bluuebunny/crossref_metadata_2025 huggingface dataset:
Tasisulam Sodium, an Antitumor Agent That Inhibits Mitotic Progression and Induces Vascular Normalization
Authors: Meier Timothy , Uhlik Mark , Chintharlapalli Sudhakar , Dowless Michele , Van Horn Robert , Stewart Julie , Blosser Wayne , Cook James , Young Debra , Ye Xiang , Evans Glenn , Credille Kelly , Ballard Darryl , Huber Lysiane , Capen Andrew , Chedid Marcio , Ilaria Robert , Smith Michele C. , Stancato Louis
Published: September 2011

LY573636-sodium (tasisulam) is a small molecule antitumor agent with a novel mechanism of action currently being investigated in a variety of human cancers. In vitro, tasisulam induced apoptosis via the intrinsic pathway, resulting in cytochrome c release and caspase-dependent cell death. Using high content cellular imaging and subpopulation analysis of a wide range of in vitro and in vivo cancer models, tasisulam increased the proportion of cells with 4N DNA content and phospho-histone H3 expression, leading to G2–M accumulation and subsequent apoptosis. Tasisulam also blocked VEGF, epidermal growth factor, and fibroblast growth factor–induced endothelial cell cord formation but did not block acute growth factor receptor signaling (unlike sunitinib, which blocks VEGF-driven angiogenesis at the receptor kinase level) or induce apoptosis in primary endothelial cells. Importantly, in vivo phenocopying of in vitro effects were observed in multiple human tumor xenografts. Tasisulam was as effective as sunitinib at inhibiting neovascularization in a Matrigel plug angiogenesis assay in vivo and also caused reversible, non G2–M–dependent growth arrest in primary endothelial cells. Tasisulam also induced vascular normalization in vivo. Interestingly, the combination of tasisulam and sunitinib significantly delayed growth of the Caki-1 renal cell carcinoma model, whereas neither agent was active alone. These data show that tasisulam has a unique, dual-faceted mechanism of action involving mitotic catastrophe and antiangiogenesis, a phenotype distinct from conventional chemotherapies and published anticancer agents. Mol Cancer Ther; 10(11); 2168–78. ©2011 AACR.
Micelle-Encapsulated Thiostrepton as an Effective Nanomedicine for Inhibiting Tumor Growth and for Suppressing FOXM1 in Human Xenografts
Authors: Wang Ming , Gartel Andrei L.
Published: September 2011

The thiazole antiobiotic, thiostrepton, has been found to induce cell death in cancer cells through proteasome inhibition. As a proteasome inhibitor, thiostrepton has also been shown to suppress the expression of FOXM1, the oncogenic forkhead transcription factor overexpressed in cancer cells. In this study, we explored the potential in vivo anticancer properties of thiostrepton, delivered through nanoparticle encapsulation to xenograft models of breast and liver cancer. We encapsulated thiostrepton into micelles assembled from amphiphilic lipid-PEG (polyethylene glycol) molecules, where thiostrepton is solubilized within the inner lipid compartment of the micelle. Upon assembly, hydrophobic thiostrepton molecules are solubilized into the lipid component of the micelle shell, formed through the self-assembly of amphipilic lipid-PEG molecules. Maximum accumulation of micelle-thiostrepton nanoparticles (100 nm in diameter, −16 mV in zeta potential) into tumors was found at 4 hours postadministration and was retained for at least 24 hours. Upon continuous treatment, we found that nanoparticle-encapsulated thiostrepton reduced tumor growth rates of MDA-MB-231 and HepG2 cancer xenografts. Furthermore, we show for the first time the in vivo suppression of the oncogenic FOXM1 after treatment with proteasome inhibitors. Immunoblotting and immunohistochemical staining also showed increased apoptosis in the treated tumors, as indicated by cleaved caspase-3 expression. Our data suggest that the thiazole antibiotic/proteasome inhibitor thiostrepton, when formulated into nanoparticles, may be highly suited as a nanomedicine for treating human cancer. Mol Cancer Ther; 10(12); 2287–97. ©2011 AACR.
Development of the Human Tensor Veli Palatini
Authors: De la Cuadra Blanco C. , Peces Peña M.D. , Rodríguez-Vázquez J.F. , Mérida-Velasco J.A. , Mérida-Velasco J.R.
Published: September 2011

The present study seeks to determine the main events that occur in the development of the tensor veli palatini (TVP). A light microscope was used on serial sections of 60 human specimens from weeks 6 to 16 of development. The TVP becomes visible in an embryo of 14.5 mm greatest length (GL; week 6) from a common blastema with the medial pterygoid muscle. In embryos of Carnegie stage 20 (week 7), the TVP is differentiated and relates to the anlage of the pterygoid hamulus. At week 8 of development, when the palatal shelves become horizontal, the presence of the anlage of the palatine aponeurosisis distinguished and is reached by the TPV. In an embryo of 30 mm GL, the chondrification nucleus of the pterygoid hamulus and the synovial bursa of the TVP are identifiable. At week 9, the TVP is continuous with the palatine aponeurosis. At week 13, a connective tissue lamina appears between the TVP and the intramembranous ossification center for the anterior process of the malleus, which we know as the goniale and interpret as an attachment of the muscle to the primary vertebrate jaw or incudomalleal joint. The TVP from its origin, innervation and relation to the goniale appears to be a muscle of mastication that, at the end of the embryonic period, reaches the palatine aponeurosis anlage and the mesenchyme of the auditory tube and specializes in the movements of the soft palate and the auditory tube.
Protein Phosphatase 2A Promotes Endothelial Survival via Stabilization of Translational Inhibitor 4E-BP1 Following Exposure to Tumor Necrosis Factor-α
Authors: Janzen Carla , Sen Suvajit , Cuevas Janis , Reddy Srinivasa T. , Chaudhuri Gautam
Published: September 2011

