bluuebunny/crossref_metadata_2025 huggingface dataset:
An artificial tetramerization domain restores efficient assembly of functional Shaker channels lacking T1
Authors: Zerangue Noa , Jan Yuh Nung , Jan Lily Yeh
Published: July 2012

One feature shared by all Shaker-type voltage-gated K
+
channels is a highly conserved domain (T1) located in the cytoplasmic N terminus. The T1 domain is a key determinant of which subtypes can form heteromultimeric channels, suggesting that T1 functions during channel assembly. To better define the role of T1 during channel assembly and separate this function from potential contributions to channel permeation and gating, we replaced the T1 domain (residues 96–183) of ShakerB with a coiled-coil sequence (GCN4-LI) that forms parallel tetramers. Deleting T1 dramatically, but not completely, abolished channel formation under most expression conditions. Channels lacking T1 are functional and K
+
-selective, although they activate at more hyperpolarized membrane potentials and inactivate less completely. Insertion of the artificial tetramerization domain (GCN4-LI) restored efficient channel formation, suggesting that tetramerization of the cytoplasmic T1 domain promotes transmembrane channel assembly by increasing the effective local subunit concentration for T1 compatible subunits. We propose that T1 tetramerization promotes subfamily-specific assembly through kinetic partitioning of the assembly process, but is not required for subsequent steps in channel assembly and folding.
Mechanisms of use-dependent plasticity in the human motor cortex
Authors: Bütefisch Cathrin M. , Davis Benjamin C. , Wise Steven P. , Sawaki Lumy , Kopylev Leonid , Classen Joseph , Cohen Leonardo G.
Published: July 2012

Practicing movements results in improvement in performance and in plasticity of the motor cortex. To identify the underlying mechanisms, we studied use-dependent plasticity in human subjects premedicated with drugs that influence synaptic plasticity. Use-dependent plasticity was reduced substantially by dextromethorphan (an
N-
methyl-
d
-aspartate receptor blocker) and by lorazepam [a γ-aminobutyric acid (GABA) type A receptor-positive allosteric modulator]. These results identify
N
-methyl-
d
-aspartate receptor activation and GABAergic inhibition as mechanisms operating in use-dependent plasticity in intact human motor cortex and point to similarities in the mechanisms underlying this form of plasticity and long-term potentiation.
Extracurricular activities in young applicants’ résumés: What are the motives behind their involvement?
Authors: Roulin Nicolas , Bangerter Adrian
Published: July 2012

Applicants use résumés to demonstrate their knowledge, skills, abilities, and other personal characteristics (KSAOs) to recruiters, through education and job‐related or non‐job‐related experiences. But research suggests that the situation for young applicants is especially competitive, since they increasingly enter the labour market with similar educational credentials and limited job‐related experience. They may thus use non‐job‐related experiences, such as participation in extracurricular activities (ECAs) during their studies, to demonstrate KSAOs to recruiters, but also to add distinction and value to their credentials. ECAs may therefore become more important in the selection of young applicants. Yet few studies have undertaken a comprehensive and systematic analysis of the relationships students have with these activities. The purpose of this study was to investigate to what extent students’ involvement in ECAs is due to internal (e.g., passion) or external (e.g., résumé‐building) motives, and what factors influence these motives. Results from a study with 197 students suggest that students engage in ECAs mainly out of internal motives. But external motives are stronger for activities started closer to entering the labour market, for students active in associative or volunteering activities (as compared to sports or artistic activities), and for students holding leadership positions in their activities. Our results suggest that labour market pressure may be a key component of applicants’ involvement in ECAs. Also, organizations and recruiters may want to consider that students tend not to engage in ECAs purely out of internal motives, but also to add value to their credentials and match employers’ expectations.
Experiences and psychosocial adjustment of Darfuri female students affected by war: An exploratory study
Authors: Badri Alia , Van den Borne H. W. , Crutzen Rik
Published: July 2012

This paper presents the personal accounts of Darfuri students studying at Ahfad University for Women in Omdurman, Sudan. Their war‐related exposure, current ongoing life challenges, emotional distress, and coping strategies were explored using a semistructured interview protocol with a sample of 20 students. Through interpretative phenomenological analysis (IPA), the Darfuri students’ stories illustrated that they were exposed to an array of traumatic war events, including personal experiences of parental separation, injury and death of family members, and shortages of essential life‐sustaining supplies in internally displaced camps. Also, they were confronted with myriad current life hassles and urban‐cultural challenges, including being physically distant from their families, and losing the shelter of parents, the encouragement of extended family members, and their rich and familiar social support networks. Urban‐cultural challenges and lack of environmental mastery applied to most Darfuri participants as they relocated to Omdurman city, which included negotiating an unfamiliar transport system, learning the routes and directions to important city landmarks, and insufficient funds for basic hygienic essentials. Emotional distress reactions were coded by forming two distinct lists: directly mentioned by the participant; and observations of emotional manifestation during the interview. Patterns emerged that may be similar to symptoms of mood and anxiety disorders; for example, the DSM‐IV criteria for symptoms of generalized anxiety disorder and major depression. Strong religious practices and beliefs (such as praying and reading the Quran), ability to form interpersonal relationships, availability of social support networks, and a positive future outlook seemed to augment their ability to cope with their subsequent emotional distress owing to war‐related exposures, current ongoing life hassles and urban‐cultural challenges.
Religious and national group identification in adolescence: A study among three religious groups in Mauritius
Authors: Ng Tseung‐Wong Caroline , Verkuyten Maykel
Published: July 2012

