bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the activator-binding residues in the second cysteine-rich regulatory domain of protein kinase Cθ (PKCθ)
Authors: Rahman Ghazi M. , Shanker Sreejesh , Lewin Nancy E. , Kedei Noemi , Hill Colin S. , Prasad B. V.  Venkataram , Blumberg Peter M. , Das Joydip
Published: January 2013

PKC (protein kinase C) θ is predominantly expressed in T-cells and is critically involved in immunity. Design of PKCθ-selective molecules to manage autoimmune disorders by targeting its activator-binding C1 domain requires the knowledge of its structure and the activator-binding residues. The C1 domain consists of twin C1 domains, C1A and C1B, of which C1B plays a critical role in the membrane translocation and activation of PKCθ. In the present study we determined the crystal structure of PKCθC1B to 1.63 Å (1 Å=0.1 nm) resolution, which showed that Trp253 at the rim of the activator-binding pocket was orientated towards the membrane, whereas in PKCδC1B the homologous tryptophan residue was orientated away from the membrane. This particular orientation of Trp253 affects the size of the activator-binding pocket and the membrane affinity. To further probe the structural constraints on activator-binding, five residues lining the activator-binding site were mutated (Y239A, T243A, W253G, L255G and Q258G) and the binding affinities of the PKCθC1B mutants were measured. These mutants showed reduced binding affinities for phorbol ester [PDBu (phorbol 12,13-dibutyrate)] and diacylglycerol [DOG (sn-1,2-dioctanoylglycerol), SAG (sn-1-stearoyl 2-arachidonyl glycerol)]. All five full-length PKCθ mutants exhibited reduced phorbol-ester-induced membrane translocation compared with the wild-type. These results provide insights into the PKCθ activator-binding domain, which will aid in future design of PKCθ-selective molecules.
Charge-pairing interactions control the conformational setpoint and motions of the FMN domain in neuronal nitric oxide synthase
Authors: Haque Mohammad Mahfuzul , Bayachou Mekki , Fadlalla Mohammed A. , Durra Deborah , Stuehr Dennis J.
Published: January 2013

The NOS (nitric oxide synthase; EC 1.14.13.39) enzymes contain a C-terminal flavoprotein domain [NOSred (reductase domain of NOS)] that binds FAD and FMN, and an N-terminal oxygenase domain that binds haem. Evidence suggests that the FMN-binding domain undergoes large conformational motions to shuttle electrons between the NADPH/FAD-binding domain [FNR (ferredoxin NADP-reductase)] and the oxygenase domain. Previously we have shown that three residues on the FMN domain (Glu762, Glu816 and Glu819) that make charge-pairing interactions with the FNR help to slow electron flux through nNOSred (neuronal NOSred). In the present study, we show that charge neutralization or reversal at each of these residues alters the setpoint [Keq(A)] of the NOSred conformational equilibrium to favour the open (FMN-deshielded) conformational state. Moreover, computer simulations of the kinetic traces of cytochrome c reduction by the mutants suggest that they have higher conformational transition rates (1.5–4-fold) and rates of interflavin electron transfer (1.5–2-fold) relative to wild-type nNOSred. We conclude that the three charge-pairing residues on the FMN domain govern electron flux through nNOSred by stabilizing its closed (FMN-shielded) conformational state and by retarding the rate of conformational switching between its open and closed conformations.
Mammalian Trit1 is a tRNA[Ser]Sec-isopentenyl transferase required for full selenoprotein expression
Authors: Fradejas Noelia , Carlson Bradley A. , Rijntjes Eddy , Becker Niels-Peter , Tobe Ryuta , Schweizer Ulrich
Published: January 2013

Selenoproteins are proteins carrying the rare amino acid Sec (selenocysteine). Full expression of selenoproteins requires modification of tRNA[Ser]Sec, including N6-isopentenylation of base A37. We show that Trit1 is a dimethylallyl:tRNA[Ser]Sec transferase. Knockdown of Trit1 reduces expression of selenoproteins. Incubation of in vitro transcribed tRNA[Ser]Sec with recombinant Trit1 transfers [14C]dimethylallyl pyrophosphate to tRNA[Ser]Sec. 37A>G tRNA[Ser]Sec is resistant to isopentenylation by Trit1.
Paradoxical Psychometric Functions (“Swan Functions”) are Explained by Dilution Masking in Four Stimulus Dimensions
Authors: Baker Daniel H. , Meese Tim S. , Georgeson Mark A.
Published: January 2013

The visual system dissects the retinal image into millions of local analyses along numerous visual dimensions. However, our perceptions of the world are not fragmentary, so further processes must be involved in stitching it all back together. Simply summing up the responses would not work because this would convey an increase in image contrast with an increase in the number of mechanisms stimulated. Here, we consider a generic model of signal combination and counter-suppression designed to address this problem. The model is derived and tested for simple stimulus pairings (e.g. A + B), but is readily extended over multiple analysers. The model can account for nonlinear contrast transduction, dilution masking, and signal combination at threshold and above. It also predicts nonmonotonic psychometric functions where sensitivity to signal A in the presence of pedestal B first declines with increasing signal strength (paradoxically dropping below 50% correct in two-interval forced choice), but then rises back up again, producing a contour that follows the wings and neck of a swan. We looked for and found these “swan” functions in four different stimulus dimensions (ocularity, space, orientation, and time), providing some support for our proposal.
Cdc42 interacts with the exocyst complex to promote phagocytosis
Authors: Mohammadi Sina , Isberg Ralph R.
Published: January 2013