Objective—

Tumor necrosis factor-α (TNFα) may change from a stimulator of reversible activation of endothelial cells (ECs) to a killer when combined with cycloheximide (CHX). The means by which endothelial cells are destined to either the survival pathway or the apoptotic pathway are not fully understood. We investigated the role of p38 mitogen-activated protein kinase (MAPK) and protein phosphatase 2A (PP2A) activation and their regulation of 4E-BP1 stability in ECs to determine whether this pathway contributes to apoptosis induced by TNFα and CHX.

Methods and Results—

Apoptosis was induced in human umbilical vein ECs (HUVECs) by treating them with a combination of TNFα and CHX (TNFα/CHX). Activation of p38 MAPK was increased in HUVECs undergoing apoptosis, which was associated with degradation of eukaryotic initiation factor 4A regulator 4E-BP1 in a p38 MAPK–dependent manner. CHX attenuated a TNFα-stimulated increase in the expression and activity of PP2A. Silencing PP2A expression with small interfering RNA transfection mimicked CHX sensitization, increasing HUVEC apoptosis with TNFα stimulation and suggesting a protective role for PP2A in the apoptotic process.

Conclusion—

Our data suggest that (1) TNFα stimulates PP2A and HUVECs elude apoptosis by PP2A-dependent dephosphorylation of p38 MAPK, and (2) CHX-induced inhibition of PP2A leads to maintenance of p38 activity and degradation of 4E-BP1, resulting in enhanced TNFα-induced apoptosis.
Genome-Wide Microarray Analyses Identify the Protein C Receptor as a Novel Calcineurin/Nuclear Factor of Activated T Cells–Dependent Gene in Vascular Smooth Muscle Cell Phenotypic Modulation
Authors: Lee Monica Y. , Garvey Sean M. , Ripley Marcia L. , Wamhoff Brian R.
Published: September 2011

Objective—

Calcineurin (Cn) and the nuclear factor of activated T cells (NFAT) family of transcription factors are critical in vascular smooth muscle cell (SMC) development and pathology. Here, we used a genomics approach to identify and validate NFAT gene targets activated during platelet-derived growth factor-BB (PDGF-BB)–induced SMC phenotypic modulation.

Methods and Results—

Genome-wide expression arrays were used to identify genes both (1) differentially activated in response to PDGF-BB and (2) whose differential expression was reduced by both the Cn inhibitor cyclosporin A and the NFAT inhibitor A-285222. The 20 most pharmacologically sensitive genes were validated by quantitative reverse transcription–polymerase chain reaction analysis of PDGF-BB-stimulated SMCs in the presence of Cn/NFAT inhibitors, including the VIVIT peptide. In all experiments, protein C receptor (PROCR) gene activation was reduced. We showed that PROCR expression was virtually absent in untreated, quiescent SMCs. PDGF-BB stimulation, however, induced significant PROCR promoter activation and downstream protein expression in a Cn/NFAT-dependent manner. Mutation of a species-conserved, NFAT binding motif significantly attenuated PDGF-BB-induced PROCR promoter activity, thereby distinguishing NFAT as the first PROCR transcriptional activator to date. Moreover, SMC PROCR expression was upregulated in the neointima as early as 7 days following acute vascular injury in rat carotid arteries.

Conclusion—

We hereby report PROCR as a novel, NFAT-dependent gene that may be implicated in vascular restenosis and consequent inward remodeling.
MicroRNA-29 in Aortic Dilation: Implications for Aneurysm Formation
Authors: Boon Reinier A. , Seeger Timon , Heydt Susanne , Fischer Ariane , Hergenreider Eduard , Horrevoets Anton J.G. , Vinciguerra Manlio , Rosenthal Nadia , Sciacca Sergio , Pilato Michele , van Heijningen Paula , Essers Jeroen , Brandes Ralf P. , Zeiher Andreas M. , Dimmeler Stefanie
Published: September 2011

Rationale:

Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown.

Objective:

We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies.

Methods and Results:

Expression profiling of aortic tissue of young versus old mice identified several age-associated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4
R/R
mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (
n
=79) or tricuspid aortic valves (
n
=30). Finally, LNA-modified antisense oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice.

Conclusion:

In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity.
Emergency Department Shift Change Is Associated With Pneumonia in Patients With Acute Ischemic Stroke
Authors: Jones Erica M. , Albright Karen C. , Fossati-Bellani Marco , Siegler James E. , Martin-Schild Sheryl
Published: September 2011

Background and Purpose—

Emergency department (ED) nurses play a pivotal role in early acute ischemic stroke patient management. We hypothesized that patients exposed to ED nursing shift changes (SC) may develop pneumonia (PNA) more frequently and have worse early outcomes than do patients who have continuity of care until stroke unit admission.

