microvasculature after experimental cerebral ischaemia and reperfusion
Authors: Burggraf Dorothe , Vosko Milan , Schubert Marion , Stassen Jean-Marie , Hamann Gerhard
Published: March 2010

Recombinant tissue plasminogen activator (rt-PA) is successfully used in human stroke, but often shows serious drawbacks. To find an alternative, we hypothesised that the novel thrombolytic microplasmin would have fewer adverse effects on haemoglobin extravasation and microvascular damage compared with the effects of rt-PA and tenecteplase (TNK). A constant period of ischaemia (3 hours) was induced in a rat suture model followed by reperfusion (24 hours). Mikroplasmin (10 mg/kg), TNK (5 mg/kg), rt-PA (9 mg/kg) and saline (control), were administered. The volume of the ischaemic lesion was calculated, the loss of collagen type IV and the extravasation of haemoglobin were quantified by Western blotting. The matrix-metalloproteinases 2 and 9 (MMP-2/-9) were quantified by zymography and their endogenous tissue inhibitors (TIMPs) were analysed by reverse zymography. Microplasmin treatment caused the lowest volume of the ischaemic lesion (51.0 ± 22.6 mm3) compared with control (167.3 ± 13.1 mm3; p<0.05). The content of col-lagen type IV was significantly increased and haemoglobin extravasation reduced (154 ± 24%; p<0.05) compared with control (442 ± 124%); MMP-2/-9 and the corresponding TIMPs remained unchanged. In comparison, TNK did not significantly reduce basal lamina damage and caused the highest extravasation. MMP-2/-9 were severely increased after TNK treatment (p<0.05). Thus, the balance between MMPs and TIMPs was shifted toward the inhibitory side with TNK. Microplasmin had a protective effect on the microvascular basal lamina and blood-brain barrier, whereas TNK was significantly disadvantageous from the viewpoint of ischaemic damage. Microplasmin also appears to be safer than other PAs in terms of damage to the microvasculature associated with thrombolytic therapy of ischaemic stroke.
The adaptor protein Ruk/CIN85 activates plasminogen activator inhibitor-1 (PAI-1) expression via hypoxia-inducible factor-1α
Authors: Samoylenko Anatoly , Dimova Elitsa , Kozlova Nina , Drobot Lyudmyla , Kietzmann Thomas
Published: March 2010

Increased levels of plasminogen activator inhibitor-1 (PAI-1) indicate an enhanced risk of ischaemic/hypoxic cardiovascular events and a poor prognosis. The expression of PAI-1 can be induced by various stimuli including hypoxia, insulin and insulin-like growth factor 1 (IGF-1). The hypoxia-inducible factor-1 (HIF-1) is critical for hypoxia or insulin/IGF-1 mediated PAI-1 induction, but the components involved in merging the signals are not known so far. The adaptor/scaffold protein Ruk/CIN85 may be a candidate since it plays important roles in the regulation of processes associated with cardiovascular and oncological diseases such as downregulation of receptor tyrosine kinases, apoptosis, adhesion and invasion. Therefore, it was the aim of this study to investigate the involvement of Ruk/CIN85 in the regulation of PAI-1 expression. It was found that Ruk/CIN85 induced PAI-1 mRNA and protein expression both under normoxia and hypoxia. The induction of PAI-1 expression by Ruk/CIN85 occurred at the transcriptional level since the half-life of PAI-1 mRNA was not affected in cells overexpressing Ruk/ CIN85 and reporter gene assays using wild-type and mutant human PAI-1 promoter luciferase constructs showed that the hypoxia responsive element was responsible for Ruk/CIN85 effects. Further, knocking down HIF-1α abolished not only the hypoxia-dependent but also the Ruk/CIN85-dependent PAI-1 induction. In addition, transient or stable overexpression of Ruk/CIN85 also induced HIF-1α protein levels and HIF-1 activity and knocking down Ruk/CIN85 reversed these effects. Thereby, Ruk/CIN85 interfered with the proline hydroxylation-dependent HIF-1α protein destabilisation. Together, these results provide the first evidence that Ruk/CIN85 induces PAI-1 expression via modulation of HIF-1α stability.
A national survey of the management of atrial fibrillation with antithrombotic drugs in Italian primary care
Authors: Filippi Alessandro , Alacqua Marianna , Cowell Warren , Shakespeare Annabelle , Mantovani Lorenzo , Bianchi Cosetta , Cricelli Claudio , Mazzaglia Giampiero
Published: March 2010

