bluuebunny/crossref_metadata_2025 huggingface dataset:
Alveolar ethmoidal rhabdomyosarcoma in a young adult male
Authors: Kelly Andrew , Moran Michael , Primrose William
Published: March 2013

We report a 22-year-old man who presented with a 3 week history of left-sided headache, orbital pain and epiphora progressing to diplopia. He was being treated by his general practitioner with a β-blocker and simple analgesia for possible diagnosis of cluster headaches. Initial examination revealed a reduction in visual acuity and poor abduction and upward gaze. Routine blood tests were normal. CT imaging was reported as a left ethmoid sinusitis with extension into a left orbit subperiosteal abscess. No pus was obtained on frontal sinus trephine and a biopsy was taken, which proved to be an alveolar-type rhabdomyosarcoma. The patient has completed a full course of chemoradiotherapy and has responded well to the treatment. His vision is back to normal and an MRI has shown complete regression of tumour.
Is the Surgical Safety Checklist successfully conducted? An observational study of social interactions in the operating rooms of a tertiary hospital
Authors: Cullati Stéphane , Le Du Sophie , Raë Anne-Claire , Micallef Martine , Khabiri Ebrahim , Ourahmoune Aimad , Boireaux Armelle , Licker Marc , Chopard Pierre
Published: March 2013

Objectives

To determine whether the items on the Time Out and the Sign Out of the Surgical Safety Checklist are properly checked by operating room (OR) staff and to explore whether the number of checked items is influenced by the severity of the intervention and the use of the checklist as a memory tool during the Time Out and the Sign Out periods.

Methods

From March to July 2010, data were collected during elective surgery at the Geneva University Hospitals, Switzerland. The main outcome was to assess whether each item of the Time Out and the Sign Out checklists have been checked, that is, ‘confirmed’ by at least one member of the team and ‘validated’ by at least one other member of the team. The secondary outcome was the number of validated items during the Time Out and the Sign Out.

Results

Time Outs (N=80) and Sign Outs (N=81) were conducted quasi systematically (99%). Items were mostly confirmed during the Time Out (range 100–72%) but less often during the Sign Out (range 86–19%). Validation of the items was far from optimal: only 13% of Time Outs and 3% of Sign Outs were properly checked (all items validated). During the Time Out, the validation process was significantly improved among the highest risk interventions (29% validation vs 15% among interventions at lower risk). During the Sign Out, a similar effect was observed (19% and 8%, respectively). A small but significant benefit was observed when using a printed checklist as a memory tool during the Sign Out, the proportion of interventions with almost all validated items being higher compared with those without the memory tool (20% and 0%, respectively).

Conclusions

Training on the proper completion of the checklist must be provided to OR teams. The severity of the interventions influenced the number of items properly checked.
Widening socioeconomic differences in mortality among men aged 65 years and older in Germany
Authors: Kibele Eva U B , Jasilionis Domantas , Shkolnikov Vladimir M
Published: March 2013

Background

Although socioeconomic mortality differences in Germany are well documented, trends in group-specific mortality and differences between the eastern and the western parts of the country remain unexplored.

Methods

Population and death counts by level of lifetime earnings (1995–1996 to 2007–2008) and broad occupational groups (1995–1996 to 2003–2004) for men aged 65 years and older were obtained from the German Federal Pension Fund. Directly standardised mortality rates and life expectancy at age 65 were used as mortality measures.

Results

Mortality declined in all socioeconomic groups in eastern and western Germany and these declines tended to be larger in higher status groups. Relative socioeconomic differences in age-standardised mortality rates and in life expectancy at age 65 widened over time. Absolute differences widened over the majority of time periods. The widening was more pronounced in eastern Germany.

Conclusions

Widening socioeconomic mortality differences in Germany, especially in eastern Germany, show that population groups did not benefit equally from the improvements in survival. The results suggest that special efforts have to be taken in order to reduce mortality among people with lower socioeconomic status, especially in eastern Germany. Health equity should be considered a priority when planning policies, practices, and changes in the healthcare system and related sectors.
Monitoring the bulk milk antibody response to BVDV: the effects of vaccination and herd infection status
Authors: Booth R. E. , Cranwell M. P. , Brownlie J.
Published: March 2013

Bovine Viral Diarrhoea Virus (BVDV) is a pestivirus in the flaviviridae family which affects cattle worldwide. Bulk milk (BM) antibody testing is frequently used as a relatively quick method of assessing herd BVDV exposure; however, an understanding of the effects of vaccination and historic infection is essential for test interpretation. This study investigated the trends exhibited by monthly BM antibody analysis in 14 herds split into three categories. Category 1 herds (vaccinating/no persistently infected (PI) animals) began the study with mid‐positive BM antibody titres and experienced an estimated increase of 0.007 optical density (OD) units per month (equating to a rise of 0.35 OD units in 50 months). Category 2 herds (not vaccinating/no PI animals) began the study with mid‐positive BM antibody titres and experienced an estimated decrease of 0.005 OD units per month with antibody levels in one category 2 herd taking 1290 days to decrease from mid‐positive to negative. Category 3 herds (vaccinating/PI animals present) began the study with high BM antibody titres which plateaued within this range throughout the 50‐month observation period. Vaccination was observed to cause transient increases in BM antibody in a number of herds in categories 1 and 3.
Thick-skinned tectonics in the Oriente foreland basin of Ecuador
Authors: Baby P. , Rivadeneira M. , Barragán R. , Christophoul F.
Published: March 2013

