bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Traffic Noise on Highway Passing from Urban Agglomeration
Authors: Vijay Ritesh , Kori Chandan , Kumar Manoj , Chakrabarti T. , Gupta Rajesh
Published: September 2014

Assessment of traffic noise pollution in developing countries is complex due to heterogeneity in traffic conditions like traffic volume, road width, honking, etc. To analyze the impact of such variables, a research study was carried out on a national highway passing from an urban agglomeration. Traffic volume and noise levels (L10, L min , L max , L eq and L90) were measured during morning and evening peak hours. Contribution of noise by individual vehicle was estimated using passenger car noise unit. Extent of noise pollution and impact of noisy vehicles were estimated using noise pollution level and traffic noise index, respectively. Noise levels were observed to be above the prescribed Indian and International standards. As per audio spectrum analysis of traffic noise, honking contributed an additional 3–4 dB(A) noise. Based on data analysis, a positive relationship was observed between noise levels and honking while negative correlation was observed between noise levels and road width. The study suggests that proper monitoring and analysis of traffic data is required for better planning of noise abatement measures.
SIMULATION ON TISSUE DIFFERENTIATIONS FOR DIFFERENT ARCHITECTURE DESIGNS IN BONE TISSUE ENGINEERING SCAFFOLD BASED ON CELLULAR STRUCTURE MODEL
Authors: ZHANG XIANBIN , GONG HE
Published: September 2014

In bone tissue engineering, mechanical stimuli are among the key factors affecting cell proliferation and differentiation. This study aimed to investigate the effects of different inlet fluid velocities and axial strains on the differentiation of bone marrow mesenchymal stem cells (BMSCs) on the surface of scaffolds with different morphologies. Five three-dimensional bone scaffold architectures with 65% porosity were designed using typical cellular structural models of trabecular bone. Apparent compressive strains between 0% and 5% were applied to simulate an unconfined compression test. Strain distributions were analyzed on the wall surface of the solid model. The interstitial fluid flow at inlet velocities ranging between 0.01 mm/s and 1 mm/s was applied to interconnected pores, simulating a steady state flow in the scaffold. The shear stress distributions on the surface of the scaffolds were calculated. The differentiation of BMSCs on the surface of the scaffolds with different morphologies was predicted according to mechanoregulation theory. This study shows that different levels of mechanical stimuli can be generated as a result of different scaffold morphologies under compressive loading and fluid flow to satisfy the mechanical requirements for different bone defect sites.
INFLUENCE OF A LIQUID ON THE NATURAL FREQUENCIES OF ALMOST CIRCULAR PLATES
Authors: GASCÓN-PÉREZ MANUEL , GARCÍA-FOGEDA PABLO
Published: September 2014

In this work, the influence of the surrounding fluid on the dynamic characteristics of almost circular plates is investigated. First the natural frequencies and normal modes for the plates in vacuum are calculated by a perturbation procedure. The method is applied for the case of elliptical plates with a low value of eccentricity. The results are compared with other available methods for this type of plates with good agreement. Next, the effect of the fluid is considered. The normal modes of the plate in vacuum are used as a base to express the vibration mode of the coupled plate-fluid system. By applying the Hankel transformation the nondimensional added virtual mass 2 increment (NAVMI) are calculated for elliptical plates. Results of the NAVMI factors and the effect of the fluid on the natural frequencies are given and it is shown that when the eccentricity of the plate is reduced to zero (circular plate) the known results of the natural frequencies for circular plates surrounded by liquid are recovered.
MODELING THE SIZE DEPENDENT STATIC AND DYNAMIC PULL-IN INSTABILITY OF CANTILEVER NANOACTUATOR BASED ON STRAIN GRADIENT THEORY
Authors: SEDIGHI HAMID M. , KOOCHI A. , ABADYAN M.
Published: September 2014

It is well-established that mechanical behavior of nanoscale systems is size dependent. In this paper, strain gradient elasticity theory is used for mathematical modeling of size dependent electromechanical instability of cantilever nanoactuator. The nanoactuator is modeled using Euler–Bernoulli beam theory and equation of motion is derived using Hamilton's principle. In order to solve the nonlinear governing equation, reduced order method (ROM) is employed. The dynamic pull-in instability of the nanoactuator is investigated through plotting the time history and phase portrait of the system. Static and dynamic pull-in voltage of nanoactuator as a function of dimensionless length scale parameters is determined. The obtained results show that when thickness of the nanoactuator is comparable with the intrinsic material length scales, size effect can substantially influence the pull-in behavior of the system.
Chapter 11 The Iberian Mediterranean shelves
Authors: Lobo F. J. , Ercilla G. , Fernández-Salas L. M. , Gámez D.
Published: September 2014