The aims of this study were to investigate trends in the incidence of diagnosed atrial fibrillation (AF), and to identify factors associated with the prescription of antithrombotics (ATs) and to identify the persistence of patients with oral anticoagulant (OAC) treatment in primary care. Data were obtained from 400 Italian primary care physicians providing information to the Health Search/Thales Database from 2001 to 2004. The age-standardised incidence of AF was: 3.9–3.0 cases, and 3.6–3.0 cases per 1,000 person-years in males and females, respectively. During the study period, 2,016 (37.2%) patients had no prescription, 1,663 (30.7%) were prescribed an antiplatelet (AP) agent, 1,440 (26.6%) were prescribed an OAC and 301 (5.5%) had both prescriptions. The date of diagnosis (p = 0.0001) affected the likelihood of receiving an OAC. AP, but not OAC, use significantly increased with a worsening stroke risk profile using the CHADS2 risk score. Older age increased the probability (p < 0.0001) of receiving an AP, but not an OAC. Approximately 42% and 24% of patients persisted with OAC treatment at one and two years, respectively, the remainder interrupted or discontinued their treatment. Underuse and discontinuation of OAC treatment is common in incident AF patients. Risk stratification only partially influences AT management.
Association between the Thr325Ile polymorphism of the thrombinactivatable fibrinolysis inhibitor and stroke in the Ludwigshafen Risk and Cardiovascular Health Study
Authors: Lorenz Martin , März Winfried , Cousin Emmanuelle , Mace Sandrine , Deleuze Jean-Francois , Kozian Detlef
Published: March 2010

The thrombin-activatable fibrinolysis inhibitor (TAFI) is a key mediator in the regulation of endogenous fibrinolysis, down-regulating clot lysis by degrading the C-terminal lysine residues from fibrin, which are important for binding and activating plasminogen. Elevated TAFI antigen levels have been suggested to be associated with promoter variants and the Ala147Thr polymorphism; increased TAFI stability and antifibrinolytic potential instead have been associated with the Thr325Ile polymorphism. We investigated the influence of these two polymorphisms on cardiovascular and thrombotic events in patients of the Ludwig-shafen Risk and Cardiovascular Health (LURIC) study. The LURIC study is a prospective cohort study comprising more than 3,300 patients aimed at identifying biochemical and genetic markers for metabolic and cardiovascular diseases. We demonstrate that the Ile/Ile genotype at position 325 of TAFI associates with the incidence of stroke and the age at onset of first stroke in patients of the LURIC cohort. Both the incidence of stroke and the risk of a premature event are higher in TAFI Ile325Ile patients with predisposing risk factors for thrombotic events such as diabetes mellitus, myocardial infarction or hypertension, alone or in combination. In contrast, no significant association was identified for the TAFI Ala147Thr polymorphism. The robust association of the TAFI Thr325Ile polymorphism with the incidence and the age at onset of first stroke strongly suggests a key role for TAFI in the pathogenetic mechanism of stroke.
External quality assessment (EQA) for CoaguChek monitors
Authors: Jespersen Joergen , van den Besselaar A. M. H. P. , van der Meer Felix , Palareti Gualtiero , Tripodi Armando , Shiach Caroline , Keown Michelle , Ibrahim Saied , Poller Leon
Published: March 2010