Religious group identification is an important but understudied social identity. The present study investigates religious group identification among adolescents of different faiths (Hindu, Muslim, Christian) living in multicultural Mauritius. It further explores how religious and national group identities come together among religious majority and minority adolescents. For three age groups (11 to 19 years, N = 2152) we examined the strength of adolescents’ religious and national group identification, the associations between these two identities, and the relationships to global self‐esteem. Across age and religious group, participants reported stronger identification with their religious group than with the nation. Identification with both categories declined with age, with the exception of Muslims, whose strong religious identification was found across adolescence. The association between religious and national identification was positive, albeit stronger for the majority group of Hindus and for early adolescents. We examined the manner in which religious and national identities come together using a direct self‐identification measure and by combining the separate continuous measures of identification. Four distinct clusters of identification (predominant religious identifiers, dual identifiers, neutrals, and separate individuals) that were differently associated with global self‐esteem were found. Dual identifiers reported the highest level of global self‐esteem. The clusters of identification did not fully correspond to the findings for the direct self‐identification measure. The results are discussed in terms of the meaning of dual identity and the positive manner in which adolescents can manage their multiple identities while taking into account the ideological framework in which those identities are played out.
Modal and temporal argumentation networks
Authors: Barringer H. , Gabbay D.M. , Woods J.
Published: July 2012

The traditional Dung networks depict arguments as atomic and study the relationships of attack between them. This can be generalised in two ways. One is to consider various forms of attack, support, feedback, etc. Another is to add content to nodes and put there not just atomic arguments but more structure, e.g. proofs in some logic or simply just formulas from a richer language. This paper offers to use temporal and modal language formulas to represent arguments in the nodes of a network. The suitable semantics for such networks is Kripke semantics. We also introduce a new key concept of usability of an argument. This is the beginning of a continuing research for adding contents to the nodes of an argumentation network. This research will allow us to address notions like ‘what does it exactly mean for a node to attack another’ or ‘what does it mean for a network to be consistent’ or ‘can we give proper proof rules to manipulate networks’, and more.
Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor
Authors: Nakahashi-Oda Chigusa , Tahara-Hanaoka Satoko , Shoji Masamichi , Okoshi Yasushi , Nakano-Yokomizo Takako , Ohkohchi Nobuhiro , Yasui Teruhito , Kikutani Hitoshi , Honda Shin-ichiro , Shibuya Kazuko , Nagata Shigekazu , Shibuya Akira
Published: July 2012

When a cell undergoes apoptosis, phosphatidylserine (PS) is exposed on the outer leaflet of the plasma membrane. PS acts as an “eat-me” signal to direct phagocytes expressing PS receptors to engulf the apoptotic cell. We recently reported that the immunoreceptor CD300a, which is expressed on myeloid cells, is a PS receptor. We show that CD300a does not facilitate macrophage phagocytosis of apoptotic cells. Instead, CD300a delivers an inhibitory signal in mast cells to suppress production of LPS-induced inflammatory cytokines and chemokines. After cecal ligation and puncture (CLP), when a large number of cells undergo apoptosis in the peritoneal cavity, CD300a-deficient peritoneal mast cells produced more chemoattractant and recruited more neutrophils than did wild-type (WT) mast cells. As a result, CD300a-deficient mice showed increased neutrophil recruitment and improved bacterial clearance in the peritoneal cavity, and survived longer than WT mice. Antibody blockade of CD300a–PS interactions improved bacterial clearance and extended survival of WT mice subjected to CLP. These results indicated that CD300a is a nonphagocytic PS receptor that regulates mast cell inflammatory responses to microbial infections.
Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein
Authors: Klein Florian , Gaebler Christian , Mouquet Hugo , Sather D. Noah , Lehmann Clara , Scheid Johannes F. , Kraft Zane , Liu Yan , Pietzsch John , Hurley Arlene , Poignard Pascal , Feizi Ten , Morris Lynn , Walker Bruce D. , Fätkenheuer Gerd , Seaman Michael S. , Stamatatos Leonidas , Nussenzweig Michel C.
Published: July 2012

Two to three years after infection, a fraction of HIV-1–infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti–HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti–HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti–HIV-1 serologic breadth and potency should not be limited to single epitopes.
A nonconstant coefficients differential operator associated to slice monogenic functions
Authors: Colombo Fabrizio , González-Cervantes J. , Sabadini Irene
Published: July 2012

Slice monogenic functions have had a rapid development in the past few years. One of the main properties of such functions is that they allow the definition of a functional calculus, called