The Iberian Mediterranean shelves are divided into three different geographical segments (the Northeastern Shelf, the Southeastern Shelf and the Northern Alboran Sea Shelf), the understanding of which has evolved over the years. The best known sector is the Northeastern Shelf, comprising the narrow, abrupt and prograding Catalonia Shelf and the wider, prograding Ebro Shelf–Gulf of Valencia, where pioneering Spanish marine geology studies have been conducted since the 1970s. The knowledge of the Quaternary stratigraphic architecture of the Northeastern Shelf is very detailed, and provides an outstanding example of regressive–transgressive cycles leading to shelf build-up with various margin configurations. The Southeastern Shelf exhibits a change of margin configuration from intermediate to abrupt in response to declining fluvial influence. The knowledge of this shelf is limited in comparison with the rest of the Iberian Mediterranean shelves. Abundant studies have also been performed on the Northern Alboran Sea Shelf, which, in contrast to the Northeastern Shelf, does not have a major fluvial source but numerous short, mountain rivers draining from the Betic Cordillera. For this shelf, a high-resolution sequence stratigraphy model has been proposed for the most recent Late Quaternary depositional sequence.
Chapter 13 Hellenic shelf: late Quaternary tectonics, sea-level changes, sedimentation and geohazards
Authors: Ferentinos G. , Lykousis V. , Papatheodorou G. , Iatrou M.
Published: September 2014

The Hellenic shelf lies within and around the Aegean microplate, which is one of the world's most seismically active areas, and has experienced extreme tectonism throughout Quaternary time. This activity, together with eustatic sea-level changes and water-circulation patterns over the same time period, controls the overall configuration of the Hellenic shelf, the rates of uplift and subsidence, and determines the sediment supply and depot centre, as well as the sediment-transfer processes. The above-mentioned geological processes are the causative factors for the frequent occurrence of a variety of geological hazards, such as active faults, submarine gravitational mass movements, tsunami and active gas seeping from the seabed.
Chapter 14 Late Quaternary sea-level change on the Black Sea shelves
Authors: Nicholas W. A. , Chivas Allan R.
Published: September 2014

The continental shelf of the microtidal Black Sea, with its 4125 km-long coastline, has an average width of
c.
40 km and may be subdivided into seven regions, the largest of these being the NW Shelf and the SW Shelf. Palimpsest shelf environments and terrestrially derived siliciclastic sedimentation are dominant. The Marmara Gateway, bisecting the southwestern shelf, controls the influx of Mediterranean-sourced water into the semi-enclosed Black Sea, and has been episodically open during the Quaternary. The best evidence for the most recent marine transgression of the pre-existing and isolated lake is found on the mid- and outer NW Shelf. Radiocarbon dating of marine and non-marine bivalve molluscs and peat indicates the most recent re-connection of the Black Sea with the oceanic reservoir occurred between 8200 and 8600
14
C years BP. Water levels during the transgression in the enclosed lake rose from a level 107 m or more below present values, to above the Bosphorus Sill (−35 m) in about 400
14
C years. However, the transition from low-salinity (0–5‰) lacustrine conditions to near-modern values (18‰) took ≥1000 years, indicated by the progression from freshwater to brackish molluscs and gastropods, dominated by
Dreissena
, to Mediterranean-derived estuarine taxa (e.g.
Mytilus
), suited to nutrient-rich conditions.
Chapter 17 The Myanmar continental shelf
Authors: Ramaswamy V. , Rao P. S.
Published: September 2014

The Myanmar (Burma) coastline is about 2280 km long, with the continental shelf covering an area of approximately 230 000 km
2
. The Myanmar coastline may be divided into the northern Rakhine (Arakan) coast, the central Ayeyarwady coast and the southern Tanintharyi (Tenasserim) coast. The Rakhine coast lies adjacent to the Bay of Bengal, while the Ayeyarwady and Tanintharyi coast faces the Andaman Sea. The continental shelf of Myanmar receives sediments from some of the largest rivers in the world like the Ayeyarwady (Irrawaddy), the Salween (Thanlwin) and the Ganges–Brahmaputra rivers. The Myanmar shelf is characterized by a seasonal reversal of monsoon winds and coastal currents, periodic tropical cyclones and storm surges, meso- to macrotidal conditions, and neotectonic activity. The most prominent bathymetric feature on the Ayeyarwady continental shelf is the 120 km-wide Martaban Depression, at the centre of which is located the Martaban Canyon. Most of the suspended sediment discharge of the Ayeyarwady is transported eastwards by coastal and tidal currents, and trapped in the Gulf of Martaban, resulting in the formation of an extensive mud belt covering an area of more than 45 000 km
2
. Because of these features, the Myanmar shelf ranks amongst the most globally important continental shelves in the world but remains inadequately studied owing to its inaccessibility.
Chapter 2 Continental shelves of Atlantic Canada
Authors: Shaw John , Todd Brian J. , Li Michael Z. , Mosher David C. , Kostylev Vladimir E.
Published: September 2014