Methods—

Consecutive acute ischemic stroke patients presenting to our ED were studied using chart review and prospectively collected registry data. We evaluated the association of patient presence during an ED SC (ie, 07:00–08:00, 19:00–20:00) with length of stay in the ED, PNA rates, and early outcome measures (discharge disposition, modified Rankin Scale score, and death).

Results—

Three hundred sixty-six consecutive acute ischemic stroke patients met the criteria. Of those, 54.9% were present during an SC. After adjusting for baseline National Institutes of Health Stroke Scale, admission glucose, and intravenous tissue-type plasminogen activator, patients present during SC were half as likely to be discharged home or to inpatient rehab (OR, 0.50; 95% CI, 0.26–0.96;
P
=0.04) and were 2.5 times more likely to develop PNA (OR, 2.54; 95% CI, 1.02–6.30;
P
=0.045). After additional adjustment for time in the ED, the difference in favorable discharge disposition was no longer significant, but SC was associated with 5 times the odds of PNA (OR, 5.35; 95% CI, 1.34–21.39;
P
=0.018) compared with patients with continuity of care.

Conclusions—

In our center, acute ischemic stroke patients present during an ED nursing SC experienced higher rates of PNA and had decreased rates of favorable discharge disposition compared with patients with continuity of care. Strategies to prevent PNA and improve hand-off communication during SC may reduce this risk.
Lung Cancer and Incidence of Stroke
Authors: Chen Pei-Chun , Muo Chih-Hsin , Lee Yuan-Teh , Yu Yang-Hao , Sung Fung-Chang
Published: September 2011

Background and Purpose—

Stroke is a known cerebrovascular complication in lung cancer patients; however, whether lung cancer patients are at elevated risk of developing stroke relative to the noncancer population remains unclear.

Methods—

The present study used population-based claims data from the Taiwan National Health Insurance, which identified 52 089 patients with an initial diagnosis of lung cancer between 1999 and 2007, and 104 178 matched noncancer subjects from all insured subjects age 20 years and older. Subsequent occurrence of stroke was measured until 2008, and the association between lung cancer and the hazard of developing stroke was estimated using Cox proportional hazard models.

Results—

The incidence of stroke was 1.5 times higher (25.9 versus 17.4 per 1000 person–years) in the lung cancer group compared with the comparison group. The multivariate-adjusted hazard ratio (HR) comparing lung cancer patients with the noncancer group was 1.47 (95% CI, 1.39–1.56) for stroke, 1.78 (95% CI, 1.54–2.05) for hemorrhagic stroke, and 1.43 (95% CI, 1.34–1.51) for ischemic stroke. The risk of stroke fell over time, decreasing after 1 year of follow-up for men and after 2 years of follow-up for women. Within the first year of follow-up, the risk of stroke peaked during the first 3 months for men and within 4 to 6 months for women.

Conclusions—

Lung cancer is associated with increased risk of subsequent stroke within 1 year after diagnosis for men and 2 years after diagnosis for women.
Neuroprotection by Freezing Ischemic Penumbra Evolution Without Cerebral Blood Flow Augmentation With a Postsynaptic Density-95 Protein Inhibitor
Authors: Bråtane Bernt T. , Cui Hong , Cook Douglas J. , Bouley James , Tymianski Michael , Fisher Marc
Published: September 2011

Background and Purpose—

The purpose of this study was to determine whether neuroprotection is feasible without cerebral blood flow augmentation in experimental permanent middle cerebral artery occlusion.

Methods—

Rats were subjected to permanent middle cerebral artery occlusion by the suture occlusion method and were treated 1 hour thereafter with a single 5-minute intravenous infusion of the postsynaptic density-95 protein inhibitor Tat-NR2B9c (7.5 mg/kg) or saline (n=8/group). Arterial spin-labeled perfusion-weighted MRI and diffusion weighted MRI were obtained with a 4.7-T Bruker system at 30, 45, 70, 90, 120, 150, and 180 minutes postmiddle cerebral artery occlusion to determine cerebral blood flow and apparent diffusion coefficient maps, respectively. At 24 hours, animals were neurologically scored (0 to 5), euthanized, and the brains stained with 2–3-5-triphenyl tetrazolium chloride to ascertain infarct volumes corrected for edema. Additionally, the effects of Tat-NR2B9c on adenosine 5′-triphosphate levels were measured in vitro in neurons subjected to oxygen–glucose deprivation.

Results—

Final infarct volume was decreased by 30.3% in the Tat-NR2B9c-treated animals compared with controls (
P
=0.028). There was a significant improvement in 24 hours neurological scores in the Tat-NR2B9c group compared with controls, 1.8±0.5 and 2.8±1.0, respectively (
P
=0.021). Relative to controls, Tat-NR2B9c significantly attenuated diffusion-weighted imaging lesion growth and preserved the diffusion-weighted imaging/perfusion-weighted imaging mismatch (ischemic penumbra) without affecting cerebral blood flow in the ischemic core or penumbra. Tat-NR2B9c treatment of primary neuronal cultures resulted in 26% increase in cell viability and 34% greater adenosine 5′-triphosphate levels after oxygen–glucose deprivation.

