bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust sawtooth period control based on adaptive online optimization
Authors: Bolder J.J. , Witvoet G. , de Baar M.R. , van de Wouw N. , Haring M.A.M. , Westerhof E. , Doelman N.J. , Steinbuch M.
Published: July 2012

The systematic design of a robust adaptive control strategy for the sawtooth period using electron cyclotron current drive (ECCD) is presented. Recent developments in extremum seeking control (ESC) are employed to derive an optimized controller structure and offer practical tuning guidelines for its parameters. In this technique a cost function in terms of the desired sawtooth period is optimized online by changing the ECCD deposition location based on online estimations of the gradient of the cost function. The controller design does not require a detailed model of the sawtooth instability. Therefore, the proposed ESC is widely applicable to any sawtoothing plasma or plasma simulation and is inherently robust against uncertainties or plasma variations. Moreover, it can handle a broad class of disturbances. This is demonstrated by time-domain simulations, which show successful tracking of time-varying sawtooth period references throughout the whole operating space, even in the presence of variations in plasma parameters, disturbances and slow launcher mirror dynamics. Due to its simplicity and robustness the proposed ESC is a valuable sawtooth control candidate for any experimental tokamak plasma, and may even be applicable to other fusion-related control problems.
Experimental observations of plasma edge magnetic field response to resonant magnetic perturbation on the TEXTOR Tokamak
Authors: Yang Y. , Liang Y. , Sun Y. , Zhang T. , Pearson J. , Xu Y.
Published: July 2012

The plasma response to a resonant magnetic perturbation (RMP) is experimentally measured on the TEXTOR tokamak using a fast movable magnetic probe. It is shown that, due to the plasma response, the magnetic field significantly differs from the vacuum field. Clear linear and non-linear responses to RMP are observed by varying the intensity of these perturbations or the plasma edge safety factor. Both the radial profile evolution and the dependence of plasma response on the edge safety factor show a stronger resonant effect when the RMP rotates at 5 kHz in the counter-current direction.
An analysis of lower hybrid grill coupling using an efficient full wave code
Authors: Preinhaelter Josef , Urban Jakub , Vahala Linda , Vahala George
Published: July 2012

Lower hybrid (LH) waves are very important for heating and current drive in tokamaks. Phased arrays of rectangular waveguides, generally called grills, are typically used as launchers. We develop a code which solves, in the 3D geometry of the grill structure, the problem of efficient coupling: the power density spectrum of the emitted waves, the power reflection coefficient, the power lost by the waves launched in the inaccessible region and the directivity of the waves transmitted into the accessible region. The code is also able to determine the 3D electric field in front of the grill. An efficient adaptive full wave solver is used to determine the wave propagation in a 1D plasma slab geometry. To evaluate the very large number of 2D k-space infinite integrals for the coupling elements, we have developed a method based on high order Gaussian quadratures combined with 2D B-splines in the accessible region for the plasma related part of the integrands. This method is well suited to handle large structures and many modes because the computational time is only weakly dependent on the size of the problem. An iterative evaluation of the integrands in the inaccessible region is adopted to handle the presently overlooked near singular behaviour of the integrands as well as the spectral power density associated with the eigenmodes. The role of collisions is clarified in this context.

The code is applied to several COMPASS grills operating either at 1.3 GHz or at 3.7 GHz. First we thouroughly analyse the original 1.3 GHz, 8-waveguide conventional grill at various waveguide phasing. Then, the coupling of two grill designs for 3.7 GHz is solved. The suitability of all the grills is discussed, showing compatible grill and plasma parameter ranges.
Effect of nebivolol on outcome in elderly patients with heart failure and atrial fibrillation: insights from SENIORS
Authors: Mulder Bart A. , van Veldhuisen Dirk J. , Crijns Harry J.G.M. , Böhm Michael , Cohen‐Solal Alain , Babalis Daphne , Roughton Michael , Flather Marcus D. , Coats Andrew J.S. , Van Gelder Isabelle C.
Published: July 2012

Aims

Beneficial effects of beta‐blockade remain unclear in heart failure patients who have atrial fibrillation (AF), especially in the elderly. We evaluated the effect of nebivolol on cardiovascular outcomes in elderly patients with heart failure and AF.

Methods and results

The SENIORS trial showed an overall benefit of nebivolol compared with placebo in 2128 heart failure patients >70 years of age. At baseline, AF was present in 738 (34.7%) patients. The primary outcome was all‐cause mortality or cardiovascular hospitalizations. After 21 months, the cumulative incidence of the primary outcome was significantly more common in patients with AF compared with those with sinus rhythm (38.5% vs. 30.4%, respectively, P < 0.001). In patients with AF, nebivolol had no beneficial effect on the primary outcome [nebivolol vs. placebo, 37.1% vs. 39.8%, hazard ratio (HR) 0.92, 95% confidence interval (CI), 0.73–1.17, P = 0.46], in contrast to patients with sinus rhythm (28.1% vs. 32.9%, in the nebivolol vs. placebo group, respectively, HR 0.82, 95% CI 0.67–0.99, P = 0.049). In patients with AF, the primary outcome was similar in the impaired and preserved left ventricular ejection fraction (LVEF) groups (39.0% with LVEF ≤35% vs. 37.3% in patients with LVEF > 35%). There was also no evidence of benefit of nebivolol in AF patients stratified by LVEF.