The wide continental shelves of Atlantic Canada are characterized by a series of banks separated by transverse troughs. These shelves have been imprinted by repeated Quaternary glaciations, so that fluvial valleys have been deepened into fjords and shelf-crossing troughs, and a suite of glacigenic sediments has been deposited. In shallow areas the seafloor is shaped by waves and currents, including the strong tidal currents of the macrotidal Bay of Fundy. Glacigenic sediments have been reworked by modern processes to yield thick muds in basins, and thinner deposits of sand and gravel on wave-dominated banks and the littoral zone. As a result of a cold climate and the Labrador Current, seasonal sea ice occurs to varying degrees across the region, and iceberg impact continues on much of the Newfoundland and Labrador shelves. For the purpose of description, we divide Atlantic continental shelves into four regions and focus on advances in understanding over the past several decades relating to: (1) processes on upper continental slopes; (2) glacial history in the last glacial cycle; (3) glacial land systems; (4) geographical changes caused by glacio-isostasy; and (5) sediment mobility on the offshore banks. We conclude with a brief overview of the biota.
Chapter 20 The continental shelves of SE Australia
Authors: Murray-Wallace Colin V.
Published: September 2014

The continental shelves of SE Australia from the eastern Great Australian Bight to southern New South Wales are situated within a tectonically stable, passive continental margin. The shelves began to develop during Late Cretaceous time and preserve a rich but punctuated record of shallow-marine sedimentation from the Late Paleocene to the present day. The southern margin is the world's largest modern, cool-water temperate carbonate sediment province, a function of the limited terrigenous-clastic sediment being delivered to the coast in response to continental-scale aridity, endorheic drainage and low topographical relief. With the exception of the South Australian gulfs and the protected portions of Bass Strait, the entire shelf sector of SE Australia is a high-energy, storm- and swell-dominated, microtidal province. Along the southern margin, the dominant sedimentary constituents in the modern shelf sediments are skeletal carbonate bioclasts derived from marine invertebrates that include molluscs, foraminifers, bryozoans, coralline algae and echinoids, variably intermixed with quartz sand and heavy minerals (Heterozoan Association). Sediments of Pleistocene and Holocene age are compositionally similar to their modern equivalents, and all show varying degrees of reworking and incorporation of older bioclasts to form the palimpsest sedimentary successions that characterize the entire region. The southern New South Wales sector of the Eastern Australian Shelf is dominated by siliciclastic sediments but preserves relict molluscan-rich carbonate sediments of glacial-age lowstand origin in the outer-shelf region in present water depths exceeding 100 m. The Quaternary stratigraphical record of the SE Australian continental shelves is dominated by successions that formed in the last glacial cycle, but older, inner-shelf successions have been documented from geographically restricted regions such as the South Australian gulfs, Roe and Coorong coastal plains, and the Bass Strait Islands. The outer-shelf successions are not in hydrodynamic equilibrium with modern shelf processes, as reflected in the paucity of mud, and are either largely relict (New South Wales) or dominated by complex modern bryozoan associations.
Chapter 22 Pacific margin, Canada shelf physiography: a complex history of glaciation, tectonism, oceanography and sea-level change
Authors: Barrie J. Vaughn , Hetherington Renée , Macleod Roger
Published: September 2014

Canada's western continental shelf can be broadly divided into three geographical regions: Salish Sea, Pacific North Coast and Vancouver Island Shelf. Each region's physiography has been uniquely impacted by a history of glaciation, tectonism, oceanography and sea-level change. Retreat of the Fraser Glaciation started from the Pacific towards the mainland of British Columbia first in the north on Haida Gwaii (16
14
C ka BP) then outer Vancouver Island (14
14
C ka BP), and generally progressed east with ice persisting on the Fraser lowland and northern British Columbia mainland, and possibly the central interbasin coast, until after 10
14
C ka BP. Retreat on the Pacific North Coast was rapid, while downwasting and stagnation occurred in the Salish Sea. Sea levels responded to this deglacial history, with submergence of most of the Salish Sea by over 250 m before 12
14
C ka BP then falling to approximately 100 m where it remained until approximately 10
14
C ka BP, and emergence of the Vancouver Island Shelf with the development of a forebulge. In contrast, the Pacific North Coast crustal loading of the British Columbia mainland and development of a peripheral forebulge towards Haida Gwaii resulted in submergence of the mainland by 120 m and emergence of the western basin by more than 120 m, with regional variation throughout. Holocene sedimentation is primarily restricted to the coastal inlets and fjords, except for the southern Salish Sea off the Fraser River.
Chapter 23 Continental shelves as sediment capacitors or conveyors: source-to-sink insights from the tectonically active Oceanside shelf, southern California, USA
Authors: Covault Jacob A. , Fildani Andrea
Published: September 2014

Continental shelves are the key interfaces between terrestrial sediment source areas and deep-sea depositional systems, promoting the transfer of sediment across continental margins. Work on shelves in the context of entire continental-margin sediment-routing systems has focused on their importance as capacitors of sediment during several to tens of thousands of years of post-glacial shoreline transgression and sea-level highstand. We demonstrate that the tectonically active Oceanside shelf offshore southern California has served as an efficient conveyor of sediment from land to the deep sea during millennia of significant climatic fluctuations. This conveyance is a result of littoral drift of sediment to canyon heads at narrow segments of the shelf. We compare insights from the Oceanside shelf to other shelves across the tectonically active Pacific margin of the United States, and demonstrate the importance of shelf width, climatic forcings and timescale of observation in assessing the role of shelves as sediment capacitors or conveyors.
Chapter 24 Geometry of the coastline and morphology of the convergent continental margin of Ecuador
Authors: Dumont Jean François , Santana Essy , Bonnardot Marie-Aude , Pazmiño Nelson , Pedoja Kevin , Scalabrino Bruno
Published: September 2014

