bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis of hexaphyrins and N-fused pentaphyrins bearing pyridin-4-ylsulfanyl groups
Authors: Figueira Flávio , Farinha Andreia S.F. , Tomé Augusto C. , Cavaleiro José A.S. , Almeida Paz Filipe A. , Tomé João P.C.
Published: October 2014

In recent years much attention has been devoted to expanded macrocyclic chemistry. Nevertheless, while several advancements were achieved in the synthesis of novel expanded porphyrin architectures, not much has been developed in the functionalization of these macrocycles. This report shows the selective replacement of the p-fluorine atoms of meso-pentakis(pentafluorophenyl) N-fused [22]pentaphyrin and meso-hexakis(pentafluorophenyl) [26]hexaphyrin with 4-mercaptopyridine moieties, thus increasing their potential as ligands for coordination chemistry and catalysis or electronic transfer applications striving new synthetic methodologies and a new set of specific applications for this type of compounds.
A FRAMEWORK FOR OPEN INNOVATION ASSESSMENT
Authors: TSAI CHIEN-TZU , LIAO WAN-FEN
Published: October 2014

Innovation is the key for an organization to achieve sustainable development. Open innovation which emphasizes the integration of internal and external resources in an organization has brought about a new perspective in technological developments. In order to promote and ensure the performance of the open innovation, an assessment framework and the evaluation indicators are required. This study extracted dimensions from literatures and propose knowledge operation is an important element as well as knowledge exploitation and exploration in open innovation practice. After compiling opinions from both academic researchers and business experts and flowed into hierarchy analysis, "non-R&D employee involvement" was the most significant. The developed indicators were conducted in a survey to nine industrial parks and one science park to verify the reliability of assessment. The results reflected that the medium size company which has capability and awareness in open innovation usually falls into lower performance than they expected.
The Southern Uplands Terrane in Scotland – a notional controversy revisited
Authors: Stone Philip
Published: October 2014

Synopsis

Development of a regional geological interpretation for the Southern Uplands Terrane has been driven historically by advances in graptolite biostratigraphy, sandstone petrography and turbidite sedimentology (particularly the recognition of reliable way-up criteria), then, more recently, by a growing appreciation of the nature of accretionary processes at active plate margins. The latter has led to the widely held view of the terrane as an archetypal fossil accretionary prism, built up by the accretion at the margin of Laurentia of the sedimentary cover of Iapetus oceanic crust, the cover being stripped from the oceanic crust during its subduction beneath Laurentia. The achievement of this broad consensus has not been without controversy, which still persists in respect of some aspects of the overall model. Suggestions that the northernmost (Ordovician) part of the terrane might have originated in a back-arc basin have been disproved by a combination of mineral dating and basin thermal history analysis utilizing clay mineralogy. Nevertheless, it remains possible for that part of the terrane to have a continental margin, forearc depositional history. The southernmost (mid-Silurian) part of the terrane most probably developed in a foreland basin setting, as a fold-and-thrust belt overriding Avalonia, following the closure of the Iapetus Ocean. Progress in understanding the origins of the Southern Uplands Terrane has been achieved only by the collaborative application of multidisciplinary techniques – biostratigraphic, sedimentary, structural, geochemical and geophysical. This review is a tribute to all those who have contributed.

Supplementary material:

Coloured versions of the maps comprising Figure 1, showing details of the regional lithostratigraphy, are available at
http://www.geolsoc.org.uk/SUP18769
.
Structure and stratigraphy of the Morar Group in Knoydart, NW Highlands: implications for the history of the Moine Nappe and stratigraphic links between the Moine and Torridonian successions
Authors: Krabbendam M. , Leslie A. G. , Goodenough K. M.
Published: October 2014

Synopsis

The Caledonian Orogen in northern Scotland comprises two major thrust nappes: the Moine and the Sgurr Beag Nappe. The Moine Nappe contains early Neoproterozoic Morar Group rocks (Moine Supergroup) and basement inliers. This paper describes the structure and stratigraphy of the Knoydart peninsula, a key area within the southern Moine Nappe. The geology of Knoydart is dominated by a thick internally coherent sequence of Morar Group rocks. This sequence is shown to be deformed by large-scale, west-vergent and west-facing Caledonian (early Palaeozoic) folds that represent D
2
within the southern Moine Nappe. Subsequent D
3
deformation led to refolding or tightening of F
2
folds, so that the major Morar Antiform is, in essence, a composite F
2
/F
3
fold. F
2
and F
3
folds are broadly co-axial, but F
3
folds have steeper axial planes. The F
2
/F
3
folds refold a regional-scale, originally recumbent, isoclinal F
1
fold nappe of probable Knoydartian (mid-Neoproterozoic) age. The F
1
fold nappe is cored by a thin sliver of basement gneiss; the lower limb comprises migmatitic Morar Group rocks, exposed in the Morar Window. The upper limb of the F
1
fold nappe occupies most of Knoydart and is stratigraphically coherent and right-way-up. Within this sequence, the upper unit of the Lower Morar Psammite is barely deformed, preserving trough-cross-bedding and large-scale channels in thick beds. This suggests braided river deposition, similar to the Torridon Group west of the Moine Thrust and the Morar Group in the northern part of the Moine Nappe. On the basis of lithological similarity and stratigraphic disposition, it is suggested that the lowermost part of the Morar Group in Knoydart correlates with the Neoproterozoic Sleat Group on Skye.
Metabentonites from the Sandbian Stage, Upper Ordovician, in Scotland – a geochemical comparison with their equivalents in Baltoscandia
Authors: Batchelor Richard A.
Published: October 2014