S
S

-functional calculus, for (bounded or unbounded) noncommuting operators. In the literature there exist two different definitions of slice monogenic functions that turn out to be equivalent under suitable conditions on the domains on which they are defined. Both the existing definitions are based on the validity of the Cauchy-Riemann equations in a suitable sense. The aim of this paper is to prove that slice monogenic functions belong to the kernel of the global operator defined by
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="upper G left-parenthesis x right-parenthesis colon equals StartAbsoluteValue x underbar EndAbsoluteValue squared StartFraction partial-differential Over partial-differential x 0 EndFraction plus x underbar sigma-summation Underscript j equals 1 Overscript n Endscripts x Subscript j Baseline StartFraction partial-differential Over partial-differential x Subscript j Baseline EndFraction comma">

G
(
x
)
:=

|

x
_

|

2

∂

∂

x
0

 
+
 

x
_

 

∑

j
=
1

n

x
j

∂

∂

x
j

,

G(x):=|\underline {x}|^2\frac {\partial }{\partial x_0} \ + \ \underline {x} \ \sum _{j=1}^n x_j\frac {\partial }{\partial x_j},

where

x
_

\underline {x}

is the 1-vector part of the paravector

x
=

x
0

+

x
_

x=x_0+\underline {x}

and

n
∈

N

n\in \mathbb {N}

. Despite the fact that

G
G

has nonconstant coefficients, we are able to prove that a subclass of functions in the kernel of

G
G

have a Cauchy formula. Moreover, we will study some relations among the three classes of functions and we show that the kernel of the operator

G
G

strictly contains the functions given by the other two definitions.
Adolescent fertility and risky environments: a population-level perspective across the lifespan
Authors: Placek Caitlyn D. , Quinlan Robert J.
Published: July 2012

Timing of first reproduction is a key life-history variable with important implications for global economic development and health. Life-history theory predicts that human reproductive strategies are shaped by mortality regimes. This study provides the first test of the relationship between population-level adolescent fertility (AF) and extrinsic risk at two time points. Data are from United Nations database and were analysed using mediation and moderation techniques. The goals were to determine whether (i) early risk has a stronger impact on fertility than current risk; (ii) current risk mediates the relationship between early risk and fertility outcomes; and (iii) different levels of early risk influence the relationship between current risk and fertility. Results indicated that current risk partially mediated the relationship between early risk and fertility, with early risk having the strongest impact on reproduction. Measures for early and current mortality did not show significant interaction effects. However, a series of separate regression analyses using a quantile split of early risk indicated that high levels of early risk strengthened the relationship between current risk and AF. Overall, these findings demonstrate that reproductive strategies are significantly influenced by fluctuations of early mortality as well as current environmental cues of harshness.
Ultrasonographic Prevalence and Factors Predicting Left Ventricular Diastolic Dysfunction in Patients with Liver Cirrhosis: Is There a Correlation between the Grade of Diastolic Dysfunction and the Grade of Liver Disease?
Authors: Papastergiou Vasilios , Skorda Lamprini , Lisgos Phillipos , Papakonstantinou Nikolaos , Giakoumakis Tsampikos , Ntousikos Konstantinos , Karatapanis Stylianos
Published: July 2012

Presence of cardiac dysfunction has been associated with an unfavorable prognosis in patients with liver cirrhosis. In the present study, 92 consecutive, newly-diagnosed patients with liver cirrhosis were prospectively evaluated. Liver disease was graded according to the modified Child-Turcotte-Pugh (CTP) score whereas left ventricular diastolic function was assessed by Doppler-echocardiography and graded (Stage 0 to 4) according to current guidelines. Overall, DD was diagnosed in 55/92 (59.8%) patients [DD-stage-1: 36/92 (39.1%), DD-stage-2: 19/92 (20.6%)]. Prevalence of DD-stage-1 among the different stages of liver cirrhosis was: CTP-class A: 11/29 (37.9%), B: 15/39 (38.5%), C: 10/24 (41.6%), (P>0.05in all comparisons), whereas for DD-stage-2 the corresponding proportions were CTP-class A: 3/29 (10.3%), B: 5/39 (12.8%), C: 11/24 (45.8%), (P=0.0009between CTP-class C versus A and B). Age > 53 years (Odd’s Ratio [OR]: 4.2; 95% confidence interval [CI]: 1.5–12.1) and CTP-class C (OR: 4.6; 95% CI: 1.1–20) could independently predict DD. No relation between presence of DD and the etiology of the liver disease was found. We conclude that DD is a common feature in liver cirrhosis. DD-stage-1 is fairly prevalent among all CTP-classes whereas DD-stage-2 seems to be characteristic of the advanced liver disease (CTP-class C). A high level of awareness for the presence of the syndrome is required, especially if cirrhotic patients are CTP-class C and/or of older age.
A functional methylome map of ulcerative colitis
Authors: Häsler Robert , Feng Zhe , Bäckdahl Liselotte , Spehlmann Martina E. , Franke Andre , Teschendorff Andrew , Rakyan Vardhman K. , Down Thomas A. , Wilson Gareth A. , Feber Andrew , Beck Stephan , Schreiber Stefan , Rosenstiel Philip
Published: July 2012