The pacific border of the South American plate presents a more or less symmetrical sinuosity, with a central concave curvature (the Arica Angle located between two side rays along Chile and Peru) and ending in convex arcs (the Patagonian and Talara arcs, respectively). The width of the continental and coastal margins varies significantly according to the geometry of the border. The continental margin of Ecuador corresponds to the northern part of the Talara Arc. Three different segments showing different coastal geomorphology and continental platform characteristics are identified from north to south: the northern segment (Mataje River–Galera Point) shows a wide continental shelf and slope, the upper subducted slab of the subduction plane presents a low dip; the central segment (Galera Point–Santa Elena) stands in front of the Carnegie Ridge, and presents a moderate uplift in the Manta Peninsula, in front of the Carnegie Ridge, and the upper subduction plane is subhorizontal; the southern segment includes the side and inner coasts of the Gulf of Guayaquil, below the gulf the subduction plane shows a low dip. A comparison with published 3D numerical modelling of curved subduction suggests that the geometry of the continental boundary has a significant effect on uplift or subsidence along the continental margin. Also, the subduction of asperities in the trench, such as the Carnegie Ridge, may change the coastal motion from subsiding to uplifting, as is observed in the Esmeraldas area. There is no clear evidence of a shelf developed during the Last Glacial Maximum (LGM) sea-level lowstand, probably due to the vertical motion – uplift or subsidence – observed all along the coastal margin.
Chapter 3 History of continental shelf and slope sedimentation on the US middle Atlantic margin
Authors: Miller Kenneth G. , Browning James V. , Mountain Gregory S. , Sheridan Robert E. , Sugarman Peter J. , Glenn Scott , Christensen Beth A.
Published: September 2014

We describe sedimentation on the storm-dominated, microtidal, continental shelf and slope of the eastern US passive continental margin between the Hudson and Wilmington canyons. Sediments here recorded sea-level changes over the past 100 myr and provide a classic example of the interplay among eustasy, tectonism and sedimentation. Long-term margin evolution reflects changes in morphology from a Late Cretaceous–Eocene ramp to Oligocene and younger prograding clinothem geometries, a transition found on several other margins. Deltaic systems influenced Cretaceous and Miocene sedimentation, but, in general, the Maastrichtian–Palaeogene shelf was starved of sediment. Pre-Pleistocene sequences follow a repetitive model, with fining- and coarsening-upward successions associated with transgressions and regressions, respectively. Pleistocene–Holocene sequences are generally quite thin (<20 m per sequence) and discontinuous beneath the modern shelf, reflecting starved sedimentation under high rates of eustatic change and low rates of subsidence. However, Pleistocene sequences can attain great thickness (hundreds of metres) beneath the outermost shelf and continental slope. Holocene sedimentation on the inner shelf reflects transgression, decelerating from rates of approximately 3–4 to around 2 mm a
−1
from 5 to 2 ka. Modern shelf sedimentation primarily reflects palimpsest sand sheets plastered and reworked into geostrophically controlled nearshore and shelf shore-oblique sand ridges, and does not provide a good analogue for pre-Pleistocene deposition.

Supplementary material:

References used in the comparison of all dates for New Jersey localities in Figure 3.8 are available at
http://www.geolsoc.org.uk/SUP18749
.
Chapter 4 The north and northeast Brazilian tropical shelves
Authors: Vital Helenice
Published: September 2014

The Brazilian tropical north shelf (BT N shelf) and the Brazilian tropical northeast shelf (BT NE shelf) along the Atlantic Ocean display unique conditions for tropical passive margins. Together they encompass approximately 3000 km in length, extending from Cape Orange in the north to Abrolhos Bank in the south. Both the north and NE shelves are very shallow and highly energetic systems. The first one is subject to energetic forcing from a number of different sources, including near-resonant semi-diurnal tides, large buoyancy flux from the Amazon River discharge, wind stress from the northeasterly trade winds and strong along-shelf flow associated with the North Brazil Current. The second one is subject to the full strength of the westerly-flowing South Equatorial Current, combined with high winds, moderate–high tidal range and/or waves. The BT N shelf is the largest shelf in Brazil, and is mostly covered with siliciclastic mud and sands because of the enormous water and sediment discharge from the Amazon River. In contrast, the BT NE shelf is narrow and open, and almost entirely covered by carbonate sediments due to the small amount of freshwater and sediment input.
Chapter 9 The Gulf of Cádiz continental shelves
Authors: Lobo F. J. , Le Roy P. , Mendes I. , Sahabi M.
Published: September 2014

The continental shelves fringing the Gulf of Cádiz are shallow-water environments of high scientific interest as they record the complex interplay between competing sedimentary, tectonic and oceanographic processes. These shelves receive the contributions of fluvial sources of varying significance, evolving laterally to shelf segments dominated by a vigorous oceanographic regime. In the long term, the Gulf of Cádiz margins show lateral physiographical compartmentalization related to the structural imprint.