Synopsis

Four metabentonites, including three new discoveries, are described from the Sandbian Stage, Upper Ordovician, of southern Scotland. They are compared geochemically with suites of more numerous contemporary metabentonites from Scandinavia. Two correlations are made with the Scandinavian suites that confirm relative stratigraphical age relationships. The Scottish examples represent distal ash falls from a volcanic source between Avalonia and Baltica.
New dinosaur and crocodylomorph material from the Middle Jurassic (Bathonian) Kilmaluag Formation, Skye, Scotland
Authors: Wills S. , Barrett P. M. , Walker A.
Published: October 2014

Synopsis

Archosaur specimens collected from the Kilmaluag Formation (Great Estuarine Group) of Cladach a’Ghlinne, Skye are described. These comprise crocodylomorph material; a pubis and group of osteoderms with an associated tooth; a theropod tooth; and a dinosaur limb bone. The material is regionally important as the Skye assemblage is dominated by aquatic amphibians and amphibious reptiles with terrestrial taxa being comparatively rare. The crocodylomorph pubis is referable to an indeterminate mesoeucrocodylian; the osteoderms and associated tooth to an indeterminate neosuchian. The Kilmaluag Formation has now yielded the only associated and articulated terrestrial/freshwater Middle Jurassic crocodylomorphs from the UK thus far. The theropod tooth is referable to an indeterminate theropod, and provides the first body fossil evidence of a small theropod taxon from the Bathonian of the Hebridean Basin. The dinosaur limb bone is regarded conservatively as an indeterminate dinosaur although it does possess possible theropod affinities.
Three centuries of open access to the caves in Stoney Middleton Dale Site of Special Scientific Interest, Derbyshire
Authors: Cope Mark A.
Published: October 2014

The limestone caves of Stoney Middleton Dale are a Site of Special Scientific Interest (SSSI) for features of geological interest, but have been open access since at least the eighteenth century and have a documented history of geotourism. Using the examples of Carlswark Cavern and Merlin Cavern, this chapter sets out evidence that 300 years of open access has resulted in significant disturbance to the features of geological interest. In particular, the integrity of the overall site for scientific research was affected by historical removal of speleothem formations long before it became a SSSI, with damage still occurring today. As most cave SSSIs in Derbyshire have historically had similar open-access arrangements, the examples presented highlight that there is potential for the integrity of less well historically documented caves elsewhere to have been disturbed. This article highlights the importance of establishing a baseline of historical disturbance to recognize whether the integrity of cave SSSIs have been affected and help monitor if disturbance is still occurring. For cave SSSIs to be useful for geological research, it is suggested that there is a need for the historical legacy of open access to individual caves elsewhere to be better understood.
Faster Parameterized Algorithms Using Linear Programming
Authors: Lokshtanov Daniel , Narayanaswamy N. S. , Raman Venkatesh , Ramanujan M. S. , Saurabh Saket
Published: October 2014

We investigate the parameterized complexity of
Vertex Cover
parameterized by the difference between the size of the optimal solution and the value of the linear programming (LP) relaxation of the problem. By carefully analyzing the change in the LP value in the branching steps, we argue that combining previously known preprocessing rules with the most straightforward branching algorithm yields an
O
*(2.618

k

) algorithm for the problem. Here,
k
is the excess of the vertex cover size over the LP optimum, and we write
O
*(
f
(
k
)) for a time complexity of the form
O
(
f
(
k
)
n

O
(1)

). We proceed to show that a more sophisticated branching algorithm achieves a running time of
O
*(2.3146

k

).

Following this, using previously known as well as new reductions, we give
O
*(2.3146

k

) algorithms for the parameterized versions of
Above Guarantee Vertex Cover
,
Odd Cycle Transversal
,
Split Vertex Deletion,
and
Almost 2-SAT
, and
O
*(1.5214

k

) algorithms for
König Vertex Deletion
and
Vertex Cover
parameterized by the size of the smallest odd cycle transversal and König vertex deletion set. These algorithms significantly improve the best known bounds for these problems. The most notable improvement among these is the new bound for
Odd Cycle Transversal
—this is the first algorithm that improves on the dependence on
k
of the seminal
O
*(3

k

) algorithm of Reed, Smith, and Vetta. Finally, using our algorithm, we obtain a kernel for the standard parameterization of
Vertex Cover
with at most 2
k
−
c
log
k
vertices. Our kernel is simpler than previously known kernels achieving the same size bound.
Demo hour
Authors: Dauner Joanna Maria , Karagozler Emre , Glisson Matthew , Speed Chris , Hartswood Mark , Laurier Eric , Magee Siobhan , Tynan-O'Mahony Fionn , de Jode Martin , Hudson-Smith Andrew , Harriman Jiffer , Feit Anna Maria , Oulasvirta Antti
Published: October 2014

During DIS 2014 Experience Night, conference attendees experienced a thought-provoking set of interactive systems, artworks, and techno-crafts. We selected interactive works that explore the reemergence of craft in the design of interactive systems, the role of craft in democratizing design, and the role of makers in interactive technology design. Alissa Antle and Steven Dow, DIS 2014 Demo Chairs
The usefulness of traditional usability evaluation methods
Authors: Lindgaard Gitte
Published: October 2014

