bluuebunny/crossref_metadata_2025 huggingface dataset:
MIXED VACCINATION STRATEGY IN SIRS EPIDEMIC MODEL WITH SEASONAL VARIABILITY ON INFECTION
Authors: GAO SHUJING , OUYANG HONGSHUI , NIETO JUAN J.
Published: April 2011

In many diseases seasonal fluctuations are observed. SIRS epidemic model with seasonal varying contact rate and mixed vaccination strategy (including first vaccination and pulse vaccination strategy) is investigated. The effects of the variation of dependent on the season of the contact rate and the vaccination strategy to eradicate infectious diseases are studied and discussed. A threshold for a disease to be extinct or endemic is established. The existence and global asymptotic stability of disease-free periodic solution and the permanence of the disease are illustrated. Finally, our theoretical results are confirmed by numerical simulations.
Convective flow dominates aerosol delivery to the lung segments
Authors: Darquenne C. , van Ertbruggen C. , Prisk G. K.
Published: April 2011

Most previous computational studies on aerosol transport in models of the central airways of the human lung have focused on deposition, rather than transport of particles through these airways to the subtended lung regions. Using a model of the bronchial tree extending from the trachea to the segmental bronchi ( J Appl Physiol 98: 970–980, 2005), we predicted aerosol delivery to the lung segments. Transport of 0.5- to 10-μm-diameter particles was computed at various gravity levels (0–1.6 G) during steady inspiration (100–500 ml/s). For each condition, the normalized aerosol distribution among the lung segments was compared with the normalized flow distribution by calculating the ratio (R i) of the number of particles exiting each segmental bronchus i to the flow. When R i = 1, particle transport was directly proportional to segmental flow. Flow and particle characteristics were represented by the Stokes number (Stk) in the trachea. For Stk < 0.01, R i values were close to 1 and were unaffected by gravity. For Stk > 0.01, R i varied greatly among the different outlets (R i = 0.30–1.93 in normal gravity for 10-μm particles at 500 ml/s) and was affected by gravity and inertia. These data suggest that, for Stk < 0.01, ventilation defines the delivery of aerosol to lung segments and that the use of aerosol tracers is a valid technique to visualize ventilation in different parts of the lung. At higher Stokes numbers, inertia, but not gravitational sedimentation, is the second major factor affecting the transport of large particles in the lung.
Mechanical correction of dynamometer moment for the effects of segment motion during isometric knee-extension tests
Authors: Tsaopoulos Dimitrios E. , Baltzopoulos Vasilios , Richards Paula J. , Maganaris Constantinos N.
Published: April 2011

The purpose of this study was to determine the effect of dynamometer and joint axis misalignment on measured isometric knee-extension moments using inverse dynamics based on the actual joint kinematic information derived from the real-time X-ray video and to compare the errors when the moments were calculated using measurements from external anatomical surface markers or obtained from the isokinetic dynamometer. Six healthy males participated in this study. They performed isometric contractions at 90° and 20° of knee flexion, gradually increasing to maximum effort. For the calculation of the actual knee-joint moment and the joint moment relative to the knee-joint center, determined using the external marker, two free body diagrams were used of the Cybex arm and the lower leg segment system. In the first free body diagram, the mean center of the circular profiles of the femoral epicondyles was used as the knee-joint center, whereas in the second diagram, the joint center was assumed to coincide with the external marker. Then, the calculated knee-joint moments were compared with those measured by the dynamometer. The results indicate that 1) the actual knee-joint moment was different from the dynamometer recorded moment (difference ranged between 1.9% and 4.3%) and the moment calculated using the skin marker (difference ranged between 2.5% and 3%), and 2) during isometric knee extension, the internal knee angle changed significantly from rest to the maximum contraction state by about 19°. Therefore, these differences cannot be neglected if the moment–knee-joint angle relationship or the muscle mechanical properties, such as length-tension relationship, need to be determined.
The BATTLE Trial: Personalizing Therapy for Lung Cancer
Authors: Kim Edward S. , Herbst Roy S. , Wistuba Ignacio I. , Lee J. Jack , Blumenschein George R. , Tsao Anne , Stewart David J. , Hicks Marshall E. , Erasmus Jeremy , Gupta Sanjay , Alden Christine M. , Liu Suyu , Tang Ximing , Khuri Fadlo R. , Tran Hai T. , Johnson Bruce E. , Heymach John V. , Mao Li , Fossella Frank , Kies Merrill S. , Papadimitrakopoulou Vassiliki , Davis Suzanne E. , Lippman Scott M. , Hong Waun K.
Published: April 2011

The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non–small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. (ClinicalTrials.gov numbers: NCT00409968, NCT00411671, NCT00411632, NCT00410059, and NCT00410189.)

Significance: The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with “real-time” biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment. Cancer Discovery; 1(1); 44–53. © 2011 AACR.