Conclusions—

Preservation of adenosine 5′-triphosphate levels in vitro and neuroprotection in permanent middle cerebral artery occlusion in rats is achievable without cerebral blood flow augmentation using a postsynaptic density-95 protein inhibitor.
Assessment of the Genetic Effects of Polymorphisms in the Osteoprotegerin Gene, TNFRSF11B, on Serum Osteoprotegerin Levels and Carotid Plaque Vulnerability
Authors: Straface Giuseppe , Biscetti Federico , Pitocco Dario , Bertoletti Giovanni , Misuraca Maria , Vincenzoni Claudio , Snider Francesco , Arena Vincenzo , Stigliano Egidio , Angelini Flavia , Iuliano Luigi , Boccia Stefania , de Waure Chiara , Giacchi Francesco , Ghirlanda Giovanni , Flex Andrea
Published: September 2011

Background and Purpose—

Osteoprotegerin (OPG) is a secretory glycoprotein which belongs to the tumor necrosis factor receptor family. Various mechanisms have been suggested by which calcification might alter atherosclerotic plaque stability, but the significance of this intimal calcification is controversial. High concentrations of OPG have been associated with the presence of vascular and cardiovascular diseases. This study was designed to assess the association between gene polymorphisms of the OPG gene (TNFRSF11B), the serum OPG level, and plaque stability in patients with carotid atherosclerosis.

Methods—

We studied 177 patients with internal carotid artery stenosis who underwent carotid endarterectomy and also 303 controls. Carotid endarterectomy samples removed from patients were assessed by immunohistochemistry. Concentrations of OPG were measured and gene polymorphisms were examined by polymerase chain reaction and restriction enzyme analysis and were compared, initially between patients with carotid atherosclerosis and controls, and subsequently between stable and unstable carotid plaques.

Results—

We found that the GG genotype of the
T245G
polymorphism, the
CC
genotype of the
T950C
polymorphism, and the
CC
genotype of the
G1181C
polymorphism were significantly higher in patients with carotid plaque than in controls (21.5% versus 10.9% ,
P
<0.01; 15.8% versus 7.6%,
P
<0.01; and 20.3% versus 10.9%,
P
<0.01, respectively) and that these polymorphisms were associated with high serum OPG levels (4.02 [3.07] versus 2.94 [1.81] pmol/L;
P
<0.01), which were significantly higher in patients with unstable atherosclerotic plaques (5.86 [4.02] versus 3.53 [1.87] pmol/L;
P
<0.01).

Conclusions—

The TNFRSF11B gene polymorphisms studied are associated with high serum OPG levels and might be potential markers for plaque instability.
Prediction of Malignant Middle Cerebral Artery Infarction Using Computed Tomography-Based Intracranial Volume Reserve Measurements
Authors: Minnerup Jens , Wersching Heike , Ringelstein E. Bernd , Heindel Walter , Niederstadt Thomas , Schilling Matthias , Schäbitz Wolf-Rüdiger , Kemmling André
Published: September 2011

Background and Purpose—

Early decompressive surgery in patients with malignant middle cerebral artery (MCA) infarction improves outcome. Elevation of intracranial pressure depends on both the space occupying brain edema and the intracranial volume reserve (cerebrospinal fluid [CSF]). However, CSF volume was not investigated as a predictor of malignant infarction so far. We hypothesize that assessment of CSF volume in addition to admission infarct size improves early prediction of malignant MCA infarction.

Methods—

Stroke patients with carotid-T or MCA main stem occlusion and ischemic lesion (reduced cerebral blood volume [CBV]) on perfusion CT were considered for the analysis. The end point malignant MCA infarction was defined by clinical signs of herniation. Volumes of CSF and CBV lesion were determined on admission. Receiver-operator characteristics analysis was used to calculate predictive values for radiological and clinical measurements.

Results—

Of 52 patients included, 26 (50%) developed malignant MCA infarction. Age, a decreased level of consciousness on admission, CBV lesion volume, CSF volume, and the ratio of CBV lesion volume to CSF volume were significantly different between malignant and nonmalignant groups. The best predictor of a malignant course was the ratio of CBV lesion volume to CSF volume with a cut-off value of 0.92 (96.2% sensitivity, 96.2% specificity, 96.2% positive predictive value, and 96.2% negative predictive value).

Conclusions—

Based on admission native CT and perfusion CT measurements, the ratio of ischemic lesion volume to CSF volume predicts the development of malignant MCA infarction with higher accuracy than other known predictors, including ischemic lesion volume or clinical characteristics.
Christian Conscience, Catholic Teaching and Lay Participation in Public Life
Authors: Clague Julie
Published: September 2011

Vatican II left Catholicism with some unresolved tensions: on the one hand between the authority of conscience and the teaching authority of the church and, on the other hand, concerning the proper relationship between the hierarchy and the laity. Such unfinished business continues to play itself out in public and political life. This article traces developments in the Catholic understanding of conscientious participation in public life, stretching from John F. Kennedy’s presidential candidature in 1960 up to the present writings of Pope Benedict XVI. In the post-Vatican II era, Popes John Paul II and Benedict XVI have emphasized the strong correspondence that should exist between church teaching and the Christian conscience.
Catholicism, Human Rights and the Public Sphere
Authors: McCrudden Christopher
Published: September 2011