Recent approaches on the Iberian Shelf have focused on the study of shelf sedimentary processes and long-term evolutionary patterns through the application of high-resolution seismic-sequence stratigraphy concepts. The Late Quaternary record exhibits extensive regressive-lowstand shelf-margin deltas mostly comprising nested sequences disposed in a hierarchical pattern. This complex architecture has been attributed to the leading control of orbitally driven, climatic–eustatic changes. As a result, the Iberian Shelf constitutes an excellent location to study the interaction between sedimentary processes, climatic and sea-level changes. Recently collected data in the Moroccan Shelf allow a high-resolution seismic-sequence stratigraphy scheme to be established. Significant latitudinal changes on depositional sequence architecture are driven by differential accommodation led by the reactivation of deformational fronts during the Pleistocene. As a consequence, this southern shelf constitutes a good example of tectonic control on sequence stratigraphy.
Mitigation of autophagy ameliorates hepatocellular damage following ischemia-reperfusion injury in murine steatotic liver
Authors: Gupta Nitika A. , Kolachala Vasantha L. , Jiang Rong , Abramowsky Carlos , Shenoi Asha , Kosters Astrid , Pavuluri Haritha , Anania Frank , Kirk Allan D.
Published: September 2014

Ischemia-reperfusion injury (IRI) is a common clinical consequence of hepatic surgery, cardiogenic shock, and liver transplantation. A steatotic liver is particularly vulnerable to IRI, responding with extensive hepatocellular injury. Autophagy, a lysosomal pathway balancing cell survival and cell death, is engaged in IRI, although its role in IRI of a steatotic liver is unclear. The role of autophagy was investigated in high-fat diet (HFD)-fed mice exposed to IRI in vivo and in steatotic hepatocytes exposed to hypoxic IRI (HIRI) in vitro. Two inhibitors of autophagy, 3-methyladenine and bafilomycin A1, protected the steatotic hepatocytes from HIRI. Exendin 4 (Ex4), a glucagon-like peptide 1 analog, also led to suppression of autophagy, as evidenced by decreased autophagy-associated proteins [microtubule-associated protein 1A/1B-light chain 3 (LC3) II, p62, high-mobility group protein B1, beclin-1, and autophagy-related protein 7], reduced hepatocellular damage, and improved mitochondrial structure and function in HFD-fed mice exposed to IRI. Decreased autophagy was further demonstrated by reversal of a punctate pattern of LC3 and decreased autophagic flux after IRI in HFD-fed mice. Under the same conditions, the effects of Ex4 were reversed by the competitive antagonist exendin 9-39. The present study suggests that, in IRI of hepatic steatosis, treatment of hepatocytes with Ex4 mitigates autophagy, ameliorates hepatocellular injury, and preserves mitochondrial integrity. These data suggest that therapies targeting autophagy, by Ex4 treatment in particular, may ameliorate the effects of IRI in highly prevalent steatotic liver.
L-Ornithine phenylacetate reduces ammonia in pigs with acute liver failure through phenylacetylglycine formation: a novel ammonia-lowering pathway
Authors: Kristiansen Rune Gangsøy , Rose Christopher F. , Fuskevåg Ole-Martin , Mæhre Hanne , Revhaug Arthur , Jalan Rajiv , Ytrebø Lars Marius
Published: September 2014

Glycine is an important ammoniagenic amino acid, which is increased in acute liver failure (ALF). We have previously shown that L-ornithine phenylacetate (OP) attenuates ammonia rise and intracranial pressure in pigs suffering from ALF but failed to demonstrate a stoichiometric relationship between change in plasma ammonia levels and excretion of phenylacetylglutamine in urine. The aim was to investigate the impact of OP treatment on the phenylacetylglycine pathway as an alternative and additional ammonia-lowering pathway. A well-validated and -characterized large porcine model of ALF (portacaval anastomosis, followed by hepatic artery ligation), which recapitulates the cardinal features of human ALF, was used. Twenty-four female pigs were randomized into three groups: 1) sham operated + vehicle, 2) ALF + vehicle, and 3) ALF + OP. There was a significant increase in arterial glycine concentration in ALF ( P < 0.001 compared with sham), with a three-fold increase in glycine release into the systemic circulation from the kidney compared with the sham group. This increase was attenuated in both the blood and brain of the OP-treated animals ( P < 0.001 and P < 0.05, respectively), and the attenuation was associated with renal removal of glycine through excretion of the conjugation product phenylacetylglycine in urine (ALF + vehicle: 1,060 ± 106 μmol/l; ALF + OP: 27,625 ± 2,670 μmol/l; P < 0.003). Data from this study provide solid evidence for the existence of a novel, additional pathway for ammonia removal in ALF, involving glycine production and removal, which is targeted by OP.
Effect of voluntary hypocapnic hyperventilation on the relationship between core temperature and heat loss responses in exercising humans
Authors: Fujii Naoto , Honda Yasushi , Komura Ken , Tsuji Bun , Sugihara Akira , Watanabe Kazuhito , Kondo Narihiko , Nishiyasu Takeshi
Published: September 2014