The Oriente Basin is part of the retro-arc foreland basin system that developed in the zone of transition between the Central Andes and the Northern Andes since Late Cretaceous times. It is deformed by thick-skinned tectonics related to the inversion of pre-Cretaceous extensional fault systems, which have broken the basin into three tectonic domains during three mean periods of inversion (Late Cretaceous–Palaeocene, Early Eocene and Miocene). The northern part of the present-day Sub-Andean wedge-top corresponded, during the Late Cretaceous, to the forebulge depozone. The NNE–SSW Sacha–Shushufindi Corridor (SSC) extends from the northern region of the Oriente foredeep to the Sub-Andean Cutucú Cordillera. It results from inversion of the Late Triassic–Early Jurassic rifting. The eastern Capiron–Tiputini Inverted System (CTIS) results from the inversion of the normal faults of the Late Jurassic back-arc basin. The Ishpingo–Tambococha–Tiputini (ITT) trend is located in the present-day forebulge depozone of the basin. This position presents favourable conditions for oil biodegradation. Source rocks throughout the Oriente Basin are immature or poorly mature. A large part of oil accumulations must be explained by long-distance migration from the west, before the Eocene uplift of the Cordillera Real, or from the south.
Thick-skinned tectonic style resulting from the inversion of previous structures in the southern Cordillera Oriental (NW Argentine Andes)
Authors: Carrera N. , Muñoz J. A.
Published: March 2013

Structures mapped in the southern Cordillera Oriental of the Andes show an unexpected geometry in an east–west cross-sectional view, with a remarkable predominance of west-directed thrusts. Although some of the Andean structures trend north–south perpendicular to the main east–west direction of Andean shortening, many of them clearly differ from this expected orientation. This peculiar structural style has been largely related to the inversion of the Cretaceous Salta Rift Basin; however, some of these anomalously trending Andean folds and faults do not result from the inversion of Cretaceous faults. This lack of inversion of some Cretaceous structures becomes evident where west-dipping extensional faults rest in the footwall of west-directed thrusts instead of developing east-directed thrusts, as would be expected. Detailed study of several structures and examination of the geometry and facies distribution of several basins highlight not only the role played by the inversion of Cretaceous extensional faults on the geometry of the Andean structures, but also that played by basement anisotropies on the development of both the Cretaceous extensional faults and the Andean contractional structures.
Along-strike extrusion at the transition between thin- and thick-skinned domains in the Pyrenean Orogen (northern Spain)
Authors: Carola E. , Tavani S. , Ferrer O. , Granado P. , Quintà A. , Butillé M. , Muñoz J. A.
Published: March 2013

In the south-verging portion of the western Pyrenean Orogen, a Mesozoic basin and part of the adjacent continental margin were deformed during the Pyrenean collisional stage. The slight obliquity between extensional and compressional trends, and the presence of a Mesozoic Transfer Zone, implied that both extensional domains were exposed along-strike of the belt in the same structural position. These two areas are not only characterized by the widespread reactivation of inherited fault systems but also by different styles of deformation related to the presence or absence of an evaporitic detachment level. To the east, in the Mesozoic basin, a large-displacement south-directed low-dipping thrust detached above Triassic evaporites is present. To the west, in the Mesozoic continental margin, thick-skinned and deeply rooted right-lateral and reverse faults become first-order elements. The presence of a strike-slip component produced the eastwards extrusion of the eastern portion of the Mesozoic continental margin, which imposed an along-strike shortening at the edge of the extruded block. The transitional area from thin- to thick-skinned style of deformation, from a dip-slip to a transpressive framework, and the area accommodating the extrusion are located along a north–south-orientated band representing the southern extension of a Mesozoic Transfer Zone.
Factors controlling selective abandonment and reactivation in thick-skin orogens: a case study in the Magdalena Valley, Colombia
Authors: Caballero Víctor , Parra Mauricio , Mora Andrés , López Cristina , Rojas Luis Ernesto , Quintero Isaid
Published: March 2013

The initial stages of tectonic inversion and the mechanisms of selective reactivation and abandonment of pre-existing normal faults during contractional orogenesis are explored in a partially buried Cenozoic thrust belt in the Andes of Colombia. A multidisciplinary approach that includes subsurface structural mapping, multimethod thermochronometry and detrital zircon U–Pb geochronology reveals the extent of a Palaeogene thrust belt buried underneath the Cenozoic strata of the Middle Magdalena Valley Basin. A less oblique orientation with respect to compressive stress and shorter traces in faults of the Middle Magdalena Valley Basin with respect to faults in the western part of the Eastern Cordillera, apparently acted as deformation inhibitors of the Magdalena faults in advanced Neogene stages of inversion. Protracted Cenozoic eastwards tilting of the Central Cordillera and the tectonic load from the uplifting Eastern Cordillera favoured the accumulation of a thick Cenozoic sedimentary sequence in an, at least episodically, closed basin. All the above-mentioned conditions helped to block deformation in the Magdalena Basin, favouring deformation to be taken up by structures in the western Eastern Cordillera. These relationships underscore the importance of buried structural records in elevated hinterland basins, in which the low-relief stratigraphic cover overlies a complex subsurface record, potentially including large magnitudes of deformation during early orogenesis.