This forum addresses conceptual, methodological, and professional issues that arise in the UX field's continuing effort to contribute robust information about users to product planning and design.
---David Siegel and Susan Dray, Editors
Protein kinase Cδ protects against bile acid apoptosis by suppressing proapoptotic JNK and BIM pathways in human and rat hepatocytes
Authors: Webster Cynthia R. L. , Johnston Andrea N. , Anwer M. Sawkat
Published: October 2014

Retained bile acids, which are capable of inducing cell death, activate protein kinase Cδ (PKC-δ) in hepatocytes. In nonhepatic cells, both pro- and antiapoptotic effects of PKC-δ are described. The aim of this study was to determine the role of PKC-δ in glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes and human HUH7-Na-taurocholate-cotransporting polypeptide (Ntcp) cells. Apoptosis was monitored morphologically by Hoechst staining and biochemically by immunoblotting for caspase 3 cleavage. The role of PKC-δ was evaluated with a PKC activator (phorbol myristate acetate, PMA) and PKC inhibitors (chelerythrine, H-7, or calphostin), PKC-δ knockdown, and wild-type (WT) or constitutively active (CA) PKC-δ. PKC-δ activation was monitored by immunoblotting for PKC-δ Thr505 and Tyr311 phosphorylation or by membrane translocation. JNK and Akt phosphorylation and the amount of total bisindolylmaleimide (BIM) were determined by immunoblotting. GCDC induced the translocation of PKC-δ to the mitochondria and/or plasma membrane in rat hepatocytes and HUH7-Ntcp cells and increased PKC-δ phosphorylation on Thr505, but not on Tyr311, in HUH7-Ntcp cells. GCDC-induced apoptosis was attenuated by PMA and augmented by PKC inhibition in rat hepatocytes. In HUH-Ntcp cells, transfection with CA or WT PKC-δ attenuated GCDC-induced apoptosis, whereas knockdown of PKC-δ increased GCDC-induced apoptosis. PKC-δ silencing increased GCDC-induced JNK phosphorylation, decreased GCDC-induced Akt phosphorylation, and increased expression of BIM. GCDC translocated BIM to the mitochondria in rat hepatocytes, and knockdown of BIM in HUH7-Ntcp cells decreased GCDC-induced apoptosis. Collectively, these results suggest that PKC-δ does not mediate GCDC-induced apoptosis in hepatocytes. Instead PKC-δ activation by GCDC stimulates a cytoprotective pathway that involves JNK inhibition, Akt activation, and downregulation of BIM.
Metastable and equilibrium phase diagrams of unconjugated bilirubin IXα as functions of pH in model bile systems: Implications for pigment gallstone formation
Authors: Berman Marvin D. , Carey Martin C.
Published: October 2014

Metastable and equilibrium phase diagrams for unconjugated bilirubin IXα (UCB) in bile are yet to be determined for understanding the physical chemistry of pigment gallstone formation. Also, UCB is a molecule of considerable biomedical importance because it is a potent antioxidant and an inhibitor of atherogenesis. We employed principally a titrimetric approach to obtain metastable and equilibrium UCB solubilities in model bile systems composed of taurine-conjugated bile salts, egg yolk lecithin (mixed long-chain phosphatidylcholines), and cholesterol as functions of total lipid concentration, biliary pH values, and CaCl2plus NaCl concentrations. Metastable and equilibrium precipitation pH values were obtained, and average pKavalues of the two carboxyl groups of UCB were calculated. Added lecithin and increased temperature decreased UCB solubility markedly, whereas increases in bile salt concentrations and molar levels of urea augmented solubility. A wide range of NaCl and cholesterol concentrations resulted in no specific effects, whereas added CaCl2produced large decreases in UCB solubilities at alkaline pH values only. UV-visible absorption spectra were consistent with both hydrophobic and hydrophilic interactions between UCB and bile salts that were strongly influenced by pH. Reliable literature values for UCB compositions of native gallbladder biles revealed that biles from hemolytic mice and humans with black pigment gallstones are markedly supersaturated with UCB and exhibit more acidic pH values, whereas biles from nonstone control animals and patients with cholesterol gallstone are unsaturated with UCB.
Assessment of cardiac output with transpulmonary thermodilution during exercise in humans
Authors: Calbet José A. L. , Boushel Robert
Published: October 2014

The accuracy and reproducibility of transpulmonary thermodilution (TPTd) to assess cardiac output (Q̇) in exercising men was determined using indocyanine green (ICG) dilution as a reference method. TPTd has been utilized for the assessment of Q̇ and preload indexes of global end-diastolic volume and intrathoracic blood volume, as well as extravascular lung water (EVLW) in resting humans. It remains unknown if this technique is also accurate and reproducible during exercise. Sixteen healthy men underwent catheterization of the right femoral vein (for iced saline injection), an antecubital vein (ICG injection), and femoral artery (thermistor) to determine their Q̇ by TPTd and ICG concentration during incremental one- and two-legged pedaling on a cycle ergometer and combined arm cranking with leg pedaling to exhaustion. There was a close relationship between TPTd-Q̇ and ICG-Q̇ ( r = 0.95, n = 151, standard error of the estimate: 1.452 l/min, P < 0.001; mean difference of 0.06 l/min; limits of agreement −2.98 to 2.86 l/min), and TPTd-Q̇ and ICG-Q̇ increased linearly with oxygen uptake with similar intercepts and slopes. Both methods had mean coefficients of variation close to 5% for Q̇, global end-diastolic volume, and intrathoracic blood volume. The mean coefficient of variation of EVLW, assessed with both indicators (ICG and thermal) was 17% and was sensitive enough to detect a reduction in EVLW of 107 ml when changing from resting supine to upright exercise. In summary, TPTd with bolus injection into the femoral vein is an accurate and reproducible method to assess Q̇ during exercise in humans.
Molecular Pathways: Intercellular PTEN and the Potential of PTEN Restoration Therapy
Authors: Hopkins Benjamin D. , Parsons Ramon E.
Published: October 2014