Read the Commentary on this article by Sequist et al., p. 14

Read the Commentary on this article by Rubin et al., p. 17

This article is highlighted in the In This Issue feature, p. 4
A Novel Two-Stage, Transdisciplinary Study Identifies Digoxin as a Possible Drug for Prostate Cancer Treatment
Authors: Platz Elizabeth A. , Yegnasubramanian Srinivasan , Liu Jun O. , Chong Curtis R. , Shim Joong Sup , Kenfield Stacey A. , Stampfer Meir J. , Willett Walter C. , Giovannucci Edward , Nelson William G.
Published: April 2011

Identification of novel indications for commonly prescribed drugs could accelerate translation of therapies. We investigated whether any clinically used drugs might be useful in treating prostate cancer by coupling an efficient, high-throughput laboratory-based screen and a large prospective cohort study. In stage one, we conducted an in vitro prostate cancer cell cytotoxicity screen of 3,187 compounds. Digoxin emerged as the leading candidate, given its potency in inhibiting proliferation in vitro (the concentration of the drug at which proliferation was inhibited by 50%: mean of 163 nM) and its common use. In stage two, we evaluated the association between the leading candidate drug from stage one and prostate cancer risk in 47,884 men followed up from 1986 through 2006. Regular digoxin users [vs nonusers: relative risk (RR) = 0.76; 95% confidence interval (CI), 0.61–0.95], especially users for ≥10 years (RR = 0.54; 95% CI, 0.37–0.79; P trend < 0.001), had a lower prostate cancer risk. Digoxin was highly potent in inhibiting prostate cancer cell growth in vitro, and its use was associated with a 25% lower prostate cancer risk.

Significance: Our two-stage transdisciplinary approach for drug repositioning provides compelling justification for further mechanistic and possibly clinical testing of the leading nonchemotherapy candidate, digoxin, a cardiac glycoside, as a drug for prostate cancer treatment. Perhaps of equal importance, our study illustrates the power of the transdisciplinary approach in translational cancer research. By coupling laboratory and epidemiologic methods and thinking, we reduced the probability of identifying false-positive candidate drugs for the next steps in testing. Cancer Discovery; 1(1); 68–77. ©2011 AACR.

Read the Commentary on this article by Spitz et al., p. 21

This article is highlighted in the In This Issue feature, p. 4
The BATTLE Trial: A Bold Step toward Improving the Efficiency of Biomarker-Based Drug Development
Authors: Rubin Eric H. , Anderson Keaven M. , Gause Christine K.
Published: April 2011

Successful completion of the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, reported in this issue of Cancer Discovery, is an important advance in the effort to improve clinical trial approaches to the simultaneous development of new therapeutics with matching diagnostic tests so that patients most likely to benefit from these therapies can be identified. Cancer Discovery; 1(1); 17–20. ©2011 AACR.

Commentary on Kim et al., p. 44
Relationships between Vitamin D Status and Cardio-Metabolic Risk Factors in Young European Adults
Authors: Muldowney S. , Lucey A.J. , Paschos G. , Martínez J.A. , Bandarra N. , Thorsdottir I. , Cashman K.D. , Kiely M.
Published: April 2011

Background/Aims: To explore associations between vitamin D and cardiovascular disease risk factors in young European adults. Methods: This was a cross-sectional analysis of serum 25-hydroxyvitamin D [s25(OH)D], intact parathyroid hormone (iPTH) and biomarkers of cardiovascular disease risk in 195 healthy 20- to 40-year-olds (109 women) with a BMI between 27.5 and 32.5 from Iceland (64°N; n = 82), Ireland (51°N; n = 37) and Spain (42°N; n = 76) during mid-late winter. Results: The median s25(OH)D was 52.8 nmol/l (IQR 38.1–69.9) or 21.1 ng/ml (IQR 15.2–28.0) with a latitude-dependent gradient (p ≤ 0.0001): Iceland, 41.7 nmol/l (IQR 32.7–54.2) or 16.7 ng/ml (IQR 13.1–21.7); Ireland, 52.9 nmol/l (IQR 35.3–68.6) or 21.2 ng/ml (IQR 14.1–27.4), and Spain, 67.1 nmol/l (IQR 47.1–87.1) or 26.8 ng/ml (IQR 18.8–34.8). Eleven percent of Icelandic participants had s25(OH)D concentrations <25 nmol/l (10 ng/ml) and 66% of Icelandic, 43% of Irish, and 30% of Spanish volunteers had concentrations <50 nmol/l (20 ng/ml), respectively. Overall, 17% met 3 or more of the NCEP/ATP III criteria for cardio-metabolic syndrome (MetS). Participants in the lowest third of s25(OH)D [≤42.5 nmol/l (17 ng/ml)] were more likely to have MetS (OR 2.49, p = 0.045) and elevated TAG (OR 3.46, p = 0.019). Individuals with iPTH concentrations in the lowest third [2.34 pmol/l (22.2 pg/ml)] were more likely to have elevated fasting TAG (OR 4.17, p = 0.039), insulin (OR 3.15, p = 0.029) and HOMA-IR (OR 2.15, p = 0.031), and they were less likely to have elevated IL-6 (OR 0.24, p = 0.003). Conclusion: There were interactions between s25(OH)D, iPTH and cardio-metabolic risk factors which, given the increasing prevalence of overweight and obesity and a low vitamin D status among adults, require randomised controlled vitamin D intervention studies in overweight persons.
Impact of Group Size on Female Reproductive Success of Free-Ranging Rhinopithecus roxellana in the Qinling Mountains, China
Authors: Zhao Dapeng , Li Baoguo , Watanabe Kunio
Published: April 2011