Two thermolytic thermoregulatory responses, cutaneous vasodilation and sweating, begin when core temperature reaches a critical threshold, after which response magnitudes increase linearly with increasing core temperature; thus the slope indicates response sensitivity. We evaluated the influence of hypocapnia induced by voluntary hyperventilation on the core temperature threshold and sensitivity of thermoregulatory responses. Ten healthy males performed 15 min of cycling at 117 W (29.5°C, 50% RH) under three breathing conditions: 1) spontaneous ventilation, 2) voluntary normocapnic hyperventilation, and 3) voluntary hypocapnic hyperventilation. In the hypocapnic hyperventilation trial, end-tidal CO2 pressure was reduced throughout the exercise, whereas it was maintained around the normocapnic level in the other two trials. Cutaneous vascular conductances at the forearm and forehead were evaluated as laser-Doppler signal/mean arterial blood pressure, and the forearm sweat rate was measured using the ventilated capsule method. Esophageal temperature threshold was higher for the increase in cutaneous vascular conductance in the hypocapnic than normocapnic hyperventilation trial at the forearm (36.88 ± 0.36 vs. 36.68 ± 0.34°C, P < 0.05) and forehead (36.89 ± 0.31 vs. 36.75 ± 0.31°C, P < 0.05). The slope relating esophageal temperature to cutaneous vascular conductance was decreased in the hypocapnic than normocapnic hyperventilation trial at the forearm (302 ± 177 vs. 420 ± 178% baseline/°C, P < 0.05) and forehead (236 ± 164 vs. 358 ± 221% baseline/°C, P < 0.05). Neither the threshold nor the slope for the forearm sweat rate differed significantly between the hypocapnic or normocapnic hyperventilation trials. These findings indicate that in exercising humans, hypocapnia induced by voluntary hyperventilation does not influence sweating, but it attenuates the cutaneous vasodilatory response by increasing its threshold and reducing its sensitivity.
Losartan administration reduces fibrosis but hinders functional recovery after volumetric muscle loss injury
Authors: Garg Koyal , Corona Benjamin T. , Walters Thomas J.
Published: September 2014

Losartan is a Food and Drug Administration approved antihypertensive medication that is recently emerging as an antifibrotic therapy. Previously, losartan has been successfully used to reduce fibrosis and improve both muscle regeneration and function in several models of recoverable skeletal muscle injuries, such as contusion and laceration. In this study, the efficacy of losartan treatment in reducing fibrosis and improving regeneration was determined in a Lewis rat model of volumetric muscle loss (VML) injury. VML has been defined as the traumatic or surgical loss of skeletal muscle with resultant functional impairment. It is among the top 10 causes for wounded service members to be medically retired from the military. This study shows that, after several weeks of recovery, VML injury results in little to no muscle regeneration, but is marked by persistent inflammation, chronic upregulation of profibrotic markers and extracellular matrix (i.e., collagen type I), and fat deposition at the defect site, which manifest irrecoverable deficits in force production. Losartan administration at 10 mg·kg−1·day−1was able to modulate the gene expression of fibrotic markers and was also effective at reducing fibrosis (i.e., the deposition of collagen type I) in the injured muscle. However, there were no improvements in muscle regeneration, and deleterious effects on muscle function were observed instead. We propose that, in the absence of regeneration, reduction in fibrosis worsens the ability of the VML injured muscle to transmit forces, which ultimately results in decreased muscle function.
Internalization by Multiple Endocytic Pathways and Lysosomal Processing Impact Maspin-Based Therapeutics
Authors: Bodenstine Thomas M. , Seftor Richard E. B. , Seftor Elisabeth A. , Khalkhali-Ellis Zhila , Samii Nicole A. , Monarrez J. Cesar , Chandler Grace S. , Pemberton Philip A. , Hendrix Mary J. C.
Published: September 2014

Patients with metastatic disease face high rates of mortality with a paucity of therapeutic options. Protein-based therapeutics provide advantages over traditional chemotherapy through increased specificity, decreased immune impairment, and more direct means of delivery. However, development is often hindered because of insufficient knowledge about protein processing by cells when exogenously applied. This study focuses on recombinant Maspin (rMaspin), a serine protease inhibitor (SERPINB5), which alters invasive properties when directly applied to cancer cells. Previous evidence suggests differences in the effects of rMaspin treatment when compared with endogenous reexpression, with little explanation for these discrepancies. A leading hypothesis is that exogenously applied rMaspin is subject to different regulatory and/or processing mechanisms in cancer cells when compared with endogenous expression. Therefore, a more detailed understanding of the mechanisms of internalization and subcellular trafficking of rMaspin is needed to guide future translational development. We describe the molecular trafficking of rMaspin in cytoplasmic vesicles of the endosomal/lysosomal pathway and characterize its uptake by multiple endocytic mechanisms. Time-lapse laser scanning confocal microscopy shows the uptake, in real time, of dye-labeled rMaspin in cancer cells. This study indicates that cellular processing of rMaspin plays a key role by affecting its biologic activity and highlights the need for new approaches aimed at increasing the availability of rMaspin when used to treat cancer.