Conclusion

Nebivolol failed to improve outcomes in elderly patients with stable heart failure and co‐existing AF, irrespective of LVEF. Furthermore, in patients with AF, outcome was comparable between patients with preserved and impaired LVEF.
The response of herring to high crowding densities in purse-seines: survival and stress reaction
Authors: Tenningen Maria , Vold Aud , Olsen Rolf Erik
Published: July 2012

Tenningen, M., Vold, A., and Olsen, R. E. 2012. The response of herring to high crowding densities in purse-seines: survival and stress reaction. – ICES Journal of Marine Science, 69: . To study the effects of crowding in purse-seines on the survival and stress response of herring (Clupea harengus), large-scale field experiments were conducted in the North Sea during 2008 and 2009. The mortality was 28% at a crowding density of 221 kg m−3 and increased further with increasing density. Crowding densities <150 kg m−3 did not result in any additional mortality compared with the control group (0.9–2.0%). Smaller herring and herring with a lower condition factor were more vulnerable to the effects of crowding. Blood analyses showed a significant increase in cortisol, lactate, and blood ions in the crowded fish. Lactate returned to control levels 2 d post-stress, whereas cortisol and blood ion levels continued to increase during the 4- to 5-d monitoring period. Furthermore, plasma glucose appeared to be substantially reduced at the end of the trial, indicating that the herring were incapable of restoring homeostasis and were approaching energy exhaustion. These results provide important information about the crowding densities that can be tolerated in the purse-seine fisheries for herring and will benefit future development of guidelines for purse-seine slipping operations.
Structured growth and genetic drift raise relatedness in the social amoeba
Dictyostelium discoideum
Authors: Buttery Neil J. , Jack Chandra N. , Adu-Oppong Boahemaa , Snyder Kate T. , Thompson Christopher R. L. , Queller David C. , Strassmann Joan E.
Published: July 2012

One condition for the evolution of altruism is genetic relatedness between altruist and beneficiary, often achieved through active kin recognition. Here, we investigate the power of a passive process resulting from genetic drift during population growth in the social amoeba
Dictyostelium discoideum
. We put labelled and unlabelled cells of the same clone in the centre of a plate, and allowed them to proliferate outward. Zones formed by genetic drift owing to the small population of actively growing cells at the colony edge. We also found that single cells could form zones of high relatedness. Relatedness increased at a significantly higher rate when food was in short supply. This study shows that relatedness can be significantly elevated before the social stage without a small founding population size or recognition mechanism.
It pays to cheat: tactical deception in a cephalopod social signalling system
Authors: Brown Culum , Garwood Martin P. , Williamson Jane E.
Published: July 2012

Signals in intraspecific communication should be inherently honest; otherwise the system is prone to collapse. Theory predicts, however, that honest signalling systems are susceptible to invasion by cheats, the extent of which is largely mediated by fear of reprisal. Cuttlefish facultatively change their shape and colour, an ability that evolved to avoid predators and capture prey. Here, we show that this ability is tactically employed by male mourning cuttlefish (
Sepia plangon
) to mislead conspecifics during courtship in a specific social context amenable to cheating 39 per cent of the time, while it was never employed in other social contexts. Males deceive rival males by displaying male courtship patterns to receptive females on one side of the body, and simultaneously displaying female patterns to a single rival male on the other, thus preventing the rival from disrupting courtship. The use of tactical deception in such a complex communication network indicates that sociality has played a key role in the cognitive evolution of cephalopods.
Quantitative assessment of collagen fibre orientations from two-dimensional images of soft biological tissues
Authors: Schriefl Andreas J. , Reinisch Andreas J. , Sankaran Sethuraman , Pierce David M. , Holzapfel Gerhard A.
Published: July 2012

In this work, we outline an automated method for the extraction and quantification of material parameters characterizing collagen fibre orientations from two-dimensional images. Morphological collagen data among different length scales were obtained by combining the established methods of Fourier power spectrum analysis, wedge filtering and progressive regions of interest splitting. Our proposed method yields data from which we can determine parameters for computational modelling of soft biological tissues using fibre-reinforced constitutive models and gauge the length scales most appropriate for obtaining a physically meaningful measure of fibre orientations, which is representative of the true tissue morphology of the two-dimensional image. Specifically, we focus on three parameters quantifying different aspects of the collagen morphology: first, using maximum-likelihood estimation, we extract location parameters that accurately determine the angle of the principal directions of the fibre reinforcement (i.e. the preferred fibre directions); second, using a dispersion model, we obtain dispersion parameters quantifying the collagen fibre dispersion about these principal directions; third, we calculate the weighted error entropy as a measure of changes in the entire fibre distributions at different length scales, as opposed to their average behaviour. With fully automated imaging techniques (such as multiphoton microscopy) becoming increasingly popular (which often yield large numbers of images to analyse), our method provides an ideal tool for quickly extracting mechanically relevant tissue parameters which have implications for computational modelling (e.g. on the mesh density) and can also be used for the inhomogeneous modelling of tissues.
Discovering the ‘true form:’ Hooke's
Micrographia
and the visual vocabulary of engraved portraits
Authors: Doherty Meghan C.
Published: July 2012

This essay uses Robert Hooke's
Micrographia
to examine the intersection of visual conventions for portraiture with the viewing of the microscopic world. In the preface to his
Micrographia
, Robert Hooke asserts that he has discovered ‘a new visible World’ through the help of newly invented optical devices that add ‘artificial Organs to the natural’. I claim that Hooke was also aided by the visual vocabulary developed by engravers for translating a three-dimensional world into a two-dimensional representation of it, and that his awareness of these conventions sets his illustrations apart from his predecessors.
Visually targeted reaching in horse-head grasshoppers
Authors: Niven Jeremy E. , Ott Swidbert R. , Rogers Stephen M.
Published: July 2012