Group size influences female reproductive success through scramble/contest feeding competition, predation pressures and infanticide risks in primates. The Sichuan snub-nosed monkey (Rhinopithecus roxellana) is an endangered folivorous colobine species living in a multilevel society. From 2002 to 2008, we studied a free-ranging band of R. roxellana in the Qinling Mountains of China to examine the effect of group size on female reproductive success. During our observation period, the number of monkeys in the study band fluctuated from 61 to 108, and the number of one-male/multi-female groups within it varied from 7 to 10. A significant negative linear relationship was found between group size and birth rate, but group size was not significantly correlated with infant survival rate or interbirth interval. These results suggest that group size influences female reproductive success via within-group scramble competition in this folivorous species.
Impact of Sleep Quality on Cardiovascular Outcomes in Hemodialysis Patients: Results from the Frequent Hemodialysis Network Study
Authors: Unruh Mark , Tamura Manjula Kurella , Larive Brett , Rastogi Anjay , James Sam , Schiller Brigitte , Gassman Jennifer , Chan Christopher , Lockridge Robert , Kliger Alan
Published: April 2011

Background: Poor sleep quality is a common, persistent, and important problem to patients with end-stage renal disease (ESRD). This report examines whether sleep quality is associated with dialysis treatment factors and other modifiable clinical factors in a large group of hemodialysis (HD) patients. Methods: Cross-sectional analyses were conducted on baseline data collected from participants in the Frequent Hemodialysis Network trials. Sleep quality was measured using the Medical Outcomes Study Sleep Problems Index II (SPI II), a 9-item measure of sleep quality with higher scores reflecting poorer sleep quality. Results: The participants had an age of 51.2 ± 13.6 years, 61% were male, 38% were black, and 42% had diabetes. Higher pre-dialysis serum phosphorus (per 0.5 mg/ml) (OR 0.91; 95% CI 0.85, 0.96) and depression (OR 0.16; 95% CI 0.10, 0.25) were independently associated with decrements in sleep quality. There was also a difference in time to recovery from dialysis for the fourth versus the first SPI II quartile (5.1 h; p < 0.0001). Conclusion: These findings underscore the link between sleep and daytime function and suggest that improving sleep may provide an opportunity to improve outcomes in ESRD. Whether sleep problems may be improved by reduction of serum phosphorus or treatment of depression in the HD population merits further investigation.
Proactive Approach in Detecting Elderly Subjects with Cognitive Decline in General Practitioners’ Practices
Authors: Hanzevacki M. , Ozegovic G. , Simovic I. , Bajic Z.
Published: April 2011

Background: Although cognitive decline is a common finding among the elderly and is considered a risk factor for developing dementia, it is rarely diagnosed by general practitioners (GPs). Aim: To evaluate cognitive function with the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) in asymptomatic subjects in daily GP practice and compare subjects who confirmed having cognitive problems with subjects who did not. Methods: 388 consecutive subjects >65 years of age who consulted their GP were interviewed and tested with MMSE and MoCA. Results: None of the study subjects spontaneously complained of cognitive or memory problems. 155 subjects (39.94%) confirmed having cognitive problems and 233 (60.05%) did not even when asked. The prevalence of mild cognitive impairment (MCI) was 18.30% (95% CI 14.36–22.04) and the prevalence of cognitive impairment/no dementia (CIND) was 17.27% (95% CI 13.50–21.04). Delayed memory recall as a separate cognitive domain in MoCA was significantly worse in subjects with MCI (p = 0.00958) and in those with CIND (p = 0.0208). Conclusion: There is a significant number of patients in daily GP practices with unrecognized, but objectively verifiable, cognitive deficits who do not report having cognitive problems. They can be identified by assessment with MMSE and MoCA already in the GP practice.
Role of Phosphoinositide-Specific Phospholipase C η2 in Isolated and Syndromic Mental Retardation
Authors: Lo Vasco Vincenza Rita
Published: April 2011

Deletions in the distal region of the short arm of chromosome 1 (1p36) are widely diffuse, both as somatic abnormalities in tumors and as constitutive in the congenital 1p36 deletion syndrome. The deletion size varies from 1.5 to 10 Mb, with common breakpoints located from 1p36.13 to 1p36.33. Patients bearing constitutional deletion of a smaller region, 1p36.3, present with a number of features, including mental retardation. The gene PLCH2, codifying for the phosphoinositide-specific phospholipase C (PI-PLC) η2, maps on the 1p36.32 region. PI-PLC η2, expressed in the brain after birth, is a key enzyme in cellular calcium mobilization. In the brain, calcium plays a role in axon growth and retraction, growth cone guidance, synapse formation, and responses to various neurotransmitters. For its role in the nervous system, PI-PLC η2 might be a putative candidate gene for the neurodevelopmental delay observed in patients bearing 1p36.3 deletions.
Telmisartan Exerts Antiatherosclerotic Effects by Activating Peroxisome Proliferator-Activated Receptor-γ in Macrophages
Authors: Matsumura Takeshi , Kinoshita Hiroyuki , Ishii Norio , Fukuda Kazuki , Motoshima Hiroyuki , Senokuchi Takafumi , Taketa Kayo , Kawasaki Shuji , Nishimaki-Mogami Tomoko , Kawada Teruo , Nishikawa Takeshi , Araki Eiichi
Published: April 2011

Objective—

Telmisartan, an angiotensin type I receptor blocker (ARB), protects against the progression of atherosclerosis. Here, we investigated the molecular basis of the antiatherosclerotic effects of telmisartan in macrophages and apolipoprotein E–deficient mice.