Phosphatase and Tensin homolog deleted on chromosome Ten (PTEN) acts as a tumor suppressor through both PI3K-dependent and -independent mechanisms. Reduced PTEN activity has been shown to affect not only tumor cell proliferation and survival but also the microenvironmental context in which nascent tumors develop. As a result of the multifaceted tumor-suppressive roles of PTEN, tumors evolve by selecting for clones in which PTEN activity is lost. PTEN activity within tumors can be modulated in numerous ways, including direct mutation, epigenetic regulation, and amplification or mutation of other proteins that can regulate or degrade PTEN. These events functionally prevent PTEN protein from acting within tumor cells. Paracrine roles for PTEN gene products (exosomal PTEN and PTEN-L) have recently been identified, through which PTEN gene products produced in one cell are able to enter recipient cells and contribute to PTEN functions. In preclinical models purified PTEN-L protein was able to enter tumor xenografts and downregulate PI3K signaling as well as cause tumor cell death. Here, we review the role of PTEN as a multifaceted tumor suppressor and reflect upon the potential for PTEN restoration therapy. Clin Cancer Res; 20(21); 5379–83. ©2014 AACR.
Ibrutinib for the Treatment of Mantle Cell Lymphoma
Authors: Herrera Alex F. , Jacobsen Eric D.
Published: October 2014

Ibrutinib (PCI-32765)—a potent, covalent inhibitor of Bruton tyrosine kinase (BTK), an important kinase in the B-cell receptor signaling pathway—was recently approved by the FDA for the treatment of relapsed or refractory mantle cell lymphoma (MCL). The drug was granted accelerated approval based on the findings of an international, multicenter, single-arm phase II study that enrolled patients with relapsed or refractory MCL. In the study, ibrutinib (560 mg daily) was well tolerated as a single agent and resulted in an overall response rate of 68% and an estimated median response duration of 17.5 months. Ibrutinib's response rate and duration of response compare favorably with those for other novel agents approved for the treatment of relapsed or refractory MCL, while being less toxic than most chemotherapy or chemoimmunotherapy regimens. Ibrutinib is currently being studied in combination with chemoimmunotherapy, monoclonal antibody therapy, and novel agents in both the initial and the relapsed/refractory treatment settings. We review the mechanism of action, preclinical and clinical development, and the role of ibrutinib in the context of other available treatments. Clin Cancer Res; 20(21); 5365–71. ©2014 AACR.
The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints
Authors: Llosa Nicolas J. , Cruise Michael , Tam Ada , Wicks Elizabeth C. , Hechenbleikner Elizabeth M. , Taube Janis M. , Blosser Richard L. , Fan Hongni , Wang Hao , Luber Brandon S. , Zhang Ming , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Sears Cynthia L. , Anders Robert A. , Pardoll Drew M. , Housseau Franck
Published: October 2014

We examined the immune microenvironment of primary colorectal cancer using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry, and functional analysis of tumor-infiltrating lymphocytes. A subset of colorectal cancer displayed high infiltration with activated CD8+ cytotoxic T lymphocyte (CTL) as well as activated Th1 cells characterized by IFNγ production and the Th1 transcription factor TBET. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly upregulated expression of multiple immune checkpoints, including five—PD-1, PD-L1, CTLA-4, LAG-3, and IDO—currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of colorectal cancer.

Significance: The findings reported in this article are the first to demonstrate a link between a genetically defined subtype of cancer and its corresponding expression of immune checkpoints in the tumor microenvironment. The mismatch repair–defective subset of colorectal cancer selectively upregulates at least five checkpoint molecules that are targets of inhibitors currently being clinically tested. Cancer Discov; 5(1); 43–51. ©2014 AACR.

See related commentary by Xiao and Freeman, p. 16

This article is highlighted in the In This Issue feature, p. 1
Basal and Resting Metabolic Rates of Physically Disabled Adult Subjects: A Systematic Review of Controlled Cross-Sectional Studies
Authors: Innocencio da Silva Gomes Ainá , dos Santos Vigário Patrícia , Mainenti Míriam Raquel Meira , de Figueiredo Ferreira Marina , Ribeiro Beatriz Gonçalves , de Abreu Soares Eliane
Published: October 2014