The etiology of inflammatory bowel diseases is only partially explained by the current genetic risk map. It is hypothesized that environmental factors modulate the epigenetic landscape and thus contribute to disease susceptibility, manifestation, and progression. To test this, we analyzed DNA methylation (DNAm), a fundamental mechanism of epigenetic long-term modulation of gene expression. We report a three-layer epigenome-wide association study (EWAS) using intestinal biopsies from 10 monozygotic twin pairs (n= 20 individuals) discordant for manifestation of ulcerative colitis (UC). Genome-wide expression scans were generated using Affymetrix UG 133 Plus 2.0 arrays (layer 1). Genome-wide DNAm scans were carried out using Illumina 27k Infinium Bead Arrays to identify methylation variable positions (MVPs, layer 2), and MeDIP-chip on Nimblegen custom 385k Tiling Arrays to identify differentially methylated regions (DMRs, layer 3). Identified MVPs and DMRs were validated in two independent patient populations by quantitative real-time PCR and bisulfite-pyrosequencing (n= 185). The EWAS identified 61 disease-associated loci harboring differential DNAm incisof a differentially expressed transcript. All constitute novel candidate risk loci for UC not previously identified by GWAS. Among them are several that have been functionally implicated in inflammatory processes, e.g., complement factorCFI, the serine protease inhibitorSPINK4, and the adhesion moleculeTHY1(also known asCD90). Our study design excludes nondisease inflammation as a cause of the identified changes in DNAm. This study represents the first replicated EWAS of UC integrated with transcriptional signatures in the affected tissue and demonstrates the power of EWAS to uncover unexplained disease risk and molecular events of disease manifestation.
Unique Drought Resistance Functions of theHighly ABA-InducedClade A Protein Phosphatase 2Cs
Authors: Bhaskara Govinal Badiger , Nguyen Thao Thi , Verslues Paul E.
Published: July 2012

Six Arabidopsis (Arabidopsis thaliana) clade A protein phosphatase 2Cs (PP2Cs) have established abscisic acid (ABA) signaling roles; however, phenotypic roles of the remaining three “HAI” PP2Cs, Highly ABA-Induced1 (HAI1), AKT1-Interacting PP2C1/HAI2, and HAI3, have remained unclear. HAI PP2C mutants had enhanced proline and osmoregulatory solute accumulation at low water potential, while mutants of other clade A PP2Cs had no or lesser effect on these drought resistance traits. hai1-2 also had increased expression of abiotic stress-associated genes, including dehydrins and late embryogenesis abundant proteins, but decreased expression of several defense-related genes. Conversely, the HAI PP2Cs had relatively less impact on several ABA sensitivity phenotypes. HAI PP2C single mutants were unaffected in ABA sensitivity, while double and triple mutants were moderately hypersensitive in postgermination ABA response but ABA insensitive in germination. The HAI PP2Cs interacted most strongly with PYL5 and PYL7 to -10 of the PYL/RCAR ABA receptor family, with PYL7 to -10 interactions being relatively little affected by ABA in yeast two-hybrid assays. HAI1 had especially limited PYL interaction. Reduced expression of the main HAI1-interacting PYLs at low water potential when HAI1 expression was strongly induced also suggests limited PYL regulation and a role of HAI1 activity in negatively regulating specific drought resistance phenotypes. Overall, the HAI PP2Cs had greatest effect on ABA-independent low water potential phenotypes and lesser effect on classical ABA sensitivity phenotypes. Both this and their distinct PYL interaction demonstrate a new level of functional differentiation among the clade A PP2Cs and a point of cross talk between ABA-dependent and ABA-independent drought-associated signaling.
2,3,9,10,15,16-Hexaazatetracyclo[6.6.2.04,16.011,15]hexadecane dihydrate
Authors: How Fiona N.-F. , Rahima Z. A. , Tan Yee Seng , Abdul Halim S. Nadiah , Ng Seik Weng
Published: July 2012

The four six-membered fused rings in the title compound, C10H20N6·2H2O, adopt chair conformations; the H atoms of the four secondary N atoms occupy axial positions. Hydrogen bonds of the types N—H...N, N—H...O and O—H...N link the organic and water molecules into a three-dimensional network.
Bis[1-phenyl-3-(1H-1,2,4-triazol-1-yl-κN4)propan-1-one]bis(thiocyanato-κN)copper(II)
Authors: Cai Hua , Guo Ying , Li Jian-Gang
Published: July 2012

The title compound, [Cu(NCS)2(C11H11N3O)2], contains two independent CuIIatoms. Each CuIIatom, lying on an inversion center, is coordinated by two N atoms from two NCS−anions and two N atoms from two monodentate 1-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-one ligands in a distorted square-planar geometry. Two S atoms from adjacent molecules occupy the axial positions with long Cu...S distances [3.0495 (10) and 3.1045 (9) Å] and complete the overall distorted octahedral coordination sphere. Weak intermolecular C—H...O hydrogen bonds are present.
2-(Anthracen-9-yl)-10-methoxybenzo[h]quinoline acetone hemisolvate
Authors: Dong Zhenming , Liu Bo , Cui Xinxin , Liu Yufang
Published: July 2012

The asymmetric unit of the title structure, C28H19NO·0.5C3H6O, comprises one 2-(anthracen-9-yl)-10-methoxybenzo[h]quinoline molecule and an acteone molecule with an occupany of 0.5. The solvent molecule is disordered around a centre of symmetry. Its occupancy was determined from NMR data and kept fixed during the refinement. The two conjugated ring systems of the molecule are almost perpendicular to each other; the interplanar angle between the anthracene and quinoline ring systems is 84.9 (2)°.
(E)-2-(2,3-Dimethylanilino)-N′-(thiophen-2-ylmethylidene)benzohydrazide
Authors: Fun Hoong-Kun , Chia Tze Shyang , Bhat Mashooq A. , Al-Omar Mohamed A. , Abdel-Aziz Hatem A.
Published: July 2012