Visually targeted reaching to a specific object is a demanding neuronal task requiring the translation of the location of the object from a two-dimensionsal set of retinotopic coordinates to a motor pattern that guides a limb to that point in three-dimensional space. This sensorimotor transformation has been intensively studied in mammals, but was not previously thought to occur in animals with smaller nervous systems such as insects. We studied horse-head grasshoppers (Orthoptera: Proscopididae) crossing gaps and found that visual inputs are sufficient for them to target their forelimbs to a foothold on the opposite side of the gap. High-speed video analysis showed that these reaches were targeted accurately and directly to footholds at different locations within the visual field through changes in forelimb trajectory and body position, and did not involve stereotyped searching movements. The proscopids estimated distant locations using peering to generate motion parallax, a monocular distance cue, but appeared to use binocular visual cues to estimate the distance of nearby footholds. Following occlusion of regions of binocular overlap, the proscopids resorted to peering to target reaches even to nearby locations. Monocular cues were sufficient for accurate targeting of the ipsilateral but not the contralateral forelimb. Thus, proscopids are capable not only of the sensorimotor transformations necessary for visually targeted reaching with their forelimbs but also of flexibly using different visual cues to target reaches.
Evolutionary dynamics of genome segmentation in multipartite viruses
Authors: Iranzo Jaime , Manrubia Susanna C.
Published: July 2012

Multipartite viruses are formed by a variable number of genomic fragments packed in independent viral capsids. This fact poses stringent conditions on their transmission mode, demanding, in particular, a high multiplicity of infection (MOI) for successful propagation. The actual advantages of the multipartite viral strategy are as yet unclear. The origin of multipartite viruses represents an evolutionary puzzle. While classical theories suggested that a faster replication rate or higher replication fidelity would favour shorter segments, recent experimental results seem to point to an increased stability of virions with incomplete genomes as a factor able to compensate for the disadvantage of mandatory complementation. Using as main parameters differential stability as a function of genome length and MOI, we calculate the conditions under which a set of complementary segments of a viral genome would outcompete the non-segmented variant. Further, we examine the likeliness that multipartite viral forms could be the evolutionary outcome of the competition among the defective genomes of different lengths that spontaneously arise under replication of a complete, wild-type genome. We conclude that only multipartite viruses with a small number of segments could be produced in our scenario, and discuss alternative hypotheses for the origin of multipartite viruses with more than four segments.
Genomic and antigenic characterization of the newly emerging Chinese duck egg-drop syndrome flavivirus: genomic comparison with Tembusu and Sitiawan viruses
Authors: Liu Peipei , Lu Hao , Li Shuang , Moureau Gregory , Deng Yong-Qiang , Wang Yongyue , Zhang Lijiao , Jiang Tao , de Lamballerie Xavier , Qin Cheng-Feng , Gould Ernest A. , Su Jingliang , Gao George F.
Published: July 2012

Duck egg-drop syndrome virus (DEDSV) is a newly emerging pathogenic flavivirus causing avian diseases in China. The infection occurs in laying ducks characterized by a severe drop in egg production with a fatality rate of 5–15 %. The virus was found to be most closely related to Tembusu virus (TMUV), an isolate from mosquitoes in South-east Asia. Here, we have sequenced and characterized the full-length genomes of seven DEDSV strains, including the 5′- and 3′-non-coding regions (NCRs). We also report for the first time the ORF sequences of TMUV and Sitiawan virus (STWV), another closely related flavivirus isolated from diseased chickens. We analysed the phylogenetic and antigenic relationships of DEDSV in relation to the Asian viruses TMUV and STWV, and other representative flaviviruses. Our results confirm the close relationship between DEDSV and TMUV/STWV and we discuss their probable evolutionary origins. We have also characterized the cleavage sites, potential glycosylation sites and unique motifs/modules of these viruses. Additionally, conserved sequences in both 5′- and 3′-NCRs were identified and the predicted secondary structures of the terminal sequences were studied. Antigenic cross-reactivity comparisons of DEDSV with related pathogenic flaviviruses identified a surprisingly close relationship with dengue virus (DENV) and raised the question of whether or not DEDSV may have a potential infectious threat to man. Importantly, DEDSV can be efficiently recognized by a broadly cross-reactive flavivirus mAb, 2A10G6, derived against DENV. The significance of these studies is discussed in the context of the emergence, evolution, epidemiology, antigenicity and pathogenicity of the newly emergent DEDSV.
Hobi-like pestivirus: both biotypes isolated from a diseased animal
Authors: Decaro Nicola , Mari Viviana , Pinto Pierfrancesco , Lucente Maria Stella , Sciarretta Rossana , Cirone Francesco , Colaianni Maria Loredana , Elia Gabriella , Thiel Heinz-Jürgen , Buonavoglia Canio
Published: July 2012

A Hobi-like pestivirus pair consisting of cytopathogenic (cp) and non-cytopathogenic (noncp) strains, Italy 83/10cp and Italy 83/10ncp, was isolated from the lung of a heifer that died of respiratory disease. The noncp and cp viruses were isolated on Madin–Darby bovine kidney cells and separated by plaque purification and end point dilution. Analysis of the nearly full-length genomes revealed that the two viruses were very closely related to each other and to the noncp Hobi-like strain Italy 1/10-1, which had been isolated a few weeks earlier from the same herd. One major difference between noncp and cp viruses concerned the presence of a cellular Jiv sequence in the 3′ domain of the NS2-encoding region of the cp strain. This is the first study, to our knowledge, reporting the isolation and molecular characterization of a Hobi-like virus pair.
Ethyl 3-(4-methoxyphenyl)-2-phenyl-3-(4-phenyl-1,2,3-selenadiazol-5-yl)propanoate
Authors: Sugumar P. , Sankari S. , Manisankar P. , Ponnuswamy M. N.
Published: July 2012