Implications: Novel characterization of internalization and subcellular trafficking of rMaspin provides new insights for future therapeutic development. Mol Cancer Res; 12(10); 1480–91. ©2014 AACR.
Overexpression of Reactive Oxygen Species Scavenger Enzymes Is Associated with a Good Prognosis in Triple-Negative Breast Cancer
Authors: Kim Darae , Koo Ja Seung , Lee Soohyeon
Published: September 2014

Objective: The aim of this study was to investigate the expression of redox proteins in triple-negative breast cancer (TNBC), a breast cancer type which harbors an aggressive phenotype, and to demonstrate the relationships between the expression of reactive oxygen species (ROS) markers and clinical outcome. Methods: From 2000 to 2005, we analyzed tissue samples from 135 cases of TNBC obtained from curative surgeries at the Severance Hospital, Seoul, South Korea. Immunochemical staining for redox proteins was performed. Results: The median patient age was 48 (range 27-76) years. TNM staging was as follows: T1 (n = 52, 38.5%), T2 (n = 81, 60%), T3 (n = 2, 1.5%), N0 (n = 88, 65.2%), N1 (n = 35, 25.9%), N2 (n = 8, 5.9%) and N3 (n = 4, 3.0%). Median follow-up was 59 (range 12-99) months. The high-expression catalase group tended to have a lower N stage (p = 0.016), lower tumor recurrence (p = 0.02) as well as longer overall survival rates (p = 0.05). After adjusting for patient age as well as tumor and nodal stage, we found that primary breast cancers with high catalase expression levels did not have an improved clinical outcome. A high MTC4 expression in the stroma was strongly associated with increased manganese superoxide dismutase expression (p = 0.015) and a significantly longer overall survival (p = 0.032). Conclusion: Considering the lack of targeted molecules as well as molecular heterogeneity of TNBC, ROS markers may provide clues to clinical outcome in TNBC. i 2014 S. Karger AG, Basel
Synaptic Development and Neuronal Myelination Are Altered with Growth Restriction in Fetal Guinea Pigs
Authors: Piorkowska Karolina , Thompson Jennifer , Nygard Karen , Matushewski Brad , Hammond Robert , Richardson Bryan
Published: September 2014

This study examines aberrant synaptogenesis and myelination of neuronal connections as possible links to neurological sequelae in growth-restricted fetuses. Pregnant guinea pig sows were subjected to uterine blood flow restriction or sham surgeries at midgestation. The animals underwent necropsy at term with fetuses grouped according to body weight and brain-to-liver weight ratios as follows: appropriate for gestational age (n = 12); asymmetrically fetal growth restricted (aFGR; n = 8); symmetrically fetal growth restricted (sFGR; n = 8), and large for gestational age (n = 8). Fetal brains were perfusion fixed and paraffin embedded to determine immunoreactivity for synaptophysin and synaptopodin as markers of synaptic development and maturation, respectively, and for myelin basic protein as a marker for myelination, which was further assessed using Luxol fast blue staining. The most pertinent findings were that growth-restricted guinea pig fetuses exhibited reduced synaptogenesis and synaptic maturation as well as reduced myelination, which were primarily seen in subareas of the hippocampus and associated efferent tracts. These neurodevelopmental changes were more pronounced in the sFGR compared to the aFGR animals. Accordingly, altered hippocampal development involving synaptogenesis and myelination may represent a mechanism by which cognitive deficits manifest in human growth-restricted offspring in later life.
New Multiple Sclerosis Phenotypic Classification
Authors: Lublin Fred D.
Published: September 2014

Background: In 1996, the clinical course of multiple sclerosis (MS) was characterized as relapsing-remitting, primary progressive, secondary progressive or progressive relapsing. Since then, an increased understanding of MS and its pathology prompted a re-examination of these clinical phenotypes. Main recommendations of the 2013 revisions are provided herein. Summary: Clinically isolated syndrome has been added, and progressive relapsing MS has been eliminated, from the clinical course descriptions. All forms of MS should be further subcategorized as either active or non-active. Active MS is defined as the occurrence of clinical relapse or the presence of new T2 or gadolinium-enhancing lesions over a specified period of time, preferably at least one year. An additional subcategory for patients with progressive MS differentiates between those who have shown signs of disability progression over a given time period and those who have remained stable. The term ‘worsening' is recommended to describe patients whose disease is advancing for any reason, whereas ‘disease progression' should be reserved for those with progressive disease who are truly progressing (as opposed to worsening from a relapse). The term ‘benign' should be used with caution as the course of MS can worsen at any time, even after many years of apparent stability. Key Messages: Newer characterizations of MS phenotypes include a consideration of disease activity (based on the clinical relapse rate and imaging findings) and disease progression. Accurate clinical course descriptions are useful for communication, prognostication, clinical trial design and to guide everyday clinical decision-making. © 2014 S. Karger AG, Basel
Advances in the Management of Multiple Sclerosis Spasticity: Multiple Sclerosis Spasticity Nervous Pathways
Authors: Centonze Diego
Published: September 2014