In the title compound, C20H19N3OS, the central benzene ring makes dihedral angles of 45.36 (9) and 55.33 (9)° with the thiophene ring and the dimethyl-substituted benzene ring, respectively. The dihedral angle between the thiophene ring and dimethyl-substituted benzene ring is 83.60 (9)°. The thiophene ring and the benzene ring are twisted from the mean plane of the C(=O)—N—N=C bridge [maximum deviation = 0.0860 (13) Å], with dihedral angles of 23.86 (9) and 24.77 (8)°, respectively. An intramolecular N—H...O hydrogen bond generates anS(6) ring. In the crystal, molecules are linked by N—H...O and C—H...O hydrogen bonds to the same acceptor atom, forming sheets lying parallel to thebcplane. The crystal packing also features C—H...π interactions.
Bis(μ-2-carboxymethyl-2-hydroxybutanedioato)bis[diaquamanganese(II)]–1,2-bis(pyridin-4-yl)ethane–water (1/1/2)
Authors: Hwang In Hong , Kim Pan-Gi , Kim Cheal , Kim Youngmee
Published: July 2012

The asymmetric unit of the title compound, [Mn2(C6H6O7)2(H2O)4]·C12H12N2·2H2O, comprises half of a centrosymmetric dimer, half of a 1,2-bis(pyridin-4-yl)ethane and one water molecule. Two citrate ligands bridge two MnIIions, the MnIIion being coordinated by four O atoms from the citrate(2−) ligands and two water O atoms, forming a distorted octahedral environment. In the crystal, O—H...O hydrogen bonds link the centrosymmetric dimers and lattice water molecules into a three-dimensional structure which is further stabilized by intermolecular π–π interactions [centroid–centroid distance = 3.792 (2) Å].
Evaluation of the CEL‐100 videolaryngoscopeTM for double‐lumen tracheal tube insertion after failure using the Macintosh laryngoscope
Authors: Lin W. Q. , Quan S. B. , Liu W. J. , Zhang T. H. , Li H. T. , Zhong Z. J. , Cao L. H.
Published: July 2012

We prospectively evaluated the CEL‐100 videolaryngoscopeTM for insertion of double‐lumen tracheal tubes in 48 consecutive patients who had been found to have an unanticipated Cormack and Lehane grade 3 (n = 43) and grade 4 (n = 5) laryngeal view and in whom two attempts at tracheal intubation using the Macintosh laryngoscope had failed. When the CEL‐100 was subsequently employed, the glottic view improved in 45 (94%) patients. The view improved by one grade in 15 (31%) patients and by two grades in 30 (63%) patients, compared with the Macintosh blade (p < 0.001). Double‐lumen tracheal tube insertion was successful when using the CEL‐100 in 43 out of 48 patients (90%; 95% CI 81–98%). This occurred on the first attempt in 27 (56%) patients, 14 (29%) on the second and two (4%) on the third. We conclude that the CEL‐100 videolaryngoscope is an effective device in this context, and we therefore propose that this device can be used in circumstances when double‐lumen tube insertion proves difficult.
Effects of sugammadex and rocuronium mast cell number and degranulation in rat liver
Authors: Tomak Y. , Yılmaz A. , Bostan H. , Tümkaya L. , Altuner D. , Kalkan Y. , Erdivanlı B.
Published: July 2012

We investigated the effect of rocuronium‐ and sugammadex‐induced mast cell increase and degranulation in rat portal triads. Forty‐two rats, in six groups, received either rocuronium 1 mg.kg−1; sugammadex 15 mg.kg−1; sugammadex 100 mg.kg−1; rocuronium 1 mg.kg−1 and 5 min later, sugammadex 15 mg.kg−1; rocuronium 1 mg.kg−1 and 5 min later, sugammadex 100 mg.kg−1; or isotonic saline. Total mast cell numbers were significantly higher with rocuronium only, than in all other groups (p < 0.003), although in all active groups, the number was greater than the control. Total mast cell number was significantly higher with rocuronium and low‐dose sugammadex compared with low‐dose sugammadex only. The number of tryptase‐positive mast cells with rocuronium only was significantly higher than in all other groups (p < 0.003). Tryptase‐positive mast cell numbers in both groups receiving both rocuronium and sugammadex were significantly higher compared with both groups receiving sugammadex only. Rocuronium increased mast cell numbers, and degranulation was mitigated by sugammadex. These results suggest that sugammadex may be beneficial in treatment of rocuronium‐induced anaphylaxis.
Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass*
Authors: Sharma V. , Fan J. , Jerath A. , Pang K. S. , Bojko B. , Pawliszyn J. , Karski J. M. , Yau T. , McCluskey S. , Wąsowicz M.
Published: July 2012