Methods and Results—

In macrophages, telmisartan increased peroxisome proliferator-activated receptor-γ (PPARγ) activity and PPAR ligand-binding activity. In contrast, 3 other ARBs, losartan, valsartan, and olmesartan, did not affect PPARγ activity. Interestingly, high doses of telmisartan activated PPARα in macrophages. Telmisartan induced the mRNA expression of CD36 and ATP-binding cassette transporters A1 and G1 (ABCA1/G1), and these effects were abrogated by PPARγ small interfering RNA. Telmisartan, but not other ARBs, inhibited lipopolysaccharide-induced mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α, and these effects were abrogated by PPARγ small interfering RNA. Moreover, telmisartan suppressed oxidized low-density lipoprotein-induced macrophage proliferation through PPARγ activation. In apolipoprotein E
−/−
mice, telmisartan increased the mRNA expression of ABCA1 and ABCG1, decreased atherosclerotic lesion size, decreased the number of proliferative macrophages in the lesion, and suppressed MCP-1 and tumor necrosis factor-α mRNA expression in the aorta.

Conclusion—

Telmisartan induced ABCA1/ABCG1 expression and suppressed MCP-1 expression and macrophage proliferation by activating PPARγ. These effects may induce antiatherogenic effects in hypertensive patients.
Serum Amyloid A Facilitates the Binding of High-Density Lipoprotein From Mice Injected With Lipopolysaccharide to Vascular Proteoglycans
Authors: Chiba Tsuyoshi , Chang Mary Y. , Wang Shari , Wight Thomas N. , McMillen Timothy S. , Oram John F. , Vaisar Tomas , Heinecke Jay W. , De Beer Frederick C. , De Beer Maria C. , Chait Alan
Published: April 2011

Objective—

Levels of serum amyloid A (SAA), an acute-phase protein carried on high-density lipoprotein (HDL), increase in inflammatory states and are associated with increased risk of cardiovascular disease. HDL colocalizes with vascular proteoglycans in atherosclerotic lesions. However, its major apolipoprotein, apolipoprotein A-I, has no proteoglycan-binding domains. Therefore, we investigated whether SAA, which has proteoglycan-binding domains, plays a role in HDL retention by proteoglycans.

Methods and Results—

HDL from control mice and mice deficient in both SAA1.1 and SAA2.1 (SAA knockout mice) injected with bacterial lipopolysaccharide (LPS) was studied. SAA mRNA expression in the liver and plasma levels of SAA increased dramatically in C57BL/6 mice after LPS administration, although HDL cholesterol did not change. Fast protein liquid chromatography analysis showed most of the SAA to be in HDL. Mass spectrometric analysis indicated that HDL from LPS-injected control mice had high levels of SAA1.1/2.1 and reduced levels of apolipoprotein A-I. HDL from LPS-injected control mice demonstrated high-affinity binding to biglycan relative to normal mouse HDL. In contrast, HDL from LPS-injected SAA knockout mice showed very little binding to biglycan, consistent with SAA facilitating the binding of HDL to vascular proteoglycans.

Conclusion—

SAA enrichment of HDL under inflammatory conditions plays an important role in the binding of HDL to vascular proteoglycans.
Role of Interleukin 17 in Inflammation, Atherosclerosis, and Vascular Function in Apolipoprotein E–Deficient Mice
Authors: Madhur Meena S. , Funt Samuel A. , Li Li , Vinh Antony , Chen Wei , Lob Heinrich E. , Iwakura Yoichiro , Blinder Yelena , Rahman Ayaz , Quyyumi Arshed A. , Harrison David G.
Published: April 2011

Objective—

Interleukin 17A (IL17A) is involved in many inflammatory processes, but its role in atherosclerosis remains controversial. We examined the role of IL17A in mouse and human atherosclerosis.

Methods and Results—

Atherosclerosis was induced in apolipoprotein E (ApoE)
−/−
and IL17A/ApoE
−/−
mice using high-fat feeding, angiotensin II infusion, or partial carotid ligation. In ApoE
−/−
mice, 3 months of high-fat diet induced interferon-γ production by splenic lymphocytes, and this was abrogated in IL17A/ApoE
−/−
mice. IL17A/ApoE
−/−
mice had reduced aortic superoxide production, increased aortic nitric oxide levels, decreased aortic leukocyte and dendritic cell infiltration, and reduced weight gain after a high-fat diet compared with ApoE
−/−
mice. Despite these favorable effects, IL17A deficiency did not affect aortic plaque burden after a high-fat diet or angiotensin II infusion. In a partial carotid ligation model, IL17A deficiency did not affect percentage of stenosis but reduced outward remodeling. In this model, neutralization of the related isoform, IL17F, in IL17A/ApoE
−/−
mice did not alter atherosclerosis. Finally, there was no correlation between IL17A levels and carotid intima-media thickness in humans.

Conclusion—

IL17 contributes to vascular and systemic inflammation in experimental atherosclerosis but does not alter plaque burden. The changes in plaque composition caused by IL17 might modulate plaque stability.
Intravenous Gene Therapy With PIM-1 Via a Cardiotropic Viral Vector Halts the Progression of Diabetic Cardiomyopathy Through Promotion of Prosurvival Signaling
Authors: Katare Rajesh , Caporali Andrea , Zentilin Lorena , Avolio Elisa , Sala-Newby Graciela , Oikawa Atsuhiko , Cesselli Daniela , Beltrami Antonio Paolo , Giacca Mauro , Emanueli Costanza , Madeddu Paolo
Published: April 2011

Rationale:

Studies in transgenic mice showed the key role of (Pim-1) (proviral integration site for Moloney murine leukemia virus-1) in the control of cardiomyocyte function and viability.