In the title compound, C26H24N2O3Se, the selenadiazole ring is planar [maximum deviation = 0.002 (2) Å]. The dihedral angle between the selenadiazole ring and the attached phenyl ring is 49.00 (13)°. The crystal structure is stabilized by intermolecular C—H...N and C—H...π interactions.
2-[3-(1,3-Benzothiazol-2-yl)-2,2-dimethylpropyl]-2-methyl-2,3-dihydro-1,3-benzothiazole
Authors: Yousuf Sammer , Siddiqui Hina , Farooq Rabia , Choudhary M. Iqbal
Published: July 2012

In the title compound, C20H22N2S2, the five-membered thiazole ring of the 2-methyl-2,3-dihydro-1,3-benzothiazole unit has an envelope conformation. The dihedral angle between the planar [maximum deviation of 0.014 (1) Å for the S atom] benzothiazole ring system and the benzene ring is 78.37 (12)°. Two intramolecular C—H...S hydrogen bonds are observed, forming rings of graph-set motifS(6). In the crystal, the molecules are consolidated in pairs through N—H...N hydrogen bonds and are arranged parallel to thebaxis.
tert-ButylN-{3-[(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino]propyl}carbamate
Authors: Resende Jackson A. L. C. , Gomez Javier A.
Published: July 2012

In the title compound, C18H21ClN2O4, the molecular sytructure is stabilized by two intramolecular N—H...O hydrogen bonds. In the crystal, molecules are linked by pairs of C—H...O hydrogen bonds, forming inversion dimers with graph-set motifR22(10). N—H...O hydrogen bonds further link the dimers intoC(10) chains along [010].
Oxido[2-{(E)-[((1E)-{(E)-2-[1-(2-oxidophenyl)ethylidene]hydrazin-1-ylidene}(prop-2-en-1-ylsulfanyl)methyl)imino]methyl}phenolato]vanadium(IV)
Authors: Takjoo Reza , Ng Seik Weng , Tiekink Edward R. T.
Published: July 2012

The VIVatom in the title complex, [V(C19H17N3O2S)O], is coordinated by two N and two O atoms of the dianionic tetradentate Schiff base ligand and the terminal oxide O atom. The N2O3donor set defines a square-pyramidal coordination geometry with the oxide O atom in the apical site. Some buckling in the tetradentate ligand is indicated by the dihedral angle of 17.92 (19)° between the six-membered chelate rings. Supramolecular chains are formed along thebaxisviaC—H...O contacts in the crystal. The chains are connected into a layer in theabplaneviaC—H...π interactions. The atoms comprising the –SCH2—CH=CH2and methyl substituents were found to be disordered in a 0.916 (2):0.088 (2) ratio. The crystal studied was found to be twinned by nonmerohedry with a 28.1 (4)% minor twin component.
Ethyl 2-(3-phenylthioureido)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate
Authors: Oliveira Jaismary G. B. de , Mendonça Francisco J. B. , Lima Maria do Carmo A. de , Simone Carlos A. de , Ellena Javier A.
Published: July 2012

In the title compound, C17H18N2O2S2, the angle between the mean plane defined by the atoms of the 5,6-dihydro-4H-cyclopenta[b]thiophene moiety (r.m.s. deviation = 0.19 Å) and the phenyl ring is 72.8°(2). The molecular conformation is stabilized by an intramolecular N—H...O interaction, which generates anS(6) ring motif. In the crystal, pairs of N—H...S hydrogen bonds link the molecules to form inversion dimers with anR22(8) ring motif.
3-(Adamantan-1-yl)-4-ethyl-1-[(4-phenylpiperazin-1-yl)methyl]-1H-1,2,4-triazole-5(4H)-thione
Authors: El-Emam Ali A. , Al-Abdullah Ebtehal S. , Al-Tuwaijri Hanaa M. , Said-Abdelbaky Mohammed , García-Granda Santiago
Published: July 2012

The title compound, C25H35N5S, has an approximately C-shaped conformation. The dihedral angle between the triazole and phenyl planes is 79.5 (2)°. The crystal structure consists of infinite chains parallel to thebaxis, constructed by C—H...S hydrogen bonds between translation-related molecules. Adjacent chains are linkedviaweak C—H...C interactions between the adamantyl and phenyl groups.
3,6-Diazaoctane-1,8-diaminium diiodide
Authors: Cukrowski Ignacy , Adeyinka Adedapo S. , Liles David C.
Published: July 2012

The asymmetric unit of the title salt, C6H20N42+·2I−, comprises half a 3,6-diazaoctane-1,8-diaminium dication plus an I−anion. The dications are symmetrical and lie across crystallographic centres of inversion. In the crystal, the ions form a network involving mainly weak N—H...I intermolecular interactions: two H atoms of the ammonium group form interactions with two I−anions and the H atom of the secondary amine forms a weak interaction with a third I−cation. The third ammonium H atom is hydrogen bonded to a secondary amine of an adjacent cation. The backbone of the cation does not form a uniformlytranschain, but is `kinked' [C—N—C—C torsion angle = 71.5 (2)°], probably to accommodate the direct hydrogen bond between the ammonium group and the secondary amine in an adjacent cation.
4-(4,5-Dihydro-1H-benzo[g]indazol-3-yl)pyridinium chloride dihydrate
Authors: Yang Luan-Fang , Hou Hong-Bo , Liu Yi-Ming
Published: July 2012