We conducted a study to assess pharmacokinetics of high‐dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High‐dose tranexamic acid involved a bolus of 30 mg.kg−1 infused over 15 min followed by a 16 mg.kg−1.h−1 infusion until chest closure with a 2 mg.kg−1 load within the pump prime. Tranexamic acid followed first‐order kinetics best described using a two‐compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra‐operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high‐dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high‐risk cardiac surgery needs to be refined.
Simultaneous oral therapeutic and intravenous 14C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin
Authors: Boulton David W. , Kasichayanula Sreeneeranj , Keung Chi Fung (Anther) , Arnold Mark E. , Christopher Lisa J. , Xu Xiaohui (Sophia) , LaCreta Frank
Published: July 2012

Aim

To determine the absolute oral bioavailability (Fp.o.) of saxagliptin and dapagliflozin using simultaneous intravenous 14C‐microdose/therapeutic oral dosing (i.v.micro + oraltherap).

Methods

The Fp.o. values of saxagliptin and dapagliflozin were determined in healthy subjects (n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography‐tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively.

Results

The geometric mean point estimates (90% confidence interval) Fp.o. values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap.

Conclusions

Simultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability.
Awareness and knowledge of developmental co‐ordination disorder among physicians, teachers and parents
Authors: Wilson B. N. , Neil K. , Kamps P. H. , Babcock S.
Published: July 2012

Background

Obtaining a diagnosis of developmental co‐ordination disorder (DCD) is a long, inconsistent and frustrating journey for families, with apparently little awareness of DCD in schools or the medical community.

Methods

An online survey was completed by 1297 participants: parents (n = 501), teachers (n = 202), family/general physicians (n = 339) and paediatricians (n = 255).

Results

Only 20% of the sample had knowledge of DCD, with 41% of the paediatricians and 23% of family/general physicians familiar. Of participants who have awareness, only 11–59% have knowledge of the impact of DCD on social, emotional and physical health. Less than 30% of physicians have awareness of the secondary consequences. Few physicians diagnose DCD and less than one‐third believe it is easy to make a diagnosis; this is in contrast to the fact that most parents report confidence in their physician's ability to make a timely diagnosis.

Conclusions

If less than one‐half of physicians have knowledge of DCD and even fewer are knowledgeable of the secondary consequences of the condition, it is not surprising that DCD is infrequently diagnosed and that families need to search for support. This survey confirms observations that the condition is not well known and there is a need for greater awareness of DCD.
Blow fly Lucilia sericata nuclease digests DNA associated with wound slough/eschar and with Pseudomonas aeruginosa biofilm
Authors: BROWN A. , HOROBIN A. , BLOUNT D. G. , HILL P. J. , ENGLISH J. , RICH A. , WILLIAMS P. M. , PRITCHARD D. I.
Published: July 2012

In chronic wounds, it may be clinically important to remove extracellular bacterial and patient DNA as its presence may impede wound healing and promote bacterial survival in biofilm, in which extracellular DNA forms part of the biofilm architecture. As medicinal maggots, larvae of Lucilia sericata Meigen (Diptera: Calliphoridae) have been shown to efficiently debride wounds it became of interest to investigate their excretions/secretions (ES) for the presence of a deoxyribonuclease (DNAse) activity. Excretions/secretions products were shown to contain a DNAse, with magnesium, sodium and calcium metal ion dependency, and a native molecular mass following affinity purification of approximately 45 kDa. The affinity purified DNAse degraded genomic bacterial DNA per se, DNA from the slough/eschar of a venous leg ulcer, and extracellular bacterial DNA in biofilms pre‐formed from a clinical isolate of Pseudomonas aeruginosa. The latter finding highlights an important attribute of the DNAse, given the frequency of P. aeruginosa infection in non‐healing wounds and the fact that P. aeruginosa virulence factors can be toxic to maggots. Maggot DNAse is thus a competent enzyme derived from a rational source, with the potential to assist in clinical wound debridement by removing extracellular DNA from tissue and biofilm, and promoting tissue viability, while liberating proteinaceous slough/eschar for debridement by the suite of proteinases secreted by L. sericata.
Responsiveness and validity of the SCORFAD, an extent and severity scale for feline hypersensitivity dermatitis
Authors: Steffan Jean , Olivry Thierry , Forster Sophie L. , Seewald Wolfgang
Published: July 2012

Background –  Hypersensitivity (allergic) dermatitis (HD) is commonly seen in cats, causing pruritus and various patterns of skin lesions, including at least one of the following: head and neck excoriations, self‐induced alopecia, eosinophilic plaques and miliary dermatitis. Few studies have evaluated the efficacy of therapeutic interventions for feline HD, and although various scales have been considered, none has been formally validated for the assessment of disease severity and its response to therapy.

Objective –  To design and validate a novel scale (SCORing Feline Allergic Dermatitis; SCORFAD) to assess the value of different criteria used as outcome measures for the treatment of feline HD and to set minimal thresholds for defining the clinical success of tested interventions.

Animals –  One hundred client‐owned cats.

Methods –  The SCORFAD scale was designed to include the four most frequently identified lesion types in feline HD (eosinophilic plaque, head and neck excoriations, self‐induced alopecia and miliary dermatitis) across 10 body regions. The extent and severity of each lesion type were graded prior to inclusion and after 3 and 6 weeks in a clinical study to compare the efficacy of two doses of ciclosporin with placebo.