This article suggests that the scope and meaning of human rights, and its relationship to religion, is anything but settled, and that this gives an opportunity to those who support a role for religion in public life to intervene. Such intervention should address four main issues. First, it should ensure that judges engage in attempting to understand religious issues from a cognitively internal viewpoint. Secondly, it should articulate a justification for freedom of religion that fully captures the core of the significance of religious belief, and the importance of the religious principles in the public sphere. Thirdly, it should ensure engagement and dialogue between the churches and others on the meaning of human dignity, given its centrality to religious and secular perspectives on rights. Lastly, the churches should consider more carefully what it means to give ‘public reasons’ in the political and cultural context, and how it can engage in the process of ‘public reasoning’ regarding human rights.
The Relevance of the Responsibility to Protect for Latin America and the Caribbean Region: Prevention and The Role of Civil Society
Authors: Rodrigues Gilberto M. A. , Serbin Andrés
Published: September 2011

The authors argue in this article that the main dimensions to be considered regarding the implementation of the Responsibility to Protect in Latin America and the Caribbean are the preventive dimension and, eventually the rebuilding dimension. The preventive dimension of the Responsibility to Protect cannot be dissociated from a general strategy of armed or violent conflict prevention, and should not be focused only in the prevention of mass atrocities. In the framework of the juridical and cultural legacy of the region, special attention should be directed to avoid considering the reactive dimension of RtoP, as well-embedded principles of national sovereignty, non-intervention and regional peaceful resolution of disputes obstruct any attempt of external intervention, even if they are related to international community initiatives. In this regard, the authors argue that the traditional role of regional organisations and mechanisms in peaceful resolution of inter-state conflicts, should be deepened, combined and coordinated with civil society initiatives, in the implementation of RtoP. The role of civil society organisations and networks should be strengthened through an increasing capacity building process, which includes developing skills and capacities to address both prevention and early warning, and which ought to be based on research, education and networking.
Making Europe's Responsibility to Protect More Credible
Authors: Petersson Jens
Published: September 2011

European nations should strengthen the United Nations military capability to manage conflicts on the African continent. The EU should also learn from the AU and incorporate a paragraph similar to §4h in the AU charter into the EU's own security political framework. Combined, these actions should make Europe's contribution to the military aspects of R2P more credible.
Can Surface-Cover Tiles Be Summed to Give Neighborhood Fluxes in Cities?
Authors: Salmond J. A. , Roth M. , Oke T. R. , Christen A. , Voogt J. A.
Published: September 2011

The paper addresses the question of whether the modeling practice of summing separate land-cover tiles to give urban fluxes at the neighborhood scale has merit. A central-city site in Basel, Switzerland, was instrumented to measure turbulent sensible heat fluxes QH from the two main land-cover types (roofs and canyons) separately and from the whole neighborhood. Path-averaged QH values were measured in the roughness sublayer (RSL) using scintillometry, and the spatially averaged QH neighborhood-scale flux was measured in the inertial sublayer (ISL) by an eddy-covariance system. The roof and canyon flux results are combined and weighted according to the respective plan-area abundance of each to give an estimated value of the neighborhood flux. The results show that this “bottom up” approach underestimates the measured ISL values by about 25% when averaged across all periods and wind directions. This finding led to consideration of possible errors from instrumentation, inappropriate turbulent source areas, failure to sample representative surfaces, and inability to fully capture RSL heat exchange. Sorting data by the two main wind directions revealed significant differences. The measured fluxes in the ISL and across the canyon top depend little upon wind direction, but daytime roof values show a marked sensitivity to wind direction. Qualitative analysis suggests this might be caused by systematic controls such as solar angle, site morphometry, and observational setup. The comparison of bottom up versus ISL is inconclusive; in some conditions agreement appears promising, and in others it does not. The question has not been proven or disproven. It may be too ambitious to test the concept at a real-world site.
How Physical Parameterizations Can Modulate Internal Variability in a Regional Climate Model
Authors: Crétat Julien , Pohl Benjamin
Published: September 2011

The authors analyze to what extent the internal variability simulated by a regional climate model is sensitive to its physical parameterizations. The influence of two convection schemes is quantified over southern Africa, where convective rainfall predominates. Internal variability is much larger with the Kain–Fritsch scheme than for the Grell–Dévényi scheme at the seasonal, intraseasonal, and daily time scales, and from the regional to the local (grid point) spatial scales. Phenomenological analyses reveal that the core (periphery) of the rain-bearing systems tends to be highly (weakly) reproducible, showing that it is their morphological features that induce the largest internal variability in the model. In addition to the domain settings and the lateral forcing conditions extensively analyzed in the literature, the physical package appears thus as a key factor that modulates the reproducible and irreproducible components of regional climate variability.
Supersaturation Fluctuations in Cirrus Clouds Driven by Colored Noise
Authors: Kärcher B.
Published: September 2011