Anticoagulant control facilities are being overwhelmed by requests for monitoring and large numbers of patients are not therefore receiving treatment. Procedures designed for point-of-care testing have therefore been developed, the most popular being the CoaguChek. The need for external quality assessment (EQA) of monitors used by patients in self-management has been stressed in a European Commission (EC) Directive. It would not however be feasible for all CoaguChek monitors to be enrolled in national or regional EQA schemes which take time to organise and analyse. The European Concerted Action on Anticoagulation (ECAA) has therefore evolved a simpler system. Its value has been assessed in collaboration with the European Concerted Action on Thrombosis (ECAT). 523 monitors were tested at nine clinics which asked patients to bring their CoaguChek instruments to be assessed with the ECAA/ECAT procedure based on a set of 5 plasma samples with certified international normalised ratios (INR). 15% or more deviation from the certified INR on a single certified plasma sample from the set was defined by the ECAA as the limit of acceptable performance. One hundred and six (20.3%) of the monitors tested showed significant deviation and higher than average incidence of significant INR deviations reported with one specific numbered lot of test strips. Recent ECAA/ECAT, Danish and Italian studies report regular EQA of CoaguChek monitors is essential. There is general agreement that this should be performed at reasonably frequent intervals, at six months or whenever there is a change of the manufacturer’s test strips.
Size, Shape, and Stamina
Authors: Lam Carolyn S.P. , Grewal Jasmine , Borlaug Barry A. , Ommen Steve R. , Kane Garvan C. , McCully Robert B. , Pellikka Patricia A.
Published: March 2010

Although several studies have examined the cardiac functional determinants of exercise capacity, few have investigated the effects of structural remodeling. The current study evaluated the association between cardiac geometry and exercise capacity. Subjects with ejection fraction ≥50% and no valvular disease, myocardial ischemia, or arrhythmias were identified from a large prospective exercise echocardiography database. Left ventricular mass index and relative wall thickness were used to classify geometry into normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. All of the subjects underwent symptom-limited treadmill exercise according to standard Bruce protocol. Maximal exercise tolerance was measured in metabolic equivalents. Of 366 (60±14 years; 57% male) subjects, 166 (45%) had normal geometry, 106 (29%) had concentric remodeling, 40 (11%) had eccentric hypertrophy, and 54 (15%) had concentric hypertrophy. Geometry was related to exercise capacity: in descending order, the maximum achieved metabolic equivalents were 9.9±2.8 in normal, 8.9±2.6 in concentric remodeling, 8.6±3.1 in eccentric hypertrophy, and 8.0±2.7 in concentric hypertrophy (all
P
<0.02 versus normal). Left ventricular mass index and relative wall thickness were negatively correlated with exercise tolerance in metabolic equivalents (
r
=−0.14;
P
=0.009 and
r
=−0.21;
P
<0.001, respectively). Augmentation of heart rate and ejection fraction with exercise were blunted in concentric hypertrophy compared with normal, even after adjusting for medications. In conclusion, the pattern of ventricular remodeling is related to exercise capacity among low-risk adults. Subjects with concentric hypertrophy display the greatest limitation, and this is related to reduced systolic and chronotropic reserve. Reverse remodeling strategies may prevent or treat functional decline in patients with structural heart disease.
Assessing the Short-Term Forecast Capability of Nonstandardized Surface Observations Using the National Digital Forecast Database (NDFD)
Authors: Hilliker Joby L. , Akasapu Girish , Young George S.
Published: March 2010

The number of surface observations from nonstandardized networks across the United States has appreciably increased the last several years. Automated Weather Services, Inc. (AWS), maintains one example of this type of network offering nonstandardized observations for ∼8000 sites. The present study assesses the utility of such a network to improve short-term (i.e., lead times <12 h) National Digital Forecast Database (NDFD) forecasts for three parameters most relevant to the energy industry—temperature, dewpoint, and wind speed. A 1-yr sample of 13 AWS sites is chosen to evaluate the magnitude of forecast improvement (skill) and influence of physical location (siting) on such improvements. Hourly predictions are generated using generalized additive modeling (GAM)—a nonlinear statistical equation incorporating a predetermined set of the most significant AWS and NDFD predictors. Two references are used for comparison: (i) persistence climatology (PC) forecasts and (ii) NDFD forecasts calibrated to the AWS sites (CNDFD). The skill, measured via the percent improvement (reduction) in the mean absolute error (MAE), of forecasts generated by the study’s technique (CNDFD+) is comparable (<5%) to PC for lead times of 1–3 h for dewpoint and wind speed. Skill relative to PC slowly increases with lead time, with temperature exhibiting the greatest relative-to-PC skill (∼30% at 12 h). When compared to baseline CNDFD forecasts, the MAE of the generated CNDFD+ forecasts is reduced 65% for temperature and dewpoint at the 1-h lead time. An exponential drop in improvement occurs for longer lead times. Wind speed improvements are notably less, with little skill (<5%) demonstrated for forecasts beyond 4 h. Overall, CNDFD+ forecasts have the greatest accuracy relative to CNDFD and PC for the middle (3–7 h) lead times tested in the study. Variations in CNDFD+ skill exist with respect to AWS location. Tested stations located in complex terrain generally exhibit greater skill relative to CNDFD than the 13-station average for temperature (and, to a lesser degree, dewpoint). Relative to PC, however, the same subset of stations exhibits skill below the 13-station average. No conclusive relationship can be made between CNDFD+ skill and the sample stations located near water.
Energetics Responses to Increases in Greenhouse Gas Concentration
Authors: Hernández-Deckers Daniel , von Storch Jin-Song
Published: March 2010