Supplementary material:

Tables and figures on the laboratory methods for the thermochronometrical and geochronometrical analyses are available at
http://www.geolsoc.org.uk/SUP18601
.
Onset of fault reactivation in the Eastern Cordillera of Colombia and proximal Llanos Basin; response to Caribbean–South American convergence in early Palaeogene time
Authors: Bayona German , Cardona Agustin , Jaramillo Carlos , Mora Andres , Montes Camilo , Caballero Victor , Mahecha Hernando , Lamus Felipe , Montenegro Omar , Jimenez Giovanny , Mesa Andres , Valencia Victor
Published: March 2013

The inversion of Mesozoic extensional structures in the Northern Andes has controlled the location of syn-orogenic successions and the dispersal of detritus since latest Maastrichtian time. Our results are supported by detailed geological mapping, integrated provenance (petrography, heavy minerals, geochronology) analysis and chronostratigraphical correlation (palynological and geochronology data) of 13 areas with Palaeogene strata across the central segment of the Eastern Cordillera. Spatial and temporal variation of sedimentation rates and provenance data indicate that mechanisms driving the location of marginal and intraplate uplifts and tectonic subsidence vary among syn-orogenic depocentres. In the late Maastrichtian–mid-Palaeocene time, crustal tilting of the Central Cordillera favoured reverse reactivation of the western border of the former extensional Cretaceous basin. The hanging wall of the reactivated fault separated two depocentres: a western depocentre (in the Magdalena Valley) and an eastern depocentre (presently along the axial zone of the Eastern Cordillera, Llanos foothills and Llanos Basin). In late Palaeocene–early Eocene time, as eastern subduction of the Caribbean Plate and intraplate magmatics advanced eastwards, reactivation of older structures migrated eastwards up to the Llanos Basin and disrupted the eastern depocentre. In early Eocene time, these three depocentres were separated by two low-amplitude uplifts that exposed dominantly Cretaceous sedimentary cover. Syn-orogenic detrital sediments supplied from the eastwards-tilted Central Cordillera reached areas of the axial domain of the Eastern Cordillera, whereas unstable metamorphic and sedimentary fragments recorded in the easternmost depocentre were supplied by basement-cored uplifts with Cretaceous and Palaeozoic sedimentary cover reported in the southern Llanos Basin. This tectonic configuration of low-amplitude uplifts separating intraplate syn-orogenic depocentres and intraplate magmatic activity in Palaeocene time was primary controlled by subduction of the Caribbean Plate.

Supplementary material:

Appendix 1 presents detailed descriptions of analytical methods used in this manuscript. Appendixes 2 to 4 include raw data of sandstone petrography, heavy minerals and U–Pb detrital zircon geochronology, respectively. All this material is available at
http://www.geolsoc.org.uk/18597
.
Inversion tectonics under increasing rates of shortening and sedimentation: Cenozoic example from the Eastern Cordillera of Colombia
Authors: Mora Andrés , Reyes-Harker Andrés , Rodriguez Guillermo , Tesón Eliseo , Ramirez-Arias Juan Carlos , Parra Mauricio , Caballero Víctor , Mora José Pedro , Quintero Isaid , Valencia Víctor , Ibañez Mauricio , Horton Brian K. , Stockli Daniel F.
Published: March 2013

The Northern Andes of Colombia is a key locality for understanding tectonic inversion of symmetric rifts. A review of available data on structural geometry and deformation timing, and new thermochronology and provenance data from selected localities, enable the construction of balanced cross-sections and shortening budgets. During early deformation in the Palaeocene, most shortening was focused in the western sector of the orogen, in the Central Cordillera and the Magdallena Valley, although widely spaced and mild inversion occur in areas as far to the east as the Llanos Basin. After a period of tectonic quiescence in the Middle Eocene, deformation resumed across a former early Mesozoic graben in the Eastern Cordillera. Peak shortening rates and out-of-sequence reactivation of the main inversion faults were in place in latest Miocene time, during a phase of topographical growth. Our results indicate that coeval activation of basement highs and adjacent slower-slip shortcuts appear to be characteristic of inverted symmetric grabens. However, before reactivation and brittle faulting occur, strain hardening is required. Deformation rates in the Eastern Cordillera correlate with the westwards velocity of the South American Plate. A threshold convergence rate of approximately 2 cm year
−1
seems to be necessary to activate shortening in the upper plate.
Airway exposure to staphylococcal enterotoxin A potentiates allergen-induced bone marrow eosinophilia and trafficking to peripheral blood and airways
Authors: Squebola-Cola Dalize M. , Mello Glaucia C. , Pissinatti Lorenzo , Schenka André A. , Anhê Gabriel F. , DeSouza Ivani A. , Condino-Neto Antonio , Antunes Edson
Published: March 2013