Results –  The SCORFAD scale was found to exhibit satisfactory content, construct, criterion and sensitivity to change. The percentage reduction in SCORFAD from baseline was determined to be the most valid assessment of clinical response. Inter‐ and intra‐observer reliability was not assessed.

Conclusions and clinical importance –  The SCORFAD scale is proposed for use as a validated tool for the assessment of disease severity and response to therapeutic interventions in clinical trials for feline HD.
Mycobacterium kansasii pericarditis in a kidney transplant recipient: a case report and comprehensive review of the literature
Authors: Cho J.‐H. , Yu C.‐H. , Jin M.‐K. , Kwon O. , Hong K.‐D. , Choi J.‐Y. , Yoon S.‐H. , Park S.‐H. , Kim C.‐D. , Kim Y.‐L.
Published: July 2012

Mycobacterium kansasii is the second most common non‐tuberculous mycobacteria in kidney transplant recipients (KTRs) and has been reported to cause disseminated infection in KTRs. We report the first case to our knowledge of M. kansasii pericarditis after kidney transplantation in a 54‐year‐old man. The patient was admitted with a 2‐month history of intermittent fever and myalgia, treated with oral prednisolone and mycophenolate mofetil prior to admission. Chest computed tomography showed enlarged mediastinal lymph node and small amount of pericardial effusion. Mediastinoscopic biopsy of mediastinal lymph node revealed reactive hyperplasia, without evidence of granuloma, but acid‐fast bacilli stain of pericardial fluid reported positive finding and pericardial fluid culture identified M. kansasii. The patient has been treated successfully with rifabutin‐based combination therapy. All available cases of M. kansasii infection in kidney transplant patients and M. kansasii pericarditis in human immunodeficiency virus‐infected patients are comprehensively reviewed.
Safety and efficacy of healthy volunteer stem cell mobilization with filgrastim G‐CSF and mobilized stem cell apheresis: results of a prospective longitudinal 5‐year follow‐up study
Authors: Mueller M. M. , Bialleck H. , Bomke B. , Brauninger S. , Varga C. , Seidl C. , Seifried E. , Tonn T. , Bonig H.
Published: July 2012

Background and Objectives  G‐CSF‐mobilized peripheral blood stem cells have long replaced marrow as the major source for allogeneic transplants. Conclusive evidence questioning the long‐term safety of G‐CSF for donors has not been provided, but the cumulative number of followed donors remains insufficient to rule out rare adverse events. A long‐term active follow‐up study of G‐CSF‐mobilized healthy volunteer donors was therefore performed.

Patients and Methods  Two hundred and three successive donors were evaluated pre‐apheresis, subjected to G‐CSF‐mobilization/apheresis, and actively followed for 5 years by the same physicians and laboratories. Follow‐up laboratory work included standard biochemical/haematological tests and T‐cell phenotyping.

Results  Donor epidemiology was typical for reported stem cell donor cohorts. Acute adverse effects of G‐CSF and apheresis were mild and transient, consistent with the previous reports. Mean circulating CD34+ cells after nine doses of G‐CSF were 124 per μl. Other biochemical/haematological parameters were also altered, consistent with G‐CSF treatment. Spleen enlargement was modest. At first follow‐up, all clinical and laboratory parameters had normalized. Leucocyte/lymphocyte counts and CD4/CD8 ratios were the same as during premobilization work‐up and remained unchanged throughout. A single severe but likely unrelated adverse event, a case of papillary thyroid carcinoma, was reported.

Conclusion  The studies add an observation time of almost 500 donor years to the growing body of evidence of the long‐term safety of G‐CSF for allogeneic donor stem cell mobilization.
Thoroughbred racehorse mitochondrial DNA demonstrates closer than expected links between maternal genetic history and pedigree records
Authors: Bower M.A. , Whitten M. , Nisbet R.E.R. , Spencer M. , Dominy K.M. , Murphy A.M. , Cassidy R. , Barrett E. , Hill E.W. , Binns M.
Published: July 2012

The potential future earnings and therefore value of Thoroughbred foals untested in the racing arena are calculated based on the performance of their forebears. Thus, lineage is of key importance. However, previous research indicates that maternally inherited mitochondrial DNA (mtDNA) does not correspond to maternal lineage according to recorded pedigree, casting doubt on the voracity of historic pedigrees. We analysed mtDNA of 296 Thoroughbred horses from 33 maternal lineages and identified an interesting trend. Subsequent to the founding of the Thoroughbred breed in the 16th century, well‐populated maternal lineages were divided into sub‐lineages. Only six in 10 of the Thoroughbreds sampled shared mitochondrial haplotype with other members of their maternal lineage, despite having a common maternal ancestor according to pedigree records. However, nine in 10 Thoroughbreds from the 103 sub‐lineages sampled shared mtDNA with horses of their maternal pedigree sub‐lineage. Thus, Thoroughbred maternal sub‐lineage pedigree represents a more accurate breeding record than previously thought. Errors in pedigrees must have occurred largely, though, not exclusively, at sub‐lineage foundation events, probably due to incomplete understanding of modes of inheritance in the past, where maternal sub‐lineages were founded from individuals, related, but not by female descent.
Modulation of Maternal Immune System During Pregnancy in the Cow
Authors: Oliveira LJ , Barreto RSN , Perecin F , Mansouri‐Attia N , Pereira FTV , Meirelles FV
Published: July 2012