In the cation of the title compound, C16H14N3+·Cl−·2H2O, the cyclohexa-1,3-diene ring displays a screw-boat conformation and the pyridine ring is slightly twisted with respect to the pyrazole ring with a dihedral angle of 4.56 (12)°. In the crystal, ions and water molecules are linked into a three-dimensional network by classical N—H...O, N—H...Cl, O—H...Cl and O—H...O hydrogen bonds and by π–π stacking interactions, with centroid–centroid distances of 3.7580 (14) and 3.7794 (14) Å.
Bis(tetraethylammonium) oxalate dihydrate
Authors: McNeese Timothy J. , Pike Robert D.
Published: July 2012

The title compound, 2C8H20N+·C2O42−·2H2O, synthesized by neutralizing H2C2O4·2H2O with (C2H5)4NOH in a 1:2 molar ratio, is a deliquescent solid. The oxalate ion is nonplanar, with a dihedral angle between carboxylate groups of 64.37 (2)°. O—H...O hydrogen bonds of moderate strength link the O atoms of the water molecules and the oxalate ions into rings parallel to thecaxis. The rings exhibit the graph-set motifR44(12). In addition, there are weak C—H...O interactions in the crystal structure.
N-Benzoyl-N-(1,4-dioxonaphthalen-2-yl)benzamide
Authors: Brandy Yakini , Butcher Ray J. , Bakare Oladapo
Published: July 2012

The title molecule, C24H15NO4, crystallizes with two molecules in the asymmetric unit (Z′ = 2). For both molecules, the two amide groups are not coplanar, as the dihedral angles of the respective NCO groups are similar at 50.37 (14) and 51.22 (13)°. However, the orientations of the substituent phenyl rings with the central naphthalene system are significantly different for the two molecules; for one molecule, these dihedral angles are 80.29 (3) and 80.95 (4)°, while for the second molecule they are 86.63 (3) and 72.82 (4)°. The crystal packing shows the molecules to be linked by weak C—H...O interactions.
syn-3-(4-Chlorobenzyl)-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ol
Authors: Kudryavtsev Konstantin V. , Vatsadze Sergey Z. , Semashko Vera S. , Churakov Andrei V.
Published: July 2012

In the title compound, C16H23ClN2O, both six-membered rings adopt chair conformations, thus allowing the formation of an intramolecular N—H...N hydrogen bond. In the crystal, adjacent molecules are combined into chains running along theacdiagonalviaO—H...N hydrogen bonds.
Angioadnexocentric nevus
Authors: HASHIMOTO Ken , AMANO Masahiro , SETOYAMA Mitsuru
Published: July 2012

An association of melanocytic nevus with eccrine glands has been well‐documented and well‐known as eccrine‐centered nevus. Non‐giant congenital nevi sometimes contain angiocentric and/or adnexocentric growth of nevus cells. Blood vessels are the most prominent site of nevus cell infiltration and propagation. In our specimen, the second was eccrine ducts. These selective sites of infiltration gave rise to a linear pattern of nevus cell distribution. Upon cursory examination at low magnification, vascular pathologies such as lymphocytic perivasculitis and particularly “coat‐sleeve‐like” pattern of erythema annulare centrifugum were suggested. S‐100 immunostained perivascular and periductal lymphocytoid cells while CD3, 4 and 8 for T cells, and CD20 and 79a for B cells, were all negative. S‐100 detected some invasive behavior of nevus cells penetrating into the vascular and ductal walls. However, Ki‐67 was negative in all cells, suggesting a benign nature of this lesion. It is postulated that intradermal nevus cells of fetal skin freely migrate through mesenchymal tissue and stop when they hit barriers such as blood vessels and eccrine ducts and propagate in situ. How does this random migration theory explain the blood vessels and eccrine ducts getting the largest share of nevus cells? It is because they are the largest barriers of fetal dermis.
Randomised clinical trial: the efficacy and safety of pancreatin enteric‐coated minimicrospheres (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis ‐ a double‐blind, placebo‐controlled study
Authors: Thorat V. , Reddy N. , Bhatia S. , Bapaye A. , Rajkumar J. S. , Kini D. D. , Kalla M. M. , Ramesh H.
Published: July 2012

Background

Pancreatic exocrine insufficiency (PEI) results in maldigestion, leading to abdominal pain, steatorrhoea, malnutrition and weight loss.

Aim

To assess the efficacy and safety of pancreatin (Creon 40000 MMS) in treating PEI due to chronic pancreatitis (CP).

Methods

This was a 1‐week, double‐blind, randomised, placebo‐controlled, parallel‐group, multicentre study in India. Men and women ≥18 years of age with proven CP and PEI [defined as a coefficient of fat absorption (CFA) ≤80% during run‐in phase] were randomised 1:1 to pancreatin or placebo (two capsules orally per main meal, one with snacks). The primary outcome measure was change in CFA from baseline to end of double‐blind treatment (analysis of covariance).

Results

Of 62 patients randomised (34 pancreatin, 28 placebo), 61 completed treatment; one patient in the placebo arm withdrew consent before completion. Patient characteristics were similar in both groups except for the proportion of men (pancreatin 82% vs. placebo 68%). Patients receiving pancreatin had a statistically significant greater improvement in fat absorption from baseline to the end of double‐blind treatment compared with those receiving placebo, with a least squares mean change (95% CI) in CFA of 18.5% (15.8–21.2) vs. 4.1% (1.0–7.2), respectively. This resulted in a treatment difference of 14.4% (10.3–18.5); P = 0.001. Patients receiving pancreatin also had a statistically significant greater improvement in nitrogen absorption and greater reductions in mean stool fat, stool frequency and stool weight compared with those receiving placebo. Treatment‐emergent adverse events occurred in 12 patients on pancreatin and in seven on placebo; none led to study discontinuation.