Fundamental properties of ice supersaturation variability in cirrus clouds are studied by means of an idealized probabilistic model. Damped supersaturation fluctuations are assumed to be exponentially correlated in time, statistically stationary, and normally distributed. The damping process is tied to the ability of the ice crystals to scavenge water vapor. The temporal evolution of supersaturation separates into an early ballistic and a late asymptotic regime. The latter allows for a stationary solution for the probability distribution of supersaturation in the presence of cloud ice and corresponds to a diffusive solution in cloud-free conditions. Low ice crystal number densities, small ice crystal sizes, short supersaturation correlation times, and large fluctuation intensities favor the spreading of cirrus ice crystal sizes, especially in conditions conducive to sublimation. Otherwise, size spreading of ice crystals is hampered by ice-induced damping of supersaturation fluctuations. The spreading of the probability distributions of ice supersaturation for very weak damping may lead to an increase of cirrus fractional coverage, as parameterized in large-scale atmospheric models, even for small mean supersaturations.
Interdecadal Variations in ENSO Teleconnection to the Indo–Western Pacific for 1870–2007
Authors: Chowdary J. S. , Xie Shang-Ping , Tokinaga Hiroki , Okumura Yuko M. , Kubota Hisayuki , Johnson Nat , Zheng Xiao-Tong
Published: September 2011

Slow modulation of interannual variability and its relationship to El Niño–Southern Oscillation (ENSO) is investigated for the period of 1870–2007 using shipboard surface meteorological observations along a frequently traveled track across the north Indian Ocean (NIO; from the Gulf of Aden through Malacca Strait) and the South China Sea (to Luzon Strait). During the decades in the late nineteenth–early twentieth century and in the late twentieth century, the El Niño–induced NIO warming persists longer than during the 1910s–mid-1970s, well into the summer following the peak of El Niño. During the epochs of the prolonged NIO warming, rainfall drops and sea level pressure rises over the tropical northwest Pacific in summer following El Niño. Conversely, during the period when the NIO warming dissipates earlier, these atmospheric anomalies are not well developed. This supports the Indian Ocean capacitor concept as a mechanism prolonging El Niño influence into summer through the persistent Indian Ocean warming after El Niño itself has dissipated.

The above centennial modulation of ENSO teleconnection to the Indo–northwest Pacific region is reproduced in an atmospheric general circulation model forced by observed SST. The modulation is correlated not with the Pacific decadal oscillation but rather with the ENSO variance itself. When ENSO is strong, its effect in the Indo–northwest Pacific strengthens and vice versa. The fact that enhanced ENSO teleconnections occurred 100 years ago during the late nineteenth–early twentieth century indicates that the recent strengthening of the ENSO correlation over the Indo–western Pacific may not entirely be due to global warming but reflect natural variability.
Terminating the Last Interglacial: The Role of Ice Sheet–Climate Feedbacks in a GCM Asynchronously Coupled to an Ice Sheet Model
Authors: Herrington Adam R. , Poulsen Christopher J.
Published: September 2011

Climatic deterioration in northeastern Canada following the last interglacial resulted in the formation and abrupt expansion of the Laurentide Ice Sheet. However, the physical mechanisms leading to rapid ice sheet expansion are not well understood. Here, the authors report on experiments using an ice sheet model asynchronously coupled to a GCM to investigate the role of ice sheet–climate feedbacks in terminating the last interglacial period. In agreement with simpler models, the experiments indicate that a specific type of ice–albedo feedback, the small ice cap instability, is the dominant process controlling rapid expansion of the Laurentide Ice Sheet. As ice elevations increase in northeastern Canada, a stationary wave forms and strengthens over the Laurentide Ice Sheet, which acts to hinder further expansion of the ice margin and reduce the effect of the small ice cap instability. The sensitivity of these feedbacks to ice topography results in a reduction in simulated ice volume when the communication interval between the GCM and ice sheet model is lengthened since this permits larger gains in ice elevation between GCM updates and biases the simulation toward a stronger stationary wave feedback. The shortest communication interval (500 yr) leads to a Laurentide ice volume of 6 × 106 km3 in 10 kyr, which is less than ice volume estimates based on the geological record but is a substantial improvement over previous GCM studies. The authors discuss potential improvements to the asynchronous coupling scheme that would more accurately resolve ice sheet–climate feedbacks, potentially leading to greater simulated ice volume.
The Prolonged 1954 Midwestern U.S. Heat Wave: Impacts and Responses
Authors: Westcott Nancy E.
Published: September 2011

The highest recorded temperature in Illinois, 117°F (47.2°C) occurred on 14 July 1954 in East St. Louis. This occurred in the midst of a widespread, long-lasting heat wave covering significant parts of 11 states: from eastern Colorado through Kansas, Oklahoma, part of Texas, Missouri, and Arkansas, southern Illinois, and extending to western Tennessee, Alabama, Georgia, and parts of the Carolinas. According to historical climate data, this event ranked as one of the top five extended periods of heat in these states since 1895. No such prolonged heat wave has occurred in the Midwest since 1954. It stands to reason that since prolonged widespread heat waves have occurred in the last 100 years, there is a distinct possibility that they will occur again, and reviewing past impacts could help us plan for future events.