Bone marrow (BM) eosinopoiesis is a common feature during allergen exposure in atopic individuals. Airway exposure to staphylococcal superantigens aggravates allergic airway disease and increases the output of BM eosinophils. However, the exact mechanisms regulating eosinophil mobilization and trafficking to the peripheral circulation and airways remain to be elucidated. Therefore, this study aimed to investigate the mechanisms determining the BM eosinopoiesis in allergic mice under exposure to staphylococcal enterotoxin A (SEA). Ovalbumin (OVA)-sensitized male BALB/C mice were intranasally exposed to SEA (1 μg), and at 4, 12, 24, and 48 h later animals were challenged with OVA (10 μg, twice a day). Measurement of IL-5, eotaxin, and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, flow cytometry for CCR3+, VLA4+, and CCR3+VLA4+, as well as adhesion assays to VCAM-1 were performed in BM. Prior airway exposure to SEA time dependently increased the BM eosinophil number in OVA-challenged mice. Eosinophils gradually disappear from peripheral blood, being recruited over time to the airways, where they achieve a maximal infiltration at 24 h. SEA exposure increased the levels of IL-5 and eotaxin (but not GM-CSF) in BM of OVA-challenged mice. Marked increases in CCR3+and CCR3+VLA4+expressions in BM eosinophils of OVA-challenged mice were observed, an effect largely reduced by prior exposure to SEA. Adhesion of BM eosinophils to VCAM-1 was increased in OVA-challenged mice, but prior SEA exposure abrogated this enhanced cell adhesion. Accumulation of BM eosinophils by airway SEA exposure takes place through IL-5- and CCR3-dependent mechanisms, along with downregulation of CCR3/VL4 and impaired cell adhesion to VCAM-1.
NFAT is required for spontaneous pulmonary hypertension in superoxide dismutase 1 knockout mice
Authors: Ramiro-Diaz Juan Manuel , Nitta Carlos H. , Maston Levi D. , Codianni Simon , Giermakowska Wieslawa , Resta Thomas C. , Bosc Laura V. Gonzalez
Published: March 2013

Elevated reactive oxygen species are implicated in pulmonary hypertension (PH). Superoxide dismutase (SOD) limits superoxide bioavailability, and decreased SOD activity is associated with PH. A decrease in SOD activity is expected to increase superoxide and reduce hydrogen peroxide levels. Such an imbalance of superoxide/hydrogen peroxide has been implicated as a mediator of nuclear factor of activated T cells (NFAT) activation in epidermal cells. We have shown that NFATc3 is required for chronic hypoxia-induced PH. However, it is unknown whether NFATc3 is activated in the pulmonary circulation in a mouse model of decreased SOD1 activity and whether this leads to PH. Therefore, we hypothesized that an elevated pulmonary arterial superoxide/hydrogen peroxide ratio activates NFATc3, leading to PH. We found that SOD1 knockout (KO) mice have elevated pulmonary arterial wall superoxide and decreased hydrogen peroxide levels compared with wild-type (WT) littermates. Right ventricular systolic pressure (RVSP) was elevated in SOD1 KO and was associated with pulmonary arterial remodeling. Vasoreactivity to endothelin-1 was also greater in SOD1 KO vs. WT mice. NFAT activity and NFATc3 nuclear localization were increased in pulmonary arteries from SOD1 KO vs. WT mice. Administration of A-285222 (selective NFAT inhibitor) decreased RVSP, arterial wall thickness, vasoreactivity, and NFAT activity in SOD1 KO mice to WT levels. The SOD mimetic, tempol, also reduced NFAT activity, NFATc3 nuclear localization, and RVSP to WT levels. These findings suggest that an elevated superoxide/hydrogen peroxide ratio activates NFAT in pulmonary arteries, which induces vascular remodeling and increases vascular reactivity leading to PH.
Cowden Syndrome-Related Mutations in PTEN Associate with Enhanced Proteasome Activity
Authors: He Xin , Arrotta Nicholas , Radhakrishnan Deepa , Wang Yu , Romigh Todd , Eng Charis
Published: March 2013

Germline mutations in PTEN have been described in a spectrum of syndromes that are collectively known as PTEN hamartoma tumor syndrome (PHTS). In addition to being mutated in the germline in PHTS, somatic loss-of-function PTEN mutations are seen in a wide range of sporadic human tumors. Here, we show evidence of upregulated proteasome activity in PHTS-derived lymphoblasts, Pten knock-in mice and cell lines expressing missense and nonsense PTEN mutations. Notably, elevated nuclear proteasome activity occurred in cells expressing the nuclear mislocalized PTEN-K62R mutant, whereas elevated cytosolic proteasome activity was observed in cells expressing the cytosolic-predominant mutant PTEN (M3M4 and C136R). Treatment with proteasome inhibitor MG-132 was able to restore both nonsense and missense mutant PTEN protein levels in vitro. PHTS patients with destabilizing PTEN mutations and proteasome hyperactivity are more susceptible to develop neurologic symptoms such as mental retardation and autism than mutation-positive patients with normal proteasome activity. A detailed molecular and functional analysis shows that PTEN mutants most likely cause proteasome hyperactivity via 2 different mechanisms, namely, induction of proteotoxic stress and loss of protein phosphatase activity. These results provide novel insights into the cellular functions of PTEN and reveal molecular mechanisms whereby PTEN mutations increase proteasome activity and lead to neurologic phenotypes. Cancer Res; 73(10); 3029–40. ©2013 AACR.
Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus
Authors: Hui Kwai Fung , Lam Benjamin H.W. , Ho Dona N. , Tsao Sai Wah , Chiang Alan K.S.
Published: March 2013