Background: Spasticity arises from hyperexcitability of the neural stretch reflex arc secondary to injury of the corticospinal tract. In response to injury, the density of glutamatergic inputs from afferent 1A fibers to motor neurons increases dramatically and adaptive changes occur in the morphology of microglia cells in the spinal cord. Summary: Involvement of the endocannabinoid system in pathophysiological mechanisms responsible for spasticity has been demonstrated in animal models of MS. Stimulation of cannabinoid (CB)1 receptors reduces the hyperglutamatergic drive from sensory afferents to spinal cord motor neurons and blocks the synaptic effects of activated microglia and pro-inflammatory mediators (e.g. TNF-α) on glutamatergic transmission. Enhancing corticospinal tract excitability through intermittent theta burst stimulation inhibits the stretch reflex and spasticity by promoting long-term potentiation, a form of synaptic plasticity that requires stimulation of CB1 receptors. Evidence indicates that the antispasticity effects of THC:CBD oromucosal spray (Sativex®) are associated with enhanced cortical long-term potentiation. Key Messages: Glutamatergic and GABAergic pathways are involved in the regulation of muscle tone. CB1 receptors, which are associated with movement, postural control, and pain and sensory perception, influence glutamatergic pathways. THC:CBD oromucosal spray was shown to reverse motor cortex plasticity from long-term depression through long-term potentiation of synaptic transmission, thereby restoring, at least in part, effective corticospinal inputs to spinal circuits.
Advances in the Management of Multiple Sclerosis Spasticity: Recent Clinical Trials
Authors: Fernández Oscar
Published: September 2014

Background: Most patients with multiple sclerosis (MS) experience spasticity as the clinical course evolves. Associated symptoms include (often painful) spasms, urinary dysfunction and sleep disturbances. THC:CBD oromucosal spray (Sativex®) is approved for symptom improvement in adult patients with moderate to severe MS-related spasticity who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity-related symptoms during an initial trial of therapy. Summary: In pivotal clinical trials of THC:CBD oromucosal spray, a meaningful proportion of patients with treatment-resistant MS spasticity achieved clinically relevant improvement with active treatment versus placebo. The utility of a 4-week trial of therapy to identify patients who respond to treatment was demonstrated in an enriched-design study. THC:CBD oromucosal spray was well tolerated in these studies, with no evidence of effects typically associated with recreational cannabis use. In a subsequent post approval clinical trial, THC:CBD oromucosal spray had no statistically significant effect on cognition and mood compared with placebo. Moreover, after 50 weeks' treatment, approximately two-thirds of patients, physicians and caregivers reported improvement from baseline in spasticity based on global impressions of change. Key Messages: In phase III clinical trials, approximately one-third of MS patients with treatment-resistant spasticity had a clinically relevant and statistically significant response to THC:CBD oromucosal spray. In addition to a reduction in spasticity, responders experienced meaningful relief from associated symptoms. THC:CBD oromucosal spray was generally well tolerated and efficacy was maintained over the longer term. A post-approval clinical trial indicated no effect of THC:CBD oromucosal spray on cognition or mood after 50 weeks of use.
Clinical Case Reviews and Poster Sessions in Multiple Sclerosis Spasticity: Main Outcomes and Highlights
Authors: Trojano Maria , Celius Elisabeth G. , Donzé Cecile , Izquierdo Guillermo , Patti Francesco , Pöhlau Dieter
Published: September 2014

Background: Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary: Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex®) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic ‘priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity.
Molecular Characterization of Clinical Isolates of Moraxella catarrhalis by Randomly Amplified Polymorphic DNA Fingerprinting
Authors: Theoga Raj Christol James , Shankar Esaki Muthu , Rothan Hussin A. , Rao Usha Anand
Published: September 2014

Moraxella catarrhalis, a less virulent microorganism that colonizes the upper respiratory tract, has recently been associated with lower respiratory disease, especially in HIV-positive immunocompromised individuals and children. Here, we correlated the DNA clustering pattern of 24 clinical isolates of M. catarrhalis for β-lactamase production and drug resistance, from different disease groups using three different arbitrarily selected primers, P1 (5′-TCACGATGCA-3′), P14 (5′-GATCAAGTCC-3′) and P17 (5′-GATCTGACAC-3′). M. catarrhalis revealed three distinct banding patterns with primer P1, four with P14 and P17. 71% (n = 17) of the isolates revealed pattern 2 with primer P1, which discriminated majority (12/21) of the isolates grouped under the major branch of the dendrogram. The minor branch had only three isolates. Separation of M. catarrhalis into two subpopulations (major and minor clusters) with primer P1 is suggestive of diverse genetic lineage. A high level of concordance between RAPD and antibiotic profile was observed. Clustering of M. catarrhalis recovered from different disease groups reflect the identical clinical background or the common geographical/temporal factors. The presence or absence of β-lactamase in a cluster confirmed their single source of origin.