Conclusions

The results provide evidence for the efficacy of pancreatin (Creon 40000 MMS) in patients with pancreatic exocrine insufficiency due to chronic pancreatitis, and confirm that this formulation is well tolerated, with a good safety profile, at the dose administered.
Pharmacological evaluation of cimetidine, a new histamine H2‐receptor antagonist, in healthy man.
Authors: Burland WL , Duncan WA , Hesselbo T , Mills JG , Sharpe PC , Haggie SJ , Wyllie JH
Published: July 2012

Cimetidine, a new H2‐receptor antagonist, was safely administered to eighteen healthy man by the intravenous, intraduodenal or oral route. 2 When gastric secretion was maximally stimulated by either histamine or pentagastrin, the simultaneous administration of cimetidine produced marked inhibition of both acid and pepsin secretion. 3 Cimetidine was well absorbed by mouth and had a blood half‐life of 2 hours. 4 Cimetidine was rapidly excreted via the kidneys and about 70% of the excreted material was unchanged drug. 5 Clinical evaluation of cimetidine in patients with peptic ulceration is recommended.
The skeletal muscle response to the repeated administration of suxamethonium and its interaction with edrophonium in anaesthetised man.
Authors: Sugai N , Hughes R , Payne JP
Published: July 2012

Tetanic and single twitch contractions of the adductor pollicis muscle in man were recorded during repeated injections of suxamethonium (0.2 mg/kg or 0.1 mg/kg) every 15 minutes. 2 Tachyphylaxis to suxamethonium developed rapidly in every patient studied when single twitch contractions were observed but tetanic contractions later showed an increasingly prolonged recovery with repeated injections. 3 Edrophonium administered at the point of 50% recovery of the tetanic contractions in patients given suxamethonium (0.2 mg/kg) repeatedly first potentiated the blockade but when the tachyphylaxis had developed fully on the single twitch, usually after the third or fourth injection, the blockade of the tetanic contractions was reversed. 4 These findings indicate that the tachyphylaxis and the change in the nature of the blockade produced by suxamethonium in man take place at the same time and might be part of the same phenomenon.
Effect of intravenous injection of salbutamol in asthma.
Authors: May CS , Paterson JW , Spiro SG , Johnson AJ
Published: July 2012

The effect of i.v. salbutamol was compared with aerosol salbutamol in ten asthmatic patients. 2 A cumulative dose of salbutamol (300 mug) given in three separate injections over 45 min resulted in a mean increase in peak expiratory flow rate (PEFR) of 38.3% and FEV1 of 36%. 3 There was no significant difference in degree of bronchodilatation to the same dose of salbutamol administered intravenously or by aerosol. 4 Palpitations, tremor, and postural hypotension were common when the drug was injected intravenously over one minute, but did not occur after aerosol administration. 5 It is suggested that sulbutamol by intravenous injection is a useful addition to the treatment of acute asthma.
Procainamide absorption studies to test the feasibility of using a sustained‐release preparation.
Authors: Shaw TR , Kumana CR , Kaye CM , Padgham C , Kaspi T , Hamer J
Published: July 2012

Using in vitro techniques it was confirmed that whilst the release of procainamide from the conventional formulation (Pronestyl) was rapid, that from the sustained‐release preparation (Cardiorytmin Retard) occurred over a prolonged period. 2 The peak plasma procainamide concentrations after single doses of Cardiorytmin Retard were relatively lower and occurred later than those after single doses of Pronestyl. Furthermore, after reaching a peak, the fall in plasma procainamide concentration was less rapid after the sustained‐release preparation. Early urinary recovery of procainamide in patients and in healthy volunteers was greater after Pronestyl than after Cardiorytmin Retard, though overall recovery in urine was similar. These findings indicate that the absorption of the sustained‐release preparation is slower, though the overall bioavailabilities of the two preparations are almost the same. 3 These results confirm the feasibility of using a sustained‐release procainamide preparation, such as Cardiorytmin Retard, since it would be possible to administer the same amount of drug in fewer daily doses without plasma concentrations becoming ineffective towards the end of each dosing interval.
The effects of atenolol (tenormin) and methyldopa on simple tests of central nervous function.
Authors: Bayliss PF , Duncan SM
Published: July 2012

Two identical studies, one comparing the effect of single doses of a new beta‐adrenoceptor blocker, atenolol (Tenormin) (50 mg and 100 mg) and placebo, and the other comparing the effect of single doses of methyldopa (250 mg and 500 mg) and placebo, in healthy volunteers, were carried out. 2 In both studies the effect of the drugs upon reaction time, critical flicker frequency, subjective drowsiness, pulse rate and blood pressure was measured. 3 Atenolol produced no effect upon reaction time, critical flicker frequency or subjective feelings, while methyldopa produced a statistically significant prolongation of reaction time and a statistically significant increase in the subjective sensation of drowsiness. 4 Atenolol produced statistically significant reductions in systolic and diastolic blood pressure and in pulse rate while methyldopa was without effect. 5 It is concluded that atenolol is unlikely to produce the side effects of sedation or drowsiness.
Absorption of enteric and non‐enteric coated prednisolone tablets.
Authors: Hulme B , James VH , Rault R
Published: July 2012