Aim: To systematically review studies that investigated the basal metabolic rate (BMR) and resting metabolic rate (RMR) of physically disabled adult subjects. Methods: The studies were identified via MedLine, Science Direct, Science Search, Scientific Electronic Library Online, Wiley, Latin American and Caribbean Health Sciences Literature, Cochrane, Indice Bibliográfico Espanõl de Ciencias de la Salud, Scopus, ProQuest Dissertations & Theses Database and System for Information on Grey Literature in Europe. No restriction on publication date was imposed. Results: Data from 6 studies were included. The results showed that physically disabled adult subjects have a lower BMR and/or RMR compared to nondisabled subjects. However, the difference between the groups disappeared when the BMR and RMR were adjusted for fat-free mass. Due to the small number of studies on this subject and the limited types of physical disabilities evaluated in the literature, we could not make a definitive conclusion. Conclusions: Disabled individuals seem to have a lower absolute BMR and/or RMR than able-bodied adults; however, this difference was not present or else it disappeared in half of the studies, after adjusting for body mass and/or fat-free mass.
Association between Pro12Ala, Pvull, Avall, Sstl and ADIPOQ Single-Nucleotide Polymorphisms with Lipid and Glycemic Profiles of Patients with Berardinelli-Seip Syndrome
Authors: Baracho Maria F.P. , Nunes Adriana B. , Hirata Mario H. , Hirata Rosario D.C. , Fajardo Christina M. , Santos Maria G.N. , Wajchenberg Bernardo L. , De Marco Luiz A. , Brandão-Neto José
Published: October 2014

Background/Aims: Berardinelli-Seip syndrome (BSS) is a recessive autosomal genetic disorder characterized by the near loss of adipose tissue with disturbance in lipid metabolism. Methods: Biochemical and hormonal parameters and Pro12Ala, Pvull, Avall, Sstl and ADIPOQ polymorphisms in 22 patients with BSS were analyzed and examined for a possible association with lipid profiles. Results: Parental consanguinity, insulin resistance and diabetes mellitus were observed in 63.6, 81.8 and 59.1% of patients, respectively. All individuals presented high triglyceride levels, and 68.1% of patients showed high cholesterol levels. The Pro/Pro genotype of the Pro12Ala polymorphism of the PPARγ2 gene was found in 86.3% of patients; the Ala/Ala variant was not observed in any patient. The PvuII polymorphism of the LPL gene showed a frequency of 50% for the P1P2 variant. The AvaII polymorphism of the LDLR gene showed a similar frequency of 40.9% for both CT and TT variants. The S1S1 genotype of the Sstl polymorphism of the APOC3 gene had a frequency of 86.3%. The CC allele of the ADIPOQ polymorphism of the adiponectin gene was found in 54.6% of patients. Conclusions: No association was found between lipid parameters and the relevant Pvull, Avall and Sstl polymorphisms. However, we did observe an association of the Pro12Ala and ADIPOQ polymorphisms with higher lipid levels, suggesting a close relationship between these factors.
Lenition of Intervocalic Alveolar Fricatives in Catalan and Spanish
Authors: Hualde José Ignacio , Prieto Pilar
Published: October 2014

We offer an acoustic study of variation in the realization of intervocalic alveolar fricatives in Catalan and Spanish. We consider the effects of phonological inventory (Catalan has a distinction between /s/ and /z/ that Spanish lacks) and position in word (i.e. effects of word boundaries). An analysis of a corpus of Map Task interviews in Catalan and Spanish revealed that Spanish word-medial and initial intervocalic /s/ segments are shorter than in Catalan. Whereas our results are consistent with the predictions of theories incorporating functional principles (i.e. contrast preservation), we also consider other possible explanations of the facts. The analysis also revealed that Spanish word-final intervocalic /s/ segments are weaker along the two dimensions that we examined (duration and voicing) than their initial and medial counterparts. We suggest that this apparently morphological effect on lenition has an articulatory explanation in terms of gestural coordination. © 2014 S. Karger AG, Basel
Visual Hallucinations in a Patient with Horner's Syndrome Secondary to Internal Carotid Dissection
Authors: Singh Amardeep , Mortzos Panteleimon , Sørensen Torben Lykke
Published: October 2014

A 67-year-old female presented with post-ganglionic Horner's syndrome. In addition to the classical symptoms of Horner's syndrome, the patient reported experiencing frightening complex visual and auditory hallucinations on two different occasions. Magnetic resonance angiography of the cerebrum, neck and upper thorax revealed internal carotid dissection. The symptoms and hallucinatory experiences resolved soon after antiplatelet therapy was commenced. We propose peduncular hallucinosis as the underlying mechanism.
Profound Amnesia after Temporal Lobectomy: An Autoimmune Process Resembling Patient H.M.
Authors: Bonello Michael , Larner Andrew J. , Marson Anthony G.
Published: October 2014

We describe a patient who developed significant cognitive decline with profound amnesia following non-dominant temporal lobectomy for refractory seizures, in whom the original suspicion of structural pathology was revised following the discovery of clinical and neuropathological markers of inflammation, neuropsychological evidence of bilateral involvement, and high titres of antibodies directed against glutamic acid decarboxylase (GAD). This case adds to the evidence that the diagnosis of non-paraneoplastic anti-GAD limbic encephalitis merits consideration in any patient with a refractory seizure disorder and cognitive decline.
Cutaneous Miliary Tuberculosis in a Chronic Kidney Disease Patient
Authors: Suraprasit Pudit , Silpa-archa Narumol , Triwongwaranat Daranporn
Published: October 2014