Objective:

We investigated whether Pim-1 represents a novel mechanistic target for the cure of diabetic cardiomyopathy, a steadily increasing cause of nonischemic heart failure.

Methods and Results:

In streptozotocin-induced type 1 diabetic mice, Pim-1 protein levels declined during progression of cardiomyopathy, along with upregulation of Pim-1 inhibitors, protein phosphatase 2A, and microRNA-1. Moreover, diabetic hearts showed low levels of antiapoptotic B-cell lymphoma-2 (Bcl-2) protein and increased proapoptotic caspase-3 activity. Studies on adult rat cardiomyocytes and murine cardiac progenitor cells challenged with high glucose confirmed the in vivo expressional changes. In rescue studies, anti-microRNA-1 boosted Pim-1 and Bcl-2 expression and promoted cardiomyocyte and cardiac progenitor cell survival under high glucose conditions. Similarly, transfection with Pim-1 plasmid prevented high glucose–induced cardiomyocyte and cardiac progenitor cell apoptosis. Finally, a single intravenous injection of human
PIM-1
via cardiotropic serotype-9 adeno-associated virus (1×10
10
or 5×10
10
genome copies per animal) at 4 weeks after diabetes induction led to sustained cardiac overexpression of Pim-1 and improved diastolic function and prevented left ventricular dilation and failure. Histological examination showed reduced cardiomyocyte apoptosis and fibrosis in association with increased c-kit
+
cells and cardiomyocyte proliferation, whereas molecular analysis confirmed activation of the prosurvival pathway and conservation of sarcoendoplasmic reticulum Ca
2+
-ATPase and α-myosin heavy chain in Pim-1–treated hearts.

Conclusions:

Pim-1 downregulation contributes in the pathogenesis of diabetic cardiomyopathy. Systemic delivery of human
PIM-1
via cardiotropic adeno-associated virus serotype-9 represents a novel and effective approach to treat diabetic cardiomyopathy.
Laminin-Binding Integrins Induce Dll4 Expression and Notch Signaling in Endothelial Cells
Authors: Estrach Soline , Cailleteau Laurence , Franco Claudio Areias , Gerhardt Holger , Stefani Caroline , Lemichez Emmanuel , Gagnoux-Palacios Laurent , Meneguzzi Guerrino , Mettouchi Amel
Published: April 2011

Rationale:

Integrins play a crucial role in controlling endothelial cell proliferation and migration during angiogenesis. The Delta-like 4 (Dll4)/Notch pathway establishes an adequate ratio between stalk and tip cell populations by restricting tip cell formation through “lateral inhibition” in response to a vascular endothelial growth factor gradient. Because angiogenesis requires a tight coordination of these cellular processes, we hypothesized that adhesion, vascular endothelial growth factor, and Notch signaling pathways are interconnected.

Objective:

This study was aimed at characterizing the cross-talk between integrin and Notch signaling in endothelial cells.

Methods and Results:

Adhesion of primary human endothelial cells to laminin-111 triggers Dll4 expression, leading to subsequent Notch pathway activation. SiRNA-mediated knockdown of α2β1 and α6β1 integrins abolishes Dll4 induction, which discloses a selective integrin signaling acting upstream of Notch pathway. The increase in Foxc2 transcription, triggered by α2β1 binding to laminin, is required but not sufficient per se for Dll4 expression. Furthermore, vascular endothelial growth factor stimulates laminin γ1 deposition, which leads to integrin signaling and Dll4 induction. Interestingly, loss of integrins α2 or α6 mimics the effects of Dll4 silencing and induces excessive network branching in an in vitro sprouting angiogenesis assay on three-dimensional matrigel.

Conclusions:

We show that, in endothelial cells, ligation of α2β1 and α6β1 integrins induces the Notch pathway, and we disclose a novel role of basement membrane proteins in the processes controlling tip vs stalk cell selection.
1
H-NMR-Based Metabolomics Study of Cerebral Infarction
Authors: Jung Jee Youn , Lee Ho-Sub , Kang Dae-Gill , Kim No Soo , Cha Min Ho , Bang Ok-Sun , Ryu Do Hyun , Hwang Geum-Sook
Published: April 2011

Background and Purpose—

Stroke is one of the leading causes of adult disability and death in developing countries. However, early diagnosis is difficult and no reliable biomarker is currently available. Thus, we applied a
1
H-NMR metabolomics approach to investigate the altered metabolic pattern in plasma and urine from patients with cerebral infarctions and sought to identify metabolic biomarkers associated with stroke.

Methods—

Metabolic profiles of plasma and urine from patients with cerebral infarctions, especially small vessel occlusion, were investigated using
1
H-NMR spectroscopy coupled with multivariate statistical analysis, such as principal components analysis and orthogonal partial least-squares discriminant analysis.

Results—

Multivariate statistical analysis showed a significant separation between patients and healthy individuals. The plasma of stroke patients was characterized by the increased excretion of lactate, pyruvate, glycolate, and formate, and by the decreased excretion of glutamine and methanol; the urine of stroke patients was characterized by decreased levels of citrate, hippurate, and glycine. These metabolites detected from plasma and urine of patients with cerebral infarctions were associated with anaerobic glycolysis, folic acid deficiency, and hyperhomocysteinemia. Furthermore, the presence of cerebral infarction in the external validation model was predicted with high accuracy.