Increasing greenhouse gas concentrations warm the troposphere. However, it is not clear whether this implies changes in the energetics. To study the energetics responses to CO2 increases, changes in the Lorenz energy cycle (LEC) are evaluated using output from the atmosphere–ocean ECHAM5/Max Planck Institute Ocean Model (MPI-OM). Equilibrium 2 × CO2 experiments and 10-yr transient experiments with 3% increase per year are analyzed.

Globally, doubling of CO2 results in a decrease in the LEC strength—defined as the total conversion of available potential energy P into kinetic energy K—but also in an increase in the zonal-mean K. These global changes are a consequence of the strengthening of the LEC in the upper troposphere and the weakening of the cycle below. The two opposite responses result from the simulated warming pattern that shows the strongest warming in the upper tropical troposphere and in the lower troposphere at high latitudes. This warming structure causes changes in the horizontal temperature variance and in mean static stability, which increase zonal-mean P in the upper troposphere and decrease it below, triggering the two opposite responses via changes in baroclinic activity. In general, the lower-region weakening is stronger in the Northern Hemisphere, while the upper-region strengthening, and the increase of zonal-mean P and K, is stronger in the Southern Hemisphere. The former is more pronounced in the transient experiments but decreases in the stabilized 2 × CO2 climate.
Rural-Urban Differences in General and Health-Related Internet Use
Authors: Hale Timothy M. , Cotten Shelia R. , Drentea Patricia , Goldner Melinda
Published: March 2010

Literature has shown that people living in rural areas are less likely to have access to the Internet for demographic and technological reasons; however, less information is available regarding rural—urban differences in online health-information seeking. Data from the National Cancer Institute’s nationally representative 2005 Health Information National Trends Survey ( N = 5,586) are used to examine these relationships. Logistic regression results show that those in rural areas use the Internet less than those who live in urban areas. Among individuals who have used the Internet, those in rural areas are less likely to use the Internet for health purposes. The persistence of a digital divide between rural and urban residents in online health searching is attributable to factors such as educational level, income, and diffusion of broadband. The article discusses the impact of these differences.
Using the Internet to Survey Small Towns and Communities: Limitations and Possibilities in the Early 21st Century
Authors: Smyth Jolene D. , Dillman Don A. , Christian Leah Melani , O'Neill Allison C.
Published: March 2010

Researchers who are interested in small towns and rural communities in the United States often find that they need to conduct their own sample surveys because many large national surveys, such as the American Community Survey, do not collect enough representative responses to make precise estimates. In collecting their own survey data, researchers face a number of challenges, such as sampling and coverage limitations. This article summarizes those challenges and tests mail and Internet methodologies for collecting data in small towns and rural communities using the U.S. Postal Service’s Delivery Sequence File as a sample frame. Findings indicate that the Delivery Sequence File can be used to sample households in rural locations by sending them invitations via postal mail to respond to either paper-and-pencil or Internet surveys. Although the mail methodology is quite successful, the results for the Internet suggest that Web surveys alone exclude potentially important segments of the population of small towns and rural communities. However, Web surveys supplemented with postal questionnaires produce results quite similar to those of mail-only surveys, representing a possible cost savings for researchers who have access to Web survey capabilities.
Operational and strategic supply model redesign for an optical chain company using digital simulation
Authors: Buil Roman , Piera Miquel Angel , Laserna Toni
Published: March 2010