A novel drug combination of a proteasome inhibitor, bortezomib, and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), was tested in nasopharyngeal carcinoma (NPC), both in vitro and in vivo. Dose-response of different concentrations of bortezomib and SAHA on inhibition of cell proliferation of NPC was determined. Mechanisms of apoptosis and effects on lytic cycle activation of Epstein–Barr virus (EBV) were investigated. Combination of bortezomib and SAHA (bortezomib/SAHA) synergistically induced killing of a panel of NPC cell lines. Pronounced increase in sub-G1, Annexin V–positive, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL)–positive cell populations were detected after treatment with bortezomib/SAHA when compared with either drug alone. Concomitantly, markedly augmented proteolytic cleavage of PARP, caspase-3, -7, -8, and -9, reactive oxygen species (ROS) generation, and caspase-8–dependent histone acetylation were observed. ROS scavenger, N-acetyl cysteine, diminished the apoptotic effects of bortezomib/SAHA, whereas caspase inhibitor Z-VAD-FMK significantly suppressed the apoptosis without decreasing the generation of ROS. Bortezomib inhibited SAHA's induction of EBV replication and abrogated production of infectious viral particles in NPC cells. Furthermore, bortezomib/SAHA potently induced apoptosis and suppressed the growth of NPC xenografts in nude mice. In conclusion, the novel drug combination of bortezomib and SAHA is highly synergistic in the killing of NPC cells in vitro and in vivo. The major mechanism of cell death is ROS-driven caspase-dependent apoptosis. Bortezomib antagonizes SAHA's activation of EBV lytic cycle in NPC cells. This study provides a strong basis for clinical testing of the combination drug regimen in patients with NPC. Mol Cancer Ther; 12(5); 747–58. ©2013 AACR.
Bcl-2/Bcl-xL Inhibition Increases the Efficacy of MEK Inhibition Alone and in Combination with PI3 Kinase Inhibition in Lung and Pancreatic Tumor Models
Authors: Tan Nguyen , Wong Maureen , Nannini Michelle A. , Hong Rebecca , Lee Leslie B. , Price Stephen , Williams Karen , Savy Pierre Pascal , Yue Peng , Sampath Deepak , Settleman Jeffrey , Fairbrother Wayne J. , Belmont Lisa D.
Published: March 2013

Although mitogen-activated protein (MAP)–extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non–small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-xL (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture. Addition of the phosphatidylinositol 3-kinase (PI3K, PIK3CA) inhibitor GDC-0941 to this treatment combination increases cell killing compared with double- or single-agent treatment. Taken together, these data suggest the efficacy of agents that target the MAPK and PI3K pathways can be improved by combination with a Bcl-2 family inhibitor. Mol Cancer Ther; 12(6); 853–64. ©2013 AACR.
Metabolic Alterations in Lung Cancer–Associated Fibroblasts Correlated with Increased Glycolytic Metabolism of the Tumor
Authors: Chaudhri Virendra K. , Salzler Gregory G. , Dick Salihah A. , Buckman Melanie S. , Sordella Raffaella , Karoly Edward D. , Mohney Robert , Stiles Brendon M. , Elemento Olivier , Altorki Nasser K. , McGraw Timothy E.
Published: March 2013

Cancer cells undergo a metabolic reprogramming but little is known about metabolic alterations of other cells within tumors. We use mass spectrometry–based profiling and a metabolic pathway–based systems analysis to compare 21 primary human lung cancer–associated fibroblast lines (CAF) to “normal” fibroblast lines (NF) generated from adjacent nonneoplastic lung tissue. CAFs are protumorigenic, although the mechanisms by which CAFs support tumors have not been elucidated. We have identified several pathways whose metabolite abundance globally distinguished CAFs from NFs, suggesting that metabolic alterations are not limited to cancer cells. In addition, we found metabolic differences between CAFs from high and low glycolytic tumors that might reflect distinct roles of CAFs related to the tumor's glycolytic capacity. One such change was an increase of dipeptides in CAFs. Dipeptides primarily arise from the breakdown of proteins. We found in CAFs an increase in basal macroautophagy which likely accounts for the increase in dipeptides. Furthermore, we show a difference between CAFs and NFs in the induction of autophagy promoted by reduced glucose. In sum, our data suggest that increased autophagy may account for metabolic differences between CAFs and NFs and may play additional as yet undetermined roles in lung cancer. Mol Cancer Res; 11(6); 579–92. ©2013 AACR.
Biodegradation of the Outer Silicone Insulation of Endocardial Leads
Authors: Kołodzińska Agnieszka , Kutarski Andrzej , Kozłowska Marta , Grabowski Marcin , Marchel Halina , Drela Nadzieja , Opolski Grzegorz
Published: March 2013

Background—

Silicone catheter insulation, larynx prostheses undergo biodegradation. The aims of the study were to verify the conviction that outer silicone lead insulation is biostable and inert in addition to determining the role of macrophages (M) and
Staphylococcus aureus
(
S aureus
) strains in the silicone lead insulation degradation.

Methods and Results—

Leads removed from 8 patients because of infective and noninfective indications were analyzed with stereomicroscope and classified according to Banacha abrasion classification, and additional analysis using scanning electron microscope was performed. The examination revealed excavations of different shape and depth in the abraded areas. Fresh silicone-insulated lead was cut into fragments. The fragments were cultured with RAW 264.7 macrophage cell line for 9 weeks. Additional lead fragments were placed with
S aureus
strains: ATCC 25923, ATCC 29213, and K9328H. Lead fragments were also cocultured with the bacterial strains and RAW M. In scanning electron microscope analysis, diminution in silicone was observed. All
S aureus
strains provoked insulation damage after 9 weeks. The lowest level of degradation of insulation concerned ATCC 25923. Silicone lead fragments in cocultures presented a further gone level of silicone biodegradation.