A 79-year-old Thai woman with advanced renal failure, dyslipidemia and anemia of chronic disease was admitted to hospital with prolonged fever, productive cough and multiple discrete small pustules on her face, trunk and extremities. A chest X-ray revealed diffuse miliary infiltration. Mycobacterium tuberculosis complex DNA was detected by polymerase chain reaction in sputum and scrapings of pustules from her skin. Blood culture identified M. tuberculosis complex. Pulmonary and cutaneous miliary tuberculosis was diagnosed. The patient's symptoms improved after 3 weeks of treatment with isoniazid, rifampicin, ethambutol and pyrazinamide. This report details a case of cutaneous miliary tuberculosis in a non-dialysis chronic kidney disease patient.
Targeting B Cells in Atherosclerosis
Authors: Tsiantoulas Dimitrios , Sage Andrew P. , Mallat Ziad , Binder Christoph J.
Published: October 2014

Atherosclerotic plaque formation is strongly influenced by different arms of the immune system, including B lymphocytes. B cells are divided into 2 main families: the B1 and the B2 cells. B1 cells are atheroprotective mainly via the production of natural IgM antibodies that bind oxidized low-density lipoprotein and apoptotic cells. B2 cells, which include follicular and marginal zone B cells, are suggested to be proatherogenic. Antibody-mediated depletion of B cells has become a valuable treatment option for certain autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis that are also characterized by the development of premature atherosclerosis. Thus, B cells represent a novel interesting target for therapeutic modulation of the atherosclerotic disease process. Here, we discuss the effect of different of B-cell subsets in experimental atherosclerosis, their mechanism of action as well as potential ways to exploit these findings for the treatment of human disease.
Prospective Association of Polycystic Ovary Syndrome With Coronary Artery Calcification and Carotid-Intima-Media Thickness
Authors: Calderon-Margalit Ronit , Siscovick David , Merkin Sharon S. , Wang Erica , Daviglus Martha L. , Schreiner Pamela J. , Sternfeld Barbara , Williams O. Dale , Lewis Cora E. , Azziz Ricardo , Schwartz Stephen M. , Wellons Melissa F.
Published: October 2014

Objective—

To study the independent associations of polycystic ovary syndrome (PCOS), and its 2 components, hyperandrogenism and anovulation, with coronary artery calcification (CAC) and carotid artery intima-media thickness (IMT).

Approach and Results—

At the year 20 of the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort of young adults, women (mean age, 45 years) with information on menses and hirsutism in their twenties were assessed for CAC (n=982) and IMT (n=988). We defined PCOS as women who had both irregular menses and hyperandrogenism (n=55); isolated oligomenorrhea (n=103) as women who only had irregular menses; and isolated hyperandrogenism (n=156) as women who had either hirsutism or increased testosterone levels. Logistic regressions and general linear models were used to estimate the associations between components of PCOS and subclinical CVD. The prevalence of CAC was 10.3% overall. Women with PCOS had a multivariable adjusted odds ratio of 2.70 (95% confidence interval, 1.31–5.60) for CAC. Women with either isolated oligomenorrhea or isolated hyperandrogenism had no increased risk of CAC when compared with unexposed women. Women with PCOS had significantly increased bulb and internal carotid-IMT measurements; however, no significant differences were noted in bulb or internal carotid artery IMT among women with either isolated oligomenorrhea or isolated hyperandrogenism when compared with unexposed women. There were no differences in common carotid-IMT among the 4 study groups.

Conclusions—

In this study, women with PCOS, manifested as both anovulation and hyperandrogenism, but not women with one of these manifestations alone, were at increased risk for the development of subclinical CVD.
Association Between Physical Activity and Peripheral Artery Disease and Carotid Artery Stenosis in a Self-Referred Population of 3 Million Adults
Authors: Stein Richard A. , Rockman Caron B. , Guo Yu , Adelman Mark A. , Riles Thomas , Hiatt William R. , Berger Jeffrey S.
Published: October 2014

Objective—

Although the relationship between physical activity and coronary heart disease is well characterized, a paucity of data exists on physical activity and vascular disease in other arterial territories. This study examined the prevalence of peripheral artery disease (PAD) and carotid artery stenosis (CAS) in association with physical activity.

Approach and Results—

The association between physical activity and vascular disease was examined in >3 million self-referred US participants in the United States from 2003 to 2008 who completed a medical and lifestyle questionnaire in the Life Line screening program. All subjects were evaluated by screening ankle brachial indices <0.90 for PAD and ultrasound imaging for CAS >50%. Multivariable logistic regression modeling was used to estimate odds of disease. Among 3 250 350 subjects, 63% of the population engaged in some leisure time vigorous physical activity. After adjustment for age, sex, race/ethnicity, hypertension, hypercholesterolemia, smoking status, diabetes mellitus, body mass index, and family history of cardiovascular disease, subjects who reported any physical activity had a significantly lower odds of PAD (odds ratio, 0.64; 95% confidence interval, 0.63–0.65) and CAS (odds ratio, 0.80; 95% confidence interval, 0.79–0.81). The association between physical activity with PAD and CAS was robust when stratified by sex, race, and age categories. Physical activity intensity frequency was associated with lower PAD and CAS in a graded manner (
P
trend <0.0001 for both). Findings seemed unaffected by confounding by comorbidity or indication.