This research examines the impacts of the heat felt in the Illinois, Missouri, and Kansas region, as well as the responses to the extreme temperatures. Impacts on human health and well-being, water resources, utilities, agriculture, and commerce are described, as well as responses by individuals, communities, and governmental bodies. The extreme heat resulted in many deaths and much discomfort. Sizeable infrastructure repair costs from buckled streets and warped railroad ties were accrued in 1954. Energy and water resources were significantly strained. However, the most costly governmental interventions were those related to the agricultural community. Recent activities in heat wave and drought preparedness that may help alleviate impacts of future heat waves are discussed.
Meclizine Metabolism and Pharmacokinetics: Formulation on Its Absorption
Authors: Wang Zhijun , Lee Benjamin , Pearce Daniel , Qian Shuai , Wang Yanfeng , Zhang Qizhi , Chow Moses S. S.
Published: September 2011

Meclizine, an antihistamine, has been widely used for prophylactic treatment and management of motion sickness. However, the onset of action of meclizine was about 1 hour for the treatment of motion sickness and vertigo. A new suspension formulation of meclizine (MOS) was developed with the intention to achieve a rapid effect. To investigate the pharmacokinetics of the new MOS formulation versus the marketed meclizine oral tablet (MOT), a phase 1 pharmacokinetic study was performed in 20 healthy volunteers. In addition, an in vitro metabolic study using human hepatic microsome and recombinant CYP enzyme was also performed to determine the metabolic pathway in the human body. The plasma concentration of MOS appeared more rapidly in comparison to the MOT. The geometric mean ratios (90% confidence interval) of AUC0–24 and AUC0‐∞ indicated no significant difference in bioavailability between the 2 formulations. CYP2D6 was found to be the dominant enzyme for metabolism of meclizine, and its genetic polymorphism could contribute to the large interindividual variability. In view of the similar bioavailability with a much shorter peak time of the plasma meclizine concentration from the MOS formulation, this new formulation is expected to produce a much quicker onset of action when used for the management of motion sickness.
The media as ‘home-making’ tools: life story of a Filipino migrant in Milan
Authors: Bonini Tiziano
Published: September 2011

According the World Tourism Organization (UNWTO) there are 850 million international passenger arrivals each year; and according to the United Nations Refugee Agency (UNHCR), in 2008 there were 42 million refugees across the globe. The condition of mobility, in all its spatial and temporal variations is a condition of daily life in a globalized world. Even those who are lucky enough not to be forced to abandon their home are at times obliged to be away from home temporarily. A migrant who is far from his country, a seasonal worker or asylum seekers, all share a sense of displacement, more or less intense. This article addresses precisely the universe of migrants, with the aim of demonstrating that this existential condition can be alleviated and eventually ‘domesticated’ (albeit temporarily) thanks to the media. The article will explore the use of media on the part of migrants and the role of the media not only in temporarily connecting them to their private homes or to their public sphere of origin, but also in recreating the ‘warmth’ of domesticity, in other words in ‘making them feel at home’. The main part of the article will attempt to partially verify this thesis by presenting the case study of a Filipino family living in Milan.
Outsourcing the procurement of agency workers: the impact of vendor managed services in English social care
Authors: Hoque Kim , Kirkpatrick Ian , Lonsdale Chris , De Ruyter Alex
Published: September 2011

In recent years marked changes have occurred in the way employers recruit and select agency workers, with this activity increasingly being outsourced to third party organizations providing ‘vendor managed services’ (VMS). Drawing on data from a study of English social services, this article explores the consequences of this outsourcing. The findings reveal that although VMS has delivered cost savings, it has also resulted in less effective placement matching, rising line manager workloads and concerns about service quality. In the conclusion the wider implications of VMS for the future development of partnerships between employers and employment agencies are discussed.
The Cardioprotective Effect of Mildronate is Diminished After Co-Treatment With l-Carnitine
Authors: Kuka Janis , Vilskersts Reinis , Cirule Helena , Makrecka Marina , Pugovics Osvalds , Kalvinsh Ivars , Dambrova Maija , Liepinsh Edgars
Published: September 2011

Mildronate, an inhibitor of l-carnitine biosynthesis and uptake, is a cardioprotective drug whose mechanism of action is thought to rely on the changes in concentration of l-carnitine in heart tissue. In the present study, we compared the cardioprotective effect of mildronate (100 mg/kg) and a combination of mildronate and l-carnitine (100 + 100 mg/kg) administered for 14 days with respect to the observed changes in l-carnitine level and carnitine palmitoyltransferase I (CPT-I)-dependent fatty acid metabolism in the heart tissues. Concentrations of l-carnitine and its precursor γ-butyrobetaine (GBB) were measured by ultraperformance liquid chromatography with tandem mass spectrometry. In addition, mitochondrial respiration, activity of CPT-I, and expression of CPT-IA/B messenger RNA (mRNA) were measured. Isolated rat hearts were subjected to ischemia–reperfusion injury. Administration of mildronate induced a 69% decrease in l-carnitine concentration and a 6-fold increase in GBB concentration in the heart tissue as well as a 27% decrease in CPT-I-dependent mitochondrial respiration on palmitoyl-coenzyme A. In addition, mildronate treatment induced a significant reduction in infarct size and also diminished the ischemia-induced respiration stimulation by exogenous cytochrome c. Treatment with a combination had no significant impact on l-carnitine concentration, CPT-I-dependent mitochondrial respiration, and infarct size. Our results demonstrated that the mildronate-induced decrease in l-carnitine concentration, concomitant decrease in fatty acid transport, and maintenance of the intactness of outer mitochondrial membrane in heart mitochondria are the key mechanisms of action for the anti-infarction activity of mildronate.
A combined functional and structural genomics approach identified an EST-SSR marker with complete linkage to the Ligon lintless-2 genetic locus in cotton (Gossypium hirsutum L.)
Authors: Hinchliffe Doug J , Turley Rickie B , Naoumkina Marina , Kim Hee Jin , Tang Yuhong , Yeater Kathleen M , Li Ping , Fang David D
Published: September 2011