Conclusions—

S aureus
, macrophages separately, and
S aureus
and macrophages cocultures initiate the biodegradation of silicone insulation. Differences in the level of biodegradation between strains of
S aureus
were observed, with the most aggressive reaction toward silicone visible in the cocultures. In vivo silicone biodegradation is initiated by tearing among surfaces of the lead insulation, macrophages may be the crucial cells for the process that may be aggravated by pathogen colonization.
Insights Into Atrioventricular Nodal Function From Patients Displaying Dual Conduction Properties
Authors: Mendenhall G. Stuart , Voigt Andrew , Saba Samir
Published: March 2013

Background—

There is a significant variability observed in the conduction properties of the atrioventricular node. In a subset of hearts, impulse transmission tends to fall into two distinct conduction regions, termed the slow and fast pathway, and a further subset are capable of dual conduction of a single input stimulus, termed double firing.

Methods and Results—

In this article, we closely characterize two distinct responses in patients with double firing properties of the atrioventricular node, separating these into discrete types: those with slow and fast pathway interaction and interdependence (interactive), and those with independent pathway properties (orthogonal). We use novel mathematical techniques to evaluate the relative decrement and unique properties of conduction during the overlapping slow and fast pathway conduction zones.

Conclusions—

Our analysis demonstrates two distinct patterns of pathway conduction in double firing patients, termed interactive and orthogonal. We show parallel overlapping segments of slow and fast pathway decremental conduction curves in interactive pathways, with no such findings with orthogonal conduction. These findings suggest anatomic correlates of pathway conduction, with interactive pathways likely having a common distal segment and orthogonal pathways able to independently activate downstream structures.
Echocardiography-Guided Left Ventricular Lead Placement for Cardiac Resynchronization Therapy
Authors: Saba Samir , Marek Josef , Schwartzman David , Jain Sandeep , Adelstein Evan , White Pamela , Oyenuga Olusegun A. , Onishi Tetsuari , Soman Prem , Gorcsan John
Published: March 2013

Background—

Cardiac resynchronization therapy improves mortality and morbidity in patients with heart failure (HF) with wide QRS complex and diminished left ventricular (LV) function, but response is variable.

Methods and Results—

The Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) was a prospective, double-blind, randomized controlled trial testing the hypothesis that an incremental benefit to cardiac resynchronization therapy would be gained by echo-guided (EG) transvenous LV lead placement versus a routine fluoroscopic approach. EG LV lead placement was attempted at the site of latest time to peak radial strain by speckle tracking echocardiography. The prespecified primary end point was first HF hospitalization or death. Of 187 New York Heart Association class II to IV patients with HF (62% ischemic; ejection fraction 26±6%; QRS 159±27 ms), 110 were randomized to EG and 77 to routine strategies. Primary events included 30 deaths and 37 HF hospitalizations over 1.8 years. Using intention-to-treat, patients randomized to an EG strategy had a significantly more favorable event-free survival (hazard ratio, 0.48; 95% confidence interval, 0.28–0.82;
P
=0.006). Exact or adjacent concordance of LV lead with latest site could be achieved in 85% of the EG group and occurred fortuitously in 66% of controls (
P
=0.010) and was associated with an improvement in event-free survival (hazard ratio, 0.40; 95% confidence interval, 0.22–0.71;
P
=0.002).

Conclusions—

A strategy of EG LV lead placement for cardiac resynchronization therapy improved patient outcomes by reducing the combined risk of death or HF hospitalizations and has implications for delivery of cardiac resynchronization therapy.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00156390.
Multicenter Prospective Observational Study on Acute and Chronic Heart Failure
Authors: Tavazzi Luigi , Senni Michele , Metra Marco , Gorini Marco , Cacciatore Giuseppe , Chinaglia Alessandra , Di Lenarda Andrea , Mortara Andrea , Oliva Fabrizio , Maggioni Aldo P. ,   on the behalf of IN-HF (Italian Network on Heart Failure) Outcome Investigators
Published: March 2013

Background—

Clinical observational studies on heart failure (HF) deal mostly with hospitalized patients, few with chronic outpatients, all with no or limited longitudinal observation.

Methods and Results—

This is a multicenter, nationwide, prospective observational trial on a population of 5610 patients, 1855 hospitalized for acute HF (AHF) and 3755 outpatients with chronic HF (CHF), followed up for 1 year. The cumulative total mortality rate at 1 year was 24% in AHF (19.2% in 797 patients with de novo HF and 27.7% in 1058 with worsening HF) and 5.9% in CHF. Cardiovascular deaths accounted for 73.1% and 65.3% and HF deaths for 42.4% and 40.5% of total deaths in AHF and CHF patients, respectively. One-year hospitalization rates were 30.7% in AHF and 22.7% in CHF patients. Among the independent predictors of 1-year all-cause death, age, low systolic blood pressure, anemia, and renal dysfunction were identified in both acute and chronic patients. A few additional variables were significant only in AHF (signs of cerebral hypoperfusion, low serum sodium, chronic obstructive pulmonary disease, and acute pulmonary edema), whereas others were observed only in CHF patients (lower body mass index, higher heart rate, New York Heart Association class, large QRS, and severe mitral regurgitation).