Decision making inside a company is usually performed by means of decision support tools at three different levels (strategic, tactical and operational) according to the working horizon. Unfortunately, the consequences of any decision at the strategic level are propagated to the tactical and even the operational levels. In order to support highly efficient flexibility while avoiding infrastructure over-sizing, resource saturation and poor coordination of activities and resources, it is important to consider the cause—effect interaction of strategic decisions with operational ones. In this paper, a discrete-event system simulation approach to evaluate the influence of the internal interactions among material, people, information and financial resources on the success of a Spanish optician supply chain is introduced. The emergent dynamics are analyzed and a redesign of the business and distribution network is proposed to foster synergy among supply chain actors.
Sensitivity of narrative organization measures using narrative retells produced by young school-age children
Authors: Heilmann John , Miller Jon F. , Nockerts Ann
Published: March 2010

Analysis of children’s productions of oral narratives provides a rich description of children’s oral language skills. However, measures of narrative organization can be directly affected by both developmental and task-based performance constraints which can make a measure insensitive and inappropriate for a particular population and/or sampling method. This study critically reviewed four methods of evaluating children’s narrative organization skills and revealed that the Narrative Scoring Scheme (NSS) was the most developmentally sensitive measure for a group of 129 5—7-year-old children who completed a narrative retell. Upon comparing the methods of assessing narrative organization skills, the NSS was unique in its incorporation of higher-level narrative features and its scoring rules, which required examiners to make subjective judgments across seven aspects of the narrative process. The discussion surrounded issues of measuring children’s narrative organization skills and, more broadly, issues surrounding sensitivity of criterion referenced assessment measures.
The effect of the multiple-choice item format on the measurement of knowledge of language structure
Authors: Currie Michael , Chiramanee Thanyapa
Published: March 2010

Noting the widespread use of multiple-choice items in tests in English language education in Thailand, this study compared their effect against that of constructed-response items. One hundred and fifty-two university undergraduates took a test of English structure first in constructed-response format, and later in three, stem-equivalent multiple-choice formats, with the distractors based on incorrect answers from the constructed-response test. A significant and substantial increase in mean, and generally in individual scores between the two tests was found although the scores in the tests were quite closely correlated, often taken to indicate that a similar construct was measured by the two test formats. However, direct comparison of the responses to the items in the two tests showed that only 26% of the responses were the same, suggesting that most of what the multiple-choice items measured was directly dependent on the item format. The study found remarkable consistency in the response patterns between the tests among three experimental groups of participants, who sat different option number formats of the multiple choice test, pointing to the possibility of a general effect of multiple-choice items in testing the learning of structure in second and foreign languages.
Challenges of information illiterate first-year entrants for the University of Botswana
Authors: Mutula Stephen M.
Published: March 2010

In Botswana, secondary schools are expected to be at the forefront in imparting information literacy to students to prepare them adequately for higher education or even for the labour market. However, students entering the University of Botswana from secondary schools to pursue academic programmes are largely information illiterate, thus posing great challenges to the university in terms of offering effective academic programmes. This paper discusses the information literacy (IL) challenges facing the University of Botswana occasioned by the admission of new students who lack the capacity to pursue university education because they are information illiterate. The conclusion proposes a framework for IL to help the University of Botswana address these challenges.
The use of electronic information services by undergraduate nursing students at the University of Namibia’s Northern Campus: A descriptive study
Authors: Megameno Ndinoshiho Joseph
Published: March 2010

This paper is based on a Masters’ dissertation submitted to the University of Cape Town, which investigated the use of electronic information services (EIS) by undergraduate nursing students at the University of Namibia’s Northern Campus. A self-administered questionnaire was administered to 163 students and interviews were conducted with 15 students in August and September 2007. The results revealed that the majority of students made the greatest use of the Internet. The OPAC was moderately used, while e-databases were substantially under-utilized. Students used EIS for a variety of purposes including obtaining academic information and current awareness. The main barriers that students faced in using EIS were the shortage of computers, unreliable Internet connection, and lack of skills. The majority of students relied upon their fellow students to acquire EIS skills. While many students were generally enthusiastic and held a positive perception of the Internet, only a few thought that the e-databases were useful.