1. Relative rates of absorption of enteric and non‐enteric preparations of prednisolone were measured in five renal transplant recipients. 2. The absorption of the enteric coated preparation is delayed and the peak plasma concentration is much lower than that attained using the same dose of the uncoated material. 3. The therapeutic implications of these observations are discussed.
Measurement of plasma prednisolone in man.
Authors: Wilson CG , Ssendagire R , May CS , Paterson JW
Published: July 2012

1. A modification of the competitive protein binding assay for prednisolone described by English, Chakraborty & Marks (1974) is presented. 2. Addition of pg quantities of [3H]‐prednisolone following oral dosage with prednisone or prednisolone. 3. Mean plasma half‐life and peak plasma concentrations in patients with respiratory disease seen following prednisolone administration agree well with previous studies in healthy volunteers performed by other workers using competitive protein binding and radioimmunoassay techniques. 4. A considerable inter‐patient variation in bioavailability after a standard dose of prednisolone (20 mg) was noted.
Prednisolone levels in the plasma and urine: a study of two preparations in man.
Authors: English J , Chakraborty J , Marks V , Trigger DJ , Thomson AG
Published: July 2012

1. A competitive protein binding method was used to measure prednisolone and cortisol in blood and urine of volunteers given prednisolone by mouth (15 mg) in the standard tablet form and a fortnight later a regulated release formulation of prednisolone metasulphobenzoate containing an equivalent amount of prednisolone. 3. Plasma prednisolone levels rose rapidly after the standard tablet and more slowly after the regulated release form. The normal activity of the hypothalamic‐pituitary‐adrenal axis as measured by the 09.00 h plasma cortisol concentration was present 24 h after ingestion of the regulated release preparation. In contrast, the 09.00 h plasma cortisol level was reduced in subjects 24 h after receiving prednisolone in the standard tablet form.
The plasma half‐life of antipyrine in chromic uraemic and normal subjects.
Authors: Maddocks JL , Wake CJ , Harber MJ
Published: July 2012

1. Antipyrine was given intravenously in a dose of 18 mg/kg body weight to twelve patients with chronic renal failure (plasma creatinine greater than 4.9 mg/100 ml) who were not taking drugs and twenty normal subjects. 2. Plasma antipyrine levels were measured by a specific method, the plasma half‐life of the drug was determined and used as an index of drug oxidation. 3. The mean (+/‐ s.d) plasma antipyrine half‐ life in patients with chronic renal failure (7.3 +/‐ 2.0 h) was significantly shorter than in normal subjects (13.2 +/‐ 4.3 h: P less than 0.002). There was no difference in the apparent volume of distribution of antipyrine between the two groups (P greater than 0.6). 4. Pretreatment of five patients with chronic renal failure and seven normal subjects with antipyrine or phenobarbitone for weeks significantly shortened the mean plasma antipyrine half‐life from 7.4 +/‐ 2.5 h to 5.0 +/‐ 1.5 h in uraemics (P less than 0.005) and from 13.2 +/‐ 4.5 h to 6.9 +/‐ 1.5 h in normal subjects (P less than 0.0025).5. These results suggest that oxidation of antipyrine by hepatic microsomal enzymes is increased in patients with chronic renal failure, but a state of maximal induction of these enzymes was not observed. The clinical implication of this finding with regard to the association between liver microsomal enzyme induction and vitamin D resistant osteomalacia is discussed.
Determination of the optimum dose of subcutaneous salbutamol in asthmatic patients.
Authors: Coady TJ , Stewart CJ , Davis HJ
Published: July 2012

Saline and salbutamol (250 mug, 500 mug, 750 mug, and 1000 mug) injections were administered under double‐blind conditions to seven chronic stable asthmatic patients. The response on the respiratory system (FEV1, FVC) and cardiovascular system (pulse rate, blood pressure and ECG) was monitored for 3 hours. Increasing the dose of salbutamol increased the peak and weighted average effects of FEV1 and pulse rate. The optimum dose, a titration of desired increases in FEV1 and undesirable increases in pulse rate, is 500 mug but doses up to 1000 mug may be administered if necessary.
beta‐Adrenoceptor blocking activity and duration of action of pindolol and propranolol in healthy volunteers.
Authors: Aellig WH
Published: July 2012

The beta‐adrenoceptor blocking activities of pindolol and propranolol have been investigated in healthy male volunteers. Pindolol was about forty times more potent than propranolol in reducing isoprenaline‐ induced tachycardia. Pindolol (5 mg) and propranolol (u99 mg) were approximately equiactive in reducing exercise‐induced tachycardia, 2 h after oral administration. The duration of action of pindolol is significantly longer than that of propranolol; 24 h after pindolol (kmg), 36+/‐5% of the masimum effect were still present, and after propranolol (100 mg) 16+/‐4% remained. Despite the long duration of action of pindolol, there was no evidence for cumulation during oral administration of 5 mg t.d.s. for 5 days.
The effect of end‐stage renal failure and haemodialysis on the elimination kinetics of sotalol.
Authors: Tjandramaga TB , Verbeeck R , Thomas J , Verbesselt R , Verberckmoes R , Schepper PJD
Published: July 2012