Conclusions—

In a large population-based study, higher levels of physical activity were independently associated with lower odds of vascular disease in the lower extremities and carotid arteries.
Laminar Shear Stress Inhibits Endothelial Cell Metabolism via KLF2-Mediated Repression of PFKFB3
Authors: Doddaballapur Anuradha , Michalik Katharina M. , Manavski Yosif , Lucas Tina , Houtkooper Riekelt H. , You Xintian , Chen Wei , Zeiher Andreas M. , Potente Michael , Dimmeler Stefanie , Boon Reinier A.
Published: October 2014

Objective—

Cellular metabolism was recently shown to regulate endothelial cell phenotype profoundly. Whether the atheroprotective biomechanical stimulus elicited by laminar shear stress modulates endothelial cell metabolism is not known.

Approach and Results—

Here, we show that laminar flow exposure reduced glucose uptake and mitochondrial content in endothelium. Shear stress–mediated reduction of endothelial metabolism was reversed by silencing the flow-sensitive transcription factor Krüppel-like factor 2 (KLF2). Endothelial-specific deletion of KLF2 in mice induced glucose uptake in endothelial cells of perfused hearts. KLF2 overexpression recapitulates the inhibitory effects on endothelial glycolysis elicited by laminar flow, as measured by Seahorse flux analysis and glucose uptake measurements. RNA sequencing showed that shear stress reduced the expression of key glycolytic enzymes, such as 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3), phosphofructokinase-1, and hexokinase 2 in a KLF2-dependent manner. Moreover, KLF2 represses PFKFB3 promoter activity. PFKFB3 knockdown reduced glycolysis, and overexpression increased glycolysis and partially reversed the KLF2-mediated reduction in glycolysis. Furthermore, PFKFB3 overexpression reversed KLF2-mediated reduction in angiogenic sprouting and network formation.

Conclusions—

Our data demonstrate that shear stress–mediated repression of endothelial cell metabolism via KLF2 and PFKFB3 controls endothelial cell phenotype.
Heme Oxygenase-1 Gene Promoter Microsatellite Polymorphism Is Associated With Progressive Atherosclerosis and Incident Cardiovascular Disease
Authors: Pechlaner Raimund , Willeit Peter , Summerer Monika , Santer Peter , Egger Georg , Kronenberg Florian , Demetz Egon , Weiss Günter , Tsimikas Sotirios , Witztum Joseph L. , Willeit Karin , Iglseder Bernhard , Paulweber Bernhard , Kedenko Lyudmyla , Haun Margot , Meisinger Christa , Gieger Christian , Müller-Nurasyid Martina , Peters Annette , Willeit Johann , Kiechl Stefan
Published: October 2014

Objective—

The enzyme heme oxygenase-1 (HO-1) exerts cytoprotective effects in response to various cellular stressors. A variable number tandem repeat polymorphism in the HO-1 gene promoter region has previously been linked to cardiovascular disease. We examined this association prospectively in the general population.

Approach and Results—

Incidence of stroke, myocardial infarction, or vascular death was registered between 1995 and 2010 in 812 participants of the Bruneck Study aged 45 to 84 years (49.4% males). Carotid atherosclerosis progression was quantified by high-resolution ultrasound. HO-1 variable number tandem repeat length was determined by polymerase chain reaction. Subjects with ≥32 tandem repeats on both HO-1 alleles compared with the rest of the population (recessive trait) featured substantially increased cardiovascular disease risk (hazard ratio [95% confidence interval], 5.45 [2.39, 12.42];
P
<0.0001), enhanced atherosclerosis progression (median difference in atherosclerosis score [interquartile range], 2.1 [0.8, 5.6] versus 0.0 [0.0, 2.2] mm;
P
=0.0012), and a trend toward higher levels of oxidized phospholipids on apolipoprotein B-100 (median oxidized phospholipids/apolipoprotein B level [interquartile range], 11364 [4160, 18330] versus 4844 [3174, 12284] relative light units;
P
=0.0554). Increased cardiovascular disease risk in those homozygous for ≥32 repeats was also detected in a pooled analysis of 7848 participants of the Bruneck, SAPHIR, and KORA prospective studies (hazard ratio [95% confidence interval], 3.26 [1.50, 7.33];
P
=0.0043).

Conclusions—

This study found a strong association between the HO-1 variable number tandem repeat polymorphism and cardiovascular disease risk confined to subjects with a high number of repeats on both HO-1 alleles and provides evidence for accelerated atherogenesis and decreased antioxidant defense in this vascular high-risk group.
Vitamin D Therapy in Individuals With Prehypertension or Hypertension
Authors: Arora Pankaj , Song Yanna , Dusek Jeffery , Plotnikoff Gregory , Sabatine Marc S. , Cheng Susan , Valcour Andre , Swales Heather , Taylor Beth , Carney Erin , Guanaga Derek , Young Joseph R. , Karol Courtney , Torre Michael , Azzahir Atum , Strachan Semerit M. , O’Neill Dillon C. , Wolf Myles , Harrell Frank , Newton-Cheh Christopher , Wang Thomas J.
Published: October 2014

Background—

A large body of epidemiological and experimental evidence suggests that vitamin D deficiency may promote hypertension. This raises the possibility that vitamin D supplementation could be a simple intervention to reduce blood pressure, but data from prospective, randomized trials are limited.