Conclusions—

These data demonstrate that a metabolomics approach may be useful for the effective diagnosis of cerebral infarction and for the further understanding of stroke pathogenesis.
Refining the Definition of the Malignant Profile
Authors: Mlynash Michael , Lansberg Maarten G. , De Silva Deidre A. , Lee Jun , Christensen Soren , Straka Matus , Campbell Bruce C.V. , Bammer Roland , Olivot Jean-Marc , Desmond Patricia , Donnan Geoffrey A. , Davis Stephen M. , Albers Gregory W.
Published: April 2011

Background and Purpose—

To refine the definition of the malignant magnetic resonance imaging profile in acute stroke patients using baseline diffusion-weighted magnetic resonance imaging (DWI) and perfusion-weighted magnetic resonance imaging (PWI) findings from the pooled DEFUSE/EPITHET database.

Methods—

Patients presenting with acute stroke within 3 to 6 hours from symptom onset were treated with tissue plasminogen activator or placebo. Baseline and follow-up DWI and PWI images from both studies were reprocessed using the same software program. A receiver operating characteristic curve analysis was used to identify Tmax and DWI volumes that optimally predicted poor outcomes (modified Rankin Scale 5–6) at 90 days in patients who achieved reperfusion.

Results—

Sixty-five patients achieved reperfusion and 46 did not reperfuse. Receiver operating characteristic analysis identified a PWI (Tmax>8 s) volume of >85 mL as the optimal definition of the malignant profile. Eighty-nine percent of malignant profile patients had poor outcome with reperfusion versus 39% of patients without reperfusion (
P
=0.02). Parenchymal hematomas occurred more frequently in malignant profile patients who experienced reperfusion versus no reperfusion (67% versus 11%,
P
<0.01). DWI analysis identified a volume of 80 mL as the best DWI threshold, but this definition was less sensitive than were PWI-based definitions.

Conclusions—

Stroke patients likely to suffer parenchymal hemorrhages and poor outcomes following reperfusion can be identified from baseline magnetic resonance imaging findings. The current analysis demonstrates that a PWI threshold (Tmax>8 s) of approximately 100 mL is appropriate for identifying these patients. Exclusion of malignant profile patients from reperfusion therapies may substantially improve the efficacy and safety of reperfusion therapies.

Clinical Trial Registration Information—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00238537.
Early Prediction of Outcome of Activities of Daily Living After Stroke
Authors: Veerbeek Janne M. , Kwakkel Gert , van Wegen Erwin E.H. , Ket Johannes C.F. , Heymans Martijn W.
Published: April 2011

Background and Purpose—

Knowledge about robust and unbiased factors that predict outcome of activities of daily living (ADL) is paramount in stroke management. This review investigates the methodological quality of prognostic studies in the early poststroke phase for final ADL to identify variables that are predictive or not predictive for outcome of ADL after stroke.

Methods—

PubMed, Ebsco/Cinahl and Embase were systematically searched for prognostic studies in which stroke patients were included ≤2 weeks after onset and final outcome of ADL was determined ≥3 months poststroke. Risk of bias scores were used to distinguish high- and low-quality studies and a qualitative synthesis was performed.

Results—

Forty-eight of 8425 identified citations were included. The median risk of bias score was 17 out of 27 (range, 6–22) points. Most studies failed to report medical treatment applied, management of missing data, rationale for candidate determinants and outcome cut-offs, results of univariable analysis, and validation and performance of the model, making the predictive value of most determinants indistinct. Six high-quality studies showed strong evidence for baseline neurological status, upper limb paresis, and age as predictors for outcome of ADL. Gender and risk factors such as atrial fibrillation were unrelated to this outcome.

Conclusions—

Because of insufficient methodological quality of most prognostic studies, the predictive value of many clinical determinants for outcome of ADL remains unclear. Future cohort studies should focus on early prediction using simple models with good clinical performance to enhance application in stroke management and research.
The Epidemiology of Slips, Trips, and Falls in a Helicopter Manufacturing Plant
Authors: Amandus Harlan , Bell Jennifer , Tiesman Hope , Biddle Elyce
Published: April 2011

Objective: The purpose of this evaluation was to evaluate the causes and costs of slips, trips, and falls (STFs) in a helicopter manufacturing plant.

Background: STFs are a significant portion of the total industry injury burden.

Method: For this study, 4,070 helicopter plant workers who were employed from January 1, 2004, through February 28, 2008, were enrolled. Company records on workers’ compensation claims, occupational health first report of injury, and payroll records on hours worked were collected. Cause and source of all injuries, including STFs, were coded for analysis.

Results: During the 4-year study period, there were 2,378 injuries and 226 STFs (46 falls [20%] to a lower level, 117 [52%] falls on the same level, 41 [18%] from loss of balance without a fall, and 22 [10%] from other events). Of the 226 STFs, 123 falls to the same level were caused by slippery substances (52), objects on floor (43), and surface hazards (28), and they cost $1,543,946. Falls to lower levels primarily involved access to stands to and from aircraft and falling off large machines.

Conclusion: More than half of the STF injury claims likely could have been prevented by housekeeping and maintenance, and this cost saving could reasonably offset a considerable portion of the cost of prevention. Training and stand modifications could be considered to prevent falls from elevation from stands, machines, and aircraft.