Background

Cotton fiber length is an important quality attribute to the textile industry and longer fibers can be more efficiently spun into yarns to produce superior fabrics. There is typically a negative correlation between yield and fiber quality traits such as length. An understanding of the regulatory mechanisms controlling fiber length can potentially provide a valuable tool for cotton breeders to improve fiber length while maintaining high yields. The cotton (Gossypium hirsutum L.) fiber mutation Ligon lintless-2 is controlled by a single dominant gene (Li

2
) that results in significantly shorter fibers than a wild-type. In a near-isogenic state with a wild-type cotton line, Li

2
is a model system with which to study fiber elongation.

Results

Two near-isogenic lines of Ligon lintless-2 (Li

2
) cotton, one mutant and one wild-type, were developed through five generations of backcrosses (BC5). An F2 population was developed from a cross between the two Li

2
near-isogenic lines and used to develop a linkage map of the Li

2
locus on chromosome 18. Five simple sequence repeat (SSR) markers were closely mapped around the Li

2
locus region with two of the markers flanking the Li

2
locus at 0.87 and 0.52 centimorgan. No apparent differences in fiber initiation and early fiber elongation were observed between the mutant ovules and the wild-type ones. Gene expression profiling using microarrays suggested roles of reactive oxygen species (ROS) homeostasis and cytokinin regulation in the Li

2
mutant phenotype. Microarray gene expression data led to successful identification of an EST-SSR marker (NAU3991) that displayed complete linkage to the Li

2
locus.

Conclusions

In the field of cotton genomics, we report the first successful conversion of gene expression data into an SSR marker that is associated with a genomic region harboring a gene responsible for a fiber trait. The EST-derived SSR marker NAU3991 displayed complete linkage to the Li

2
locus on chromosome 18 and resided in a gene with similarity to a putative plectin-related protein. The complete linkage suggests that this expressed sequence may be the Li

2
gene.
Effect of heme oxygenase-1 polymorphisms on lung function and gene expression
Authors: Tanaka Goh , Aminuddin Farzian , Akhabir Loubna , He Jian-Qing , Shumansky Karey , Connett John E , Anthonisen Nicholas R , Abboud Raja T , Paré Peter D , Sandford Andrew J
Published: September 2011

Background

Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.

Methods

We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.

Results

We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.

Conclusions

We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.
Epidemiological characteristics of Candida species colonizing oral and rectal sites of Jordanian infants
Authors: Issa Shireen Y , Badran Eman F , Akl Kamal F , Shehabi Asem A
Published: September 2011

Background

There is evidence that Candida colonization contributes to increasing invasion of candidiasis in hospitalized neonates. Few studies investigated the epidemiology and risk factors of Candida colonization among hospitalized and non-hospitalized infants. This prospective study investigated the major epidemiological characteristics of Candida species colonizing oral and rectal sites of Jordanian infants.

Methods

Infants aged one year or less who were examined at the pediatrics outpatient clinic or hospitalized at the Jordan University Hospital, Amman, Jordan, were included in this study. Culture swabs were collected from oral and rectal sites and inoculated on Sabouraud dextrose agar. All Candida isolates were confirmed by the Remel RapID yeast plus system, and further investigated for specific virulence factors and antifungal susceptibility MIC using E-test. Genotyping of C. albicans isolates was determined using random amplified polymorphic DNA (RAPD) analysis method.

Results

A total of 61/492 (12.4%) infants were colonized with Candida species by either their oral/rectal sites or both. Rectal colonization was significantly more detected than oral colonization (64.6% verses 35.4%), particularly among hospitalized infants aged more than one month. The pattern and rates of colonization were as follows: C. albicans was the commonest species isolated from both sites and accounted for 67.1% of all isolates, followed by C.kefyr (11.4%), each C. tropicalis and C. glabrata (8.9%) and C. parapsilosis (3.8%).

A various rates of Candida isolates proved to secrete putative virulence factors in vitro; asparatyl proteinase, phospholipase and hemolysin. C. albicans were associated significantly (P < 0.05) with these enzymes than other Candida species. All Candida isolates were susceptible to amphotericin B and caspofungin, whereas 97% of Candida species isolates were susceptible to fluconazole using E-test.

The genetic similarity of 53 C. albicans isolates as demonstrated by dendrogram revealed the presence of 29 genotypes, and of these one genotype accounted for 22% of the isolates.

Conclusion

This study presents important epidemiological features of Candida colonization of Jordanian infants.