Methods and Results—

A double-blind, randomized, controlled trial was conducted at 4 sites in the United States. We enrolled 534 individuals 18 to 50 years of age with low vitamin D status (25-hydroxyvitamin D levels ≤25 ng/mL) and systolic blood pressure of 120 to 159 mm Hg. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D
3
for 6 months. The primary end point was change in mean 24-hour systolic blood pressure. Secondary end points included change in ambulatory diastolic blood pressure and clinic systolic and diastolic blood pressures. The median age was 38 years, and 62% of participants were men. Forty-six percent of participants were white, and 48% were black. The median 25-hydroxyvitamin D level at baseline was 15.3 ng/mL. Four-hundred fifty-five participants (85%) had at least 1 follow-up blood pressure measurement; 383 participants (72%) completed the full 6-month study. At the end of the study, there was no significant difference in the primary end point (change in mean 24-hour systolic blood pressure, −0.8 versus −1.6 mm Hg in the high-dose and low-dose arms;
P
=0.71) or in any of the secondary end points. Furthermore, there was no evidence of association between change in 25-hydroxyvitamin D and change in 24-hour systolic blood pressure at 6 months (Spearman correlation coefficient, −0.05,
P
=0.34). Results were consistent across prespecified subgroups.

Conclusions—

Vitamin D supplementation did not reduce blood pressure in individuals with prehypertension or stage I hypertension and vitamin D deficiency. Our findings suggest that the association between vitamin D status and elevated blood pressure noted in observational studies is not causal.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01240512.
Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated With Dabigatran or Warfarin for Nonvalvular Atrial Fibrillation
Authors: Graham David J. , Reichman Marsha E. , Wernecke Michael , Zhang Rongmei , Southworth Mary Ross , Levenson Mark , Sheu Ting-Chang , Mott Katrina , Goulding Margie R. , Houstoun Monika , MaCurdy Thomas E. , Worrall Chris , Kelman Jeffrey A.
Published: October 2014

Background—

The comparative safety of dabigatran versus warfarin for treatment of nonvalvular atrial fibrillation in general practice settings has not been established.

Methods and Results—

We formed new-user cohorts of propensity score–matched elderly patients enrolled in Medicare who initiated dabigatran or warfarin for treatment of nonvalvular atrial fibrillation between October 2010 and December 2012. Among 134 414 patients with 37 587 person-years of follow-up, there were 2715 primary outcome events. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.80 (0.67–0.96); intracranial hemorrhage, 0.34 (0.26–0.46); major gastrointestinal bleeding, 1.28 (1.14–1.44); acute myocardial infarction, 0.92 (0.78–1.08); and death, 0.86 (0.77–0.96). In the subgroup treated with dabigatran 75 mg twice daily, there was no difference in risk compared with warfarin for any outcome except intracranial hemorrhage, in which case dabigatran risk was reduced. Most patients treated with dabigatran 75 mg twice daily appeared not to have severe renal impairment, the intended population for this dose. In the dabigatran 150-mg twice daily subgroup, the magnitude of effect for each outcome was greater than in the combined-dose analysis.

Conclusions—

In general practice settings, dabigatran was associated with reduced risk of ischemic stroke, intracranial hemorrhage, and death and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with nonvalvular atrial fibrillation. These associations were most pronounced in patients treated with dabigatran 150 mg twice daily, whereas the association of 75 mg twice daily with study outcomes was indistinguishable from warfarin except for a lower risk of intracranial hemorrhage with dabigatran.
Acute Hospital, Community, and Indirect Costs of Stroke Associated With Atrial Fibrillation
Authors: Hannon Niamh , Daly Leslie , Murphy Sean , Smith Samantha , Hayden Derek , Ní Chróinín Danielle , Callaly Elizabeth , Horgan Gillian , Sheehan Órla , Honari Bahman , Duggan Joseph , Kyne Lorraine , Dolan Eamon , Williams David , Wiley Miriam , Kelly Peter J.
Published: October 2014

Background and Purpose—

No economic data from population-based studies exist on acute or late hospital, community, and indirect costs of stroke associated with atrial fibrillation (AF-stroke). Such data are essential for policy development, service planning, and cost-effectiveness analysis of new therapeutic agents.

Methods—

In a population-based prospective study of incident and recurrent stroke treated in hospital and community settings, we investigated direct (healthcare related) and indirect costs for a 2-year period. Survival, disability, poststroke residence, and healthcare use were determined at 90 days, 1 year, and 2 years. Acute hospital cost was determined using a case-mix approach, and other costs using a bottom-up approach (2007 prices).

Results—

In 568 patients ascertained in 1 year (2006), the total estimated 2-year cost was $33.84 million. In the overall sample, AF-stroke accounted for 31% (177) of patients, but a higher proportion of costs (40.5% of total and 45% of nursing home costs). On a per-patient basis compared with non–AF-stroke, AF-stroke was associated with higher total (
P
<0.001) and acute hospital costs (
P
<0.001), and greater nursing home (
P
=0.001) and general practitioner (
P
<0.001) costs among 90-day survivors. After stratification by stroke severity in survivors, AF was associated with 2-fold increase in costs in patients with mild-moderate (National Institutes of Health Stroke Scale, 0–15) stroke (
P
<0.001) but not in severe stroke (National Institutes of Health Stroke Scale ≥16;
P
=0.7).

Conclusions—

In our population study, AF-stroke was associated with substantially higher total, acute hospital, nursing home, and general practitioner costs per patient. Targeted programs to identify AF and prevent AF-stroke may have significant economic benefits, in addition to health benefits.