Contents

There is a molecular crosstalk between the trophoblast and maternal immune cells of bovine endometrium. The uterine cells are able to secrete cytokine/chemokines to either induce a suppressive environment for establishment of the pregnancy or to recruit immune cells to the endometrium to fight infections. Despite morphological differences between women and cows, mechanisms for immune tolerance during pregnancy seem to be conserved. Mechanisms for uterine immunesuppression in the cow include: reduced expression of major histocompatability proteins by the trophoblast; recruitment of macrophages to the pregnant endometrium; and modulation of immune‐related genes in response to the presence of the conceptus. Recently, an eGFP transgenic cloned embryo model developed by our group showed that there is modulation of foetal proteins expressed at the site of syncytium formation, suggesting that foetal cell can regulate not only by the secretion of specific factors such as interferon‐tau, but also by regulating their own protein expression to avoid excessive maternal recognition by the local immune system. Furthermore, foetal DNA can be detected in the maternal circulation; this may reflect the occurrence of an invasion of trophoblast cells and/or their fragment beyond the uterine basement membrane in the cow. In fact, the newly description of exosome release by the trophoblast cell suggests that could be a new fashion of maternal‐foetal communication at the placental barrier. Additionally, recent global transcriptome studies on bovine endometrium suggested that the immune system is aware, from an immunological point of view, of the presence of the foetus in the cow during early pregnancy.
Convalescent resting tachycardia predicts unfavorable outcome of anorexia nervosa
Authors: Tokumura Mitsuaki , Watanabe Hisako , Esaki Takashi
Published: July 2012

Background:  In patients with anorexia nervosa (AN) who have tachycardia during the clinical course, difficulty in treatment has been observed. The purpose of the present study was to evaluate the association between heart rate (HR) in the weight loss and weight recovery periods, and outcome.

Methods:  The subjects consisted of 40 girls with AN (age at onset, 8–16 years). The outcome 1–5 years after the initiation of treatment was regarded as favorable for both bodyweight within 15% of the standard weight and regular menstruation during the last 6 months, and unfavorable for bodyweight <85% of the standard weight and absent or nearly always absent menstruation. HR during the weight loss period was obtained at the outpatient clinic on the first visit. For HR during the weight recovery period, we used the resting and peak HR obtained in exercise tolerance test, which was performed when the bodyweight successfully increased along with improvement in physical complications. The association between each HR and outcome was evaluated.

Results:  Favorable outcomes were observed in 19 of the 40 patients after the 1 year follow up but in 32 after the 5 year follow up. Resting HR during the weight recovery period was higher throughout the 5 years in the unfavorable than in the favorable outcome group, with significant differences after the 2, 4, and 5 year follow ups.

Conclusion:  In AN, resting tachycardia during the convalescent period is associated with unfavorable outcome.
Ultradian corticosterone secretion is maintained in the absence of circadian cues
Authors: Waite Eleanor J. , McKenna Mervyn , Kershaw Yvonne , Walker Jamie J. , Cho Kwangwook , Piggins Hugh D. , Lightman Stafford L.
Published: July 2012

Plasma levels of corticosterone exhibit both circadian and ultradian rhythms. The circadian component of these rhythms is regulated by the suprachiasmatic nucleus (SCN). Our studies investigate the importance of the SCN in regulating ultradian rhythmicity. Two approaches were used to dissociate the hypothalamic‐pituitary‐adrenal (HPA) axis from normal circadian input in rats: (i) exposure to a constant light (LL) environment and (ii) electrolytic lesioning of the SCN. Blood was sampled using an automated sampling system. As expected, both treatments resulted in a loss of the circadian pattern of corticosterone secretion. Ultradian pulsatile secretion of corticosterone however, was maintained across the 24 h in all animals. Furthermore, the loss of SCN input revealed an underlying relationship between locomotor and HPA activity. In control (LD) rats there was no clear correlation between ultradian locomotor activity and hormone secretion, whereas, in LL rats, episodes of ultradian activity were consistently followed by periods of increased pulsatile hormone secretion. These data clearly demonstrate that the ultradian rhythm of corticosterone secretion is generated through a mechanism independent of the SCN input, supporting recent evidence for a sub‐hypothalamic pulse generator.
THE OBJECTIVITY OF OBLIGATIONS IN DIVINE MOTIVATION THEORY: On Imitation and Submission
Authors: Johnson Daniel M.
Published: July 2012

To support her divine motivation theory of the good, which seeks to ground ethics in motives and emphasize the attractiveness of morality over against the compulsion of morality, Linda Zagzebski has proposed an original account of obligations which grounds them in motives. I argue that her account renders obligations objectionably person‐relative and that the most promising way to avoid my criticism is to embrace something quite close to a divine command theory of obligation. This requires her to combine her desired emphasis on the imitation of God with a contrasting emphasis on submission to God. I conclude that her divine motivation theory of the good, if it is to have an adequate account of obligation, is dependent on a divine will or divine command theory of obligation.