Application: Recommendations for STF prevention are discussed.
An EPG Study of Palatal Consonants in Two Australian Languages
Authors: Tabain Marija , Fletcher Janet , Butcher Andrew
Published: April 2011

This study presents EPG (electro-palatographic) data on (alveo-)palatal consonants from two Australian languages, Arrernte and Warlpiri. (Alveo-)palatal consonants are phonemic for stop, lateral and nasal manners of articulation in both languages, and are laminal articulations. However, in Arrernte, these lamino-(alveo-)palatals contrast with lamino-dental consonants for all three manners of articulation (i.e., it is a double-laminal language), whereas in Warlpiri this laminal contrast does not exist (i.e., it is a single-laminal language). Data are analyzed according to manner of articulation, vowel context and phrase position. Results suggest that in the double-laminal language Arrernte, the (alveo-)palatal articulation is further back than in the single-laminal language Warlpiri, presumably due to the presence of the lamino-dental in the Arrernte phoneme inventory. The lateral has the least contact in the back regions of the palate for both languages, but there is no significant difference in contact pattern between the stop and the nasal. However, results tentatively suggest that the nasal (alveo-)palatal is the most likely to show effects of prosodic or vocalic context, and it is suggested that this is due to the less strict airflow requirements for the nasal than for the stop or the lateral.
Sovereign wealth fund investment decisions: Temasek Holdings
Authors: Heaney Richard , Li Larry , Valencia Vicar
Published: April 2011

Sovereign wealth funds (SWFs) are investment portfolios and savings funds that are controlled and actively managed by a sovereign government. In this paper, we document the investment behaviour of a specific fund, Temasek Holdings, which is the Singapore government’s SWF. Using a sample dataset of 150 publicly listed Singapore firms over the period 2000—2004, we find evidence suggesting that Temasek has a predisposition to invest in firms that are relatively large and have few director block holders. The incentive to invest also increases in firms with lower systematic risk and with compensation schemes that provide the board of directors with stocks and options.
An evaluation model for determining the business process benefits of thixoforming
Authors: Lowe A , Ridgway K , McCarthy I , Atkinson H
Published: April 2011

This paper describes the development of a financial model for evaluating the benefits of introducing a new technology. Thixoforming is a semi-solid metal processing technique that can offer potential users a number of technical and economic advantages. This process has been commercialized for a number of products, particularly in the United States and Italy, but there is significant scope for its further exploitation, especially within UK manufacturing. One of the major obstacles to the further adoption of this technique is the ability of potential users to evaluate and quantify the benefits offered. The model developed adopts a business process perspective to this and demonstrates how ‘intangible’ benefits can be quantified.
In-process sensing of tool wear and process states using a cylindrical displacement sensor in hard turning
Authors: Kim I H , Jang D Y , Kim W J , Han D C
Published: April 2011

A cylindrical capacitance-type spindle displacement sensor was developed and its effectiveness as a system for monitoring cutting conditions during hard turning was tested in this research. The sensor was installed between the face of the spindle cover and the chucking element, and measured pure radial motion of the spindle under conditions of roundness error at the measured surface. To prove the effectiveness of the developed system, hard-turning tests using ceramic inserts and with tool steel as the workpiece were conducted. The workpiece was hardened up to 65 Rc. The variations in pure radial motion of the spindle were measured during the cutting tests. The signals from the sensor showed the same pattern of cutting force variations from the tool dynamometer due to the progress of tool wear. As the flank wear of the ceramic tool increased, both the static component of the cutting forces and the centre shift of the spindle orbit increased. Results from the research showed that the developed sensor could be utilized as an effective and cheap on-line sensing device to monitor cutting conditions and tool performance in the unmanned machining centre.
Interference-free tool orientation determination by a virtual enveloping element for five-axis machining of a freeform surface
Authors: Lee R S , Lee J N
Published: April 2011

In machining freeform surfaces on five-axis machine tools, it is very important to determine the location of the cutting tool. The commercial computer aided design/manufacturing (CAD/CAM) software for five-axis machining often lacks flexibility to specify the appropriate tool orientation and toolpath for surface machining. This paper presents a new methodology for determining feasible tool orientation of a toroidal milling cutter with collision and gouging avoidance in five-axis machining of a freeform surface. To avoid collision and rear gouging, a virtual enveloping element is proposed that is derived from the properties of the local and global surfaces. The set of tool orientations can be found first by confining the cutting tool within the virtual enveloping element. Then, the principal induced normal curvatures between the freeform surface and the cutting tool need to be evaluated to offer the criterion of gouging detection. To achieve the best combination of scallop height and machining efficiency, the contact length is also calculated for various tool orientations. The toolpaths generated by the proposed method are verified through solid cutting simulation and a trial cut on a five-axis machine.
Roundness improvement in taper machining based on two-dimensional active error compensation
Authors: Fung E H K , Yang S M , Chan F M
Published: April 2011

In this study, an on-line forecasting compensatory control (FCC) strategy is successfully employed to improve the workpiece accuracy in taper machining by compensating the relative two-dimensional motion errors between the workpiece and the cutting tool. The indirect measurement set-up is developed to determine the motion errors, in both radial and longitudinal directions, of the spindle which positions the workpiece via a master taper. Also, the straightness motion errors of the x-y slide are determined to give the actual tool positions. The reference datum in these measurements, i.e. the master form error and the slide profile, can be determined under on-machine conditions and highly accurate precalibrated references are not required. Based on the autoregressive moving average (ARMA) technique, the two-dimensional motion errors are modelled and their future values forecasted and compensated by means of a piezoelectric actuator. The adequate model order and parameters are found by performing off-line simulations. The effectiveness of the FCC strategy is also evaluated by comparing the roundness results with and without compensation. Experimental cutting with FCC reveals that a maximum improvement of 68 per cent and an average improvement of 41 per cent can be achieved for workpiece roundness in this taper machining process.
A genetic algorithm-based fixture locating positions and clamping schemes optimization
Authors: Liao Y G
Published: April 2011