Conclusions—

In this contemporary data set, patients with CHF had a relatively low mortality rate compared with those with AHF. Rates of adverse outcomes in patients admitted for AHF remain very high either in-hospital or after discharge. Most deaths were cardiovascular in origin and ≈40% of deaths were directly related to HF.
Broad Suppression of NADPH Oxidase Activity Exacerbates Ischemia/Reperfusion Injury Through Inadvertent Downregulation of Hypoxia-inducible Factor-1α and Upregulation of Peroxisome Proliferator–activated Receptor-α
Authors: Matsushima Shouji , Kuroda Junya , Ago Tetsuro , Zhai Peiyong , Ikeda Yoshiyuki , Oka Shinichi , Fong Guo-Hua , Tian Rong , Sadoshima Junichi
Published: March 2013

Rationale:

NADPH oxidase (Nox) 2 and Nox4 are major components of the Nox family which purposefully produce reactive oxidative species, namely O
2
−
and H
2
O
2
, in the heart. The isoform-specific contribution of Nox2 and Nox4 to ischemia/reperfusion (I/R) injury is poorly understood.

Objective:

We investigated the role of Nox2 and Nox4 in mediating oxidative stress and myocardial injury during I/R using loss-of-function mouse models.

Methods and Results:

Systemic (s) Nox2 knockout (KO), sNox4 KO, and cardiac-specific (c) Nox4 KO mice were subjected to I/R (30 minutes/24 hours, respectively). Both myocardial infarct size/area at risk and O
2
−
production were lower in sNox2 KO, sNox4 KO, and cNox4 KO than in wild-type mice. Unexpectedly, however, the myocardial infarct size/area at risk was greater, despite less O
2
−
production, in sNox2 KO+cNox4 KO (double-KO) mice and transgenic mice (Tg) with cardiac-specific expression of dominant-negative Nox, which suppresses both Nox2 and Nox4, than in wild-type or single KO mice. Hypoxia-inducible factor-1α was downregulated whereas peroxisome proliferator–activated receptor-α was upregulated in Tg-dominant-negative Nox mice. A cross with mice deficient in prolyl hydroxylase 2, which hydroxylates hypoxia-inducible factor-1α, rescued the I/R injury and prevented upregulation of peroxisome proliferator–activated receptor-α in Tg-dominant–negative Nox mice. A cross with peroxisome proliferator–activated receptor-α KO mice also attenuated the injury in Tg- dominant–negative Nox mice.

Conclusions:

Both Nox2 and Nox4 contribute to the increase in reactive oxidative species and injury by I/R. However, low levels of reactive oxidative species produced by either Nox2 or Nox4 regulate hypoxia-inducible factor-1α and peroxisome proliferator–activated receptor-α, thereby protecting the heart against I/R, suggesting that Noxs also act as a physiological sensor for myocardial adaptation.
AMP-Activated Protein Kinase Regulates Endothelial Cell Angiotensin-Converting Enzyme Expression via p53 and the Post-Transcriptional Regulation of microRNA-143/145
Authors: Kohlstedt Karin , Trouvain Caroline , Boettger Thomas , Shi Lei , Fisslthaler Beate , Fleming Ingrid
Published: March 2013

Rationale:

High–angiotensin-converting enzyme (ACE)-levels are associated with cardiovascular disease, but little is known about the regulation of its expression.

Objective:

To assess the molecular mechanisms regulating endothelial ACE expression focusing on the role of the AMP-activated protein kinase (AMPK) and miR-143/145.

Methods and Results:

Shear stress decreased ACE expression in cultured endothelial cells, an effect prevented by downregulating AMPKα2 but not AMPKα1. AMPKα2
−/−
mice expressed higher ACE levels than wild-type littermates resulting in impaired hindlimb vasodilatation to the ACE substrate, bradykinin. The latter response was also evident in animals lacking the AMPKα2 subunit only in endothelial cells. In cultured endothelial cells, miR-143/145 levels were increased by shear stress in an AMPKα2-dependent manner, and miR-143/145 overexpression decreased ACE expression. The effect of shear stress was unrelated to an increase in miR-143/145 promoter activity and transcription but could be attributed to post-transcriptional regulation of precursor–miR-143/145 by AMPKα2. The AMPK substrate, p53, can enhance the post-transcriptional processing of several microRNAs, including miR-143/145. We found that shear stress elicited the AMPKα2-dependent phosphorylation of p53 (on Ser15), and that p53 downregulation prevented the shear stress–induced decrease in ACE expression. Streptozotocin–induced diabetes mellitus in mice was studied as a pathophysiological model of altered AMPK activity. Diabetes mellitus increased tissue phosphorylation of the AMPK substrates, p53 and acetyl-coenzyme A carboxylase, changes that correlated with increased miR-143/145 levels and decreased ACE expression.