A single oral dose of sotalol (160 mg) was administered to control subjects with normal renal function and patients with chronic renal failure in the interdialysis period to estimate the elimination kinetics of the drug. Sotalol concentrations in body fluids were measured fluorimetrically using a modified Garrett and Schnelle (1971) method. Mean plasma half‐life (T 1/2) was approximately 5 h in normals, 42 h in patients off‐dialysis. During haemodialysis the mean plasma half‐time was on the average 7 hours. Comulative urinary excretion of the drug was considerably lower in the patient group: 9% of the dose in 48 h as opposed to 61% in normals. Comparison of sotalol concentrations in plasma versus ultrafiltrate from the coil kidney indicates that the drug in vivo is negligible bound to plasma proteins in remal patients. The net‐lowering effect of a 6 to 7 h haemodialysis on the plasma concentration decay line was by 20%. Post‐dialysis plasma concentration data suggest that the rate at which sotalol returns to plasma from body tissues appears to be the rate‐controlling factor in the elimination of sotalol by haemodialysis.
Human pharmacokinetic and pharmacodynamic studies on the atenolo (ICI 66,082), a new cardioselective beta‐adrenoceptor blocking drug.
Authors: Conway FJ , Fitzgerald JD , McAinsh J , Rowlands DJ , Simpson WT
Published: July 2012

The beta‐adrenoceptor blocking effects of orally administered atenolol on tachycardia induced by intravenous isoprenaline or by exercise have been studied in normal volunteers, and compared with the effects of similar doses of propranolol. The blood levels of atenolol at various times after oral administration were determined by g.l.c. and correlated with the degree of inhibition of tachycardia. Atenolol was shown to be a beta‐adrenoceptor blocker in man, as in animals, in that it antagonized the chronotropic effects of isoprenaline and of exercise. The inhibitory effect of atenolol on exercise‐induced tachycardia was evident at a concentration in blood of 0.2 mug/ml and virtually complete at 0.5 mug/ml. Higher concentrations than this did not produce significantly greater blockade. The effects of atenolol on exercise‐induced tachycardia were similar to those of propranolol but it was less effective in blocking the rise in heart rate and fall in diastolic blood‐pressure induced by intravenous infusion of isoprenaline. This separation of effects is considered characteristic of drugs causing preferential blockade of cardiac beta‐adrenoreceptors. The half‐life of atenolol in blood was calculated to ablut 9 hours.
Comparison of propranolol and practolol in the management of hyperthyroidism.
Authors: Murchison LE , Bewsher PD , Chesters MI , Ferrier WR
Published: July 2012

Twenty‐one hyperthyroid patients participated in an 8‐week double‐blind crossover trial of propranolol and practolol, and the effecte of these drugs on the clinical and metabolic features of the disease were studied. Propranolol was marginally more effective than practolol, as measured by the hyperthyroid diagnostic index and anxiety scale. Propranolol produced a significant reduction in the serum concentration ratio of tri‐iodothyronine to thyroxine, compatible with partial inhibition of peripheral deiodination of thyroxine. Adverse reactions occurred more frequently with propranolol than with practolol. In veiw of the efficacy of practoloo, further trials in hyperthyroid patients of newer beta1‐adrenoceptor antagonists, preferably without partial agonist activity, are indicated.
The influence of smoking on the intersubject variation in pentazocine elimination.
Authors: Vaughan DP , Beckett AH , Robbie DS
Published: July 2012

The cumulative urinary excretion over 24 h of pentazocine, under conditions of acidic urinary pH, has been measured in smokers and non‐ smokers using both male and female subjects (seventy subjects in total). A restricted urban population was studied. An overall three‐ fold inter‐subject variation in elimination was observed. The cumulative urinary excretion of pentazocine was normally distributed in both smokers and non‐smokers. Smokers metabolize 40% more pentazocine than non‐smokers. It is concluded that induction is principally responsible for the observed subject variability.
Haemodynamic long‐term effects of a new beta‐adrenoceptor blocking drug, atenolol (ICI 66082), in essential hypertension.
Authors: Lund‐Johansen P
Published: July 2012

1 Thirteen men with untreated essential hypertension in WHO stage I were studied on an outpatient basis to evaluate the haemodynamic long‐ tern effect of a new beta‐adrenoceptor blocker, atenolol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial branchial pressure were recorded at rest in a supine and sitting position and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with atenolol (dose 100‐200 mg/day) as the sole drug for 1 year and the haemodynamic study was repeated. 4 The blood pressure was reduced approximately 18% both at rest and during exercise, the heart rate approximately 25% and the cardiac output 16% at rest supine and 27% at rest sitting. During exercise the reductions in cardiac output were approximately 20%. The calculated total peripheral resistance was not decreased compared to pretreatment values. The mean arterial pressure‐heart rate product was reduced almost 40%. 5 Apart from temporary muscular fatigue during the first weeks, no side‐effects were seen. 6 Atenolol is an effective blood pressure lowering drug in mild and moderate hypertension, but the drop in blood pressure is associated with marked reduction in heart rate and cardiac output at rest as well as during exercise.
The effect of pindolol on plasma renin activity and blood pressure in hypertensive patients.
Authors: Lancaster R , Goodwin TJ , Peart WS
Published: July 2012

1 The effect of pindolol administered to twenty‐six patients with hypertension of unknown origin was compared with respect to blood pressure and plasma renin activity change after increase of the dose over a period of 6 weeks. 2 There was no clear correlation between the fall of plasma renin activity, which in some patients was very marked, and the fall in blood pressure. Some patients with a fall in plasma renin activity did not drop their pressure. Conversely, some with a fall of pressure did not drop their plasma renin activity. 3 The addition of hydrochlorothiazide to the pindolol finally caused further lowering of the blood pressure in all but one patient and the plasma renin activity rose in all but two patinets. There was no clear correlation between change in plasma renin activity and the effect on blood pressure.