Optimizing the locator positions and clamping schemes of a fixture was proven to improve the dimensional and form accuracy of a workpiece significantly. A number of approaches have been developed to optimize the designs of sheet-metal assembly fixtures and machining fixtures. However, in these previous works, the optimal selection of the positions of locators and clamps were based on a stationary set of locator and clamp conditions; i.e. the numbers of the locators and clamps were fixed during optimization. This paper proposes a genetic algorithm (GA)-based optimization method to select automatically the optimal numbers of locators and clamps as well as their optimal positions in sheet-metal assembly fixtures, such that the workpiece deformation due to the gravity effect and resulting variation due to part dimensional variation are simultaneously minimized. The application result of a real industrial part demonstrated that the proposed algorithm effectively achieves the objective.
Finite element analysis for the prediction and optimization of residual stresses caused by laser enamelling
Authors: Nisar A , Schmidt M J J , Sheikh M A , Li L
Published: April 2011

Rapid laser enamelling is applied for sealing ceramic tile grouts. In order to understand the mechanics of microcracks developed and long-term stability of the enamel glaze, finite element analysis of the thermomechanical characteristics is carried out. In the thermal stress analysis, the temperature field is used as a boundary condition to calculate mechanical effects on the material due to thermal strains. A thermoisotropic material model has been defined for five different materials involved in the process. To validate the theoretical predictions, experiments are conducted by the measurements of strain on the ceramic tile surface during laser enamelling with the help of strain gauges. Residual stresses are also determined on the ceramic tile surface with the X-ray diffraction method. The theoretical predictions of the residual stresses are in close agreement with experimental results.
An experimental study of drilling small and deep blind holes with an abrasive water jet
Authors: Orbanic H , Junkar M
Published: April 2011

In this paper an experimental study of drilling small and deep holes with a continuous abrasive water jet is presented. The abrasive water jet (AWJ) is a process that can be used for drilling a vast variety of materials. The main advantage of the AWJ is the absence of the heat-affected zone and its flexibility. Drilling tests were performed on different materials and the hole depth and diameter were observed at different machining times. It was found that when drilling different materials with a continuous jet, the depth and diameter of the hole increase with a power function. These findings were then used to develop an empirical model for predicting hole depths and diameters at different drilling times.
Electrically self-powered active disassembly
Authors: Jones N , Harrison D , Hussein H , Billett E , Chiodo J
Published: April 2011

Active disassembly using smart materials is a concept developed at Brunel University for the design of assemblies with the built-in capability for easy separation of components for recycling on exposure to certain triggering conditions. Such assemblies incorporate shape memory alloy (SMA) actuators in the product housings. These actuators in the form of clips can undergo a shape change (shape memory effect) on going above a transition temperature, and exert a force to effect disassembly. Hitherto, such a change in temperature has been effected by direct heat input external to the assembly. It is now shown in the case of assemblies that contain battery power sources, firstly, that disassembly can be achieved using the residual electrical energy in waste batteries to heat the SMA actuator electrically and, secondly, that there is enough energy left in end-of-life batteries of mobile phones and end-of-life vehicles to trigger at least 4 and 16 devices respectively.
Effects of viscosity control on microporosity in the fabrication process of aluminium foam material by a rheology forming process
Authors: Jeon Y P , Youn S W , Kang C G
Published: April 2011

Aluminium foam is an ultra-light-weight porous material consisting of aluminium and large quantities of pores. In this study, aluminium foams having a closed-cell structure were fabricated by the melt-stirring method and induction heating process. ADC12 aluminium alloy billet and TiH2 powder (1 wt %) were used as the matrix alloy and the foaming agent respectively. In order to establish the aluminium foam fabrication conditions, the effect of the process parameters such as heating temperatures (585, 595, 615 and 680 °C), heating rates (20, 30, 40 and 50 °C/min), stirring speeds (700, 1000, 1350 and 1750 r/min) and reheating temperatures (595, 605, 625 and 680 °C) on the pore morphology were investigated. For fabricated ADC12 aluminium foam samples, the size and shape of the pores in accordance with the process parameters were investigated quantitatively.
Computer aided stress and deflection analysis of Fellow's gear-shaping cutter, for different cutting process parameters
Authors: Datta P P , Banerjee R N , Chattopadhyay T K
Published: April 2011

Achieving maximum efficiency (in terms of quantity of products produced in a stipulated time) with improved accuracy and surface finish through a chatter-free high-speed cutting process are problems of the modern gear cutting industry. Modern techniques employ a generating type of cutter such as Fellow's gear-shaping cutter for the production of high-speed noiseless and accurate gears. The literature review indicates that experimental and theoretical methods had been predominantly in use in the design of gear cutting tools as compared to the computer aided methods. In this research the gear-shaping cutter is modelled using three-dimensional ten-node tetrahedral finite elements. The research is carried out at the instant when the gear-shaping cutter plunges on the workpiece and the cutting forces during the generation process become maximum. The maximum three-dimensional displacements and stress values are generated under different cutting conditions. The effects of different cutting process parameters (speed, feed and depth of cut) on the maximum stress and deflection are studied in detail.