Conclusions:

AMPKα2 suppresses endothelial ACE expression via the phosphorylation of p53 and upregulation of miR-143/145. Post-transcriptional regulation of miR-143/145 may contribute to the vascular complications associated with diabetes mellitus.
Economic Instruments for Biodiversity and Ecosystem Service Conservation & the EU State Aid Regulation†
Authors: Raitanen Elina , Similä Jukka , Siikavirta Kristian , Primmer Eeva
Published: March 2013

Many environmental services are not traded in markets but are rather public goods and their supply cannot easily be motivated by the market forces. This leads to underinvestment in the public goods relative to what would be socially desirable. Financial instruments are designed to modify behaviour by encouraging private individuals, organisations and businesses to participate actively in conservation. Nation states are ultimately responsible for providing public goods but the competition rules of the European Union restrict the use of economic instruments that constitute ‘state aid’ as defined in the Treaty on the Functioning of the European Union (TFEU). This article will analyse the regulatory frames under which economic incentives may constitute state aid in the meaning of 107 TFEU and the terms and conditions on which these aids may still be granted for land-owners.
Towards Adaptive Spatial Planning for Climate Change: Balancing Between Robustness and Flexibility
Authors: van Buuren Arwin , Driessen Peter P.J. , van Rijswick Marleen , Rietveld Piet , Salet Willem , Spit Tejo , Teisman Geert
Published: March 2013

Adaptation to climate change necessitates serious adjustments to the spatial organization of our environment. However, the uncertainties, the controversial character of the climate debate, the variety of climate change consequences and the inherently complex character of climate change puts specific demands on adapting spatial planning to climate change. Due to these characteristics of climate change, climate adaptation demands “adaptive spatial planning”. One of the main challenges is to balance between a robust and a flexible approach. On the one hand adaptive spatial planning tries to enable social and economic functions to flourish. On the other hand flexibility is required in finding creative combinations between the fulfillment of climate adaptation and other spatial interests. In this article we reconsider the strategic departure points for spatial planning (norms, values and principles), the interactive organization of planning processes, and the allocation of responsibilities, costs and benefits in planning processes which in our view constitute adaptive spatial planning practices in the context of climate change.
European and German Nature Conservation Instruments and their Adaptation to Climate Change—A Legal Analysis
Authors: Möckel Stefan , Köck Wolfgang
Published: March 2013

The article discusses the most significant legal problems facing the makers of conservation policy in the European Union and in Germany in adapting biodiversity to climate change. In the introduction, we give an overview of the possible consequences of climate change for species and landscapes and propose a number of adaptation measures. We then analyse and discuss three issues relating to the policy instruments of European and German environmental law: 1. the problems associated with protected areas in terms of justification and flexibility; 2. the need for more biotope networks, especially in agriculturally dominated landscapes; and 3. the potential and shortcomings of regional and local planning instruments.
Rethinking European Nature Conservation Legislation: Towards Sustainable Development
Authors: Kistenkas F.H.
Published: March 2013

European nature conservation law with its habitats assessment as demanded by Article 6 of the 1992 Habitats Directive is recently being regarded as rigid, rather static and not fully updated with modern sustainability and climate change demands.

As a consequence nature conservation law is said to be not always capable to facilitate sustainable development. A balancing of both ecology and socio-economic interests rather than a singular ecological criteria assessment might give way to sustainable combinations of land use in or nearby nature reserves.

While previous authors call for updating and restructuring the Habitats Directive, this paper argues that the EU legislative framework, consisting of European treaty law with its environmental law principles as well as the wording of Article 6 itself, already offers adequate opportunities to re-interpret the EU nature conservation directives within the context of sustainable land use, thus giving way to a less dogmatic approach entirely in line with modern sustainable development demands.
Broadcasters and Hidden Influentials in Online Protest Diffusion
Authors: González-Bailón Sandra , Borge-Holthoefer Javier , Moreno Yamir
Published: March 2013

This article explores the growth of online mobilizations using data from the indignados (outraged) movement in Spain, which emerged under the influence of the revolution in Egypt and as a precursor to the global Occupy mobilizations. The data track Twitter activity around the protests that took place in May 2011, which led to the formation of camp sites in dozens of cities all over the country and massive daily demonstrations during the week prior to the elections of May 22. We reconstruct the network of tens of thousands of users and monitor their message activity for a month (April 25, 2011, to May 25, 2011). Using both the structure of the network and levels of activity in message exchange, we identify four types of users and analyze their role in the growth of the protest. Drawing from theories of online activism and research on information diffusion in networks, this article centers on the following two questions: How does protest information spread in online networks? And how do different actors contribute to the growth of activity? The article aims to inform the theoretical debate on whether digital technologies are changing the logic of collective action and to provide evidence of how new media facilitates the emergence of massive offline mobilizations.
The Secular and the Religious in Tajikistan
Authors: Thibault Hélène
Published: March 2013

The increasing practice of Islam in Tajikistan in the last few years has contributed to rising social and political tensions. Based on ethnographic fieldwork conducted in Northern Tajikistan between May and October 2010, this article intends to highlight underlying religious tensions in Tajikistan, which, I argue, are the result of the emergence of conflicting voices contesting current political spaces. My intention is to revisit two concepts abundantly used in the religious literature. First, I intend to deconstruct the dichotomous relation between the state and society and try to uncover the power relations that lie behind the making, dissemination and understanding of narratives addressing the place of Islam in society. Second, I reconsider the categories of the secular and the religious by illustrating the porous character of these concepts in the Tajik context. I do so by providing accounts of local perceptions of religious politics expressed by politicians and bureaucrats, ordinary believers and representatives of the Islamic Revival Party of Tajikistan. Finally, I argue that the coexistence of different sets of religious and secular norms reveals that the struggle for political power in Tajikistan is now increasingly articulated around religious issues.