The process of phagocytosis in multicellular organisms is required for homeostasis, clearance of foreign particles, and establishment of long-term immunity, yet the molecular determinants of uptake are not well characterized. Cdc42, a Rho guanosine triphosphatase, is thought to orchestrate critical actin remodeling events needed for internalization. In this paper, we show that Cdc42 controls exocytic events during phagosome formation. Cdc42 inactivation led to a selective defect in large particle phagocytosis as well as a general decrease in the rate of membrane flow to the cell surface. Supporting the connection between Cdc42 and exocytic function, we found that the overproduction of a regulator of exocytosis, Rab11, rescued the large particle uptake defect in the absence of Cdc42. Additionally, we demonstrated a temporal interaction between Cdc42 and the exocyst complex during large particle uptake. Furthermore, disruption of exocyst function through Exo70 depletion led to a defect in large particle internalization, thereby establishing a functional role for the exocyst complex during phagocytosis.
Compression and dilation of the membrane-cortex layer generates rapid changes in cell shape
Authors: Kapustina Maryna , Elston Timothy C. , Jacobson Ken
Published: January 2013

Rapid changes in cellular morphology require a cell body that is highly flexible yet retains sufficient strength to maintain structural integrity. We present a mechanism that meets both of these requirements. We demonstrate that compression (folding) and subsequent dilation (unfolding) of the coupled plasma membrane–cortex layer generates rapid shape transformations in rounded cells. Two- and three-dimensional live-cell images showed that the cyclic process of membrane-cortex compression and dilation resulted in a traveling wave of cortical actin density. We also demonstrate that the membrane-cortex traveling wave led to amoeboid-like cell migration. The compression–dilation hypothesis offers a mechanism for large-scale cell shape transformations that is complementary to blebbing, where the plasma membrane detaches from the actin cortex and is initially unsupported when the bleb extends as a result of cytosolic pressure. Our findings provide insight into the mechanisms that drive the rapid morphological changes that occur in many physiological contexts, such as amoeboid migration and cytokinesis.
The tension mounts: Stress fibers as force-generating mechanotransducers
Authors: Burridge Keith , Wittchen Erika S.
Published: January 2013

Stress fibers (SFs) are often the most prominent cytoskeletal structures in cells growing in tissue culture. Composed of actin filaments, myosin II, and many other proteins, SFs are force-generating and tension-bearing structures that respond to the surrounding physical environment. New work is shedding light on the mechanosensitive properties of SFs, including that these structures can respond to mechanical tension by rapid reinforcement and that there are mechanisms to repair strain-induced damage. Although SFs are superficially similar in organization to the sarcomeres of striated muscle, there are intriguing differences in their organization and behavior, indicating that much still needs to be learned about these structures.
Combination of glucosamine improved therapeutic effect of low‐dose cyclosporin A in patients with atopic dermatitis: A pilot study
Authors: KWON Hyok‐Bu , AHN Byung‐Jin , CHOI Yunseok , JIN Sang Y. , CHEONG Kyung A. , LEE Joongyub , LEE Ai‐Young
Published: January 2013

Both glucosamine and cyclosporin have been reported to show immunomodulatory effect with inhibition of each different key transcription factor for cytokine gene expression and T‐cell function. The overall purpose of this pilot study was to assess the feasibility of the combination of cyclosporin with glucosamine for the treatment of patients with atopic dermatitis. Twelve patients more than 12 years old who required systemic cyclosporin were included in the study. Two of them dropped out due to violation of medication schedule. The single (S) and combination (C) regimens were crossed over every 2 weeks without a washout period between the cross‐over for 6 months. Five patients were randomly assigned to the S regimen first (SC sequence), whereas the other five were given the C first (CS sequence). The change of SCORAD index was analyzed as the primary efficacy end‐point by general linear model and piecewise linear mixed model. The SCORAD index was reduced with both SC and CS sequence regimens. In particular, index reduction with the C was more than that associated with S regimen; this difference increased as time lapsed. The glucosamine combination was predicted to cause an additive decrease in the mean percent change of the SCORAD index (~6%), with decreasing interleukin (IL)‐4 and IL‐5 cytokine levels but without increasing treatment‐related adverse events. This study suggests that the C would produce better clinical outcomes than the S regimen in patients with atopic dermatitis, although confirmatory clinical trials are warranted to determine the effect of combination.
Seismic characterization of naturally fractured reservoirs using amplitude versus offset and azimuth analysis
Authors: Far Mehdi E. , Sayers Colin M. , Thomsen Leon , Han De‐hua , Castagna John P.
Published: January 2013

P‐wave seismic reflection data, with variable offset and azimuth, acquired over a fractured reservoir can theoretically be inverted for the effective compliance of the fractures. The total effective compliance of a fractured rock, which is described using second‐ and fourth‐rank fracture tensors, can be represented as background compliance plus additional compliance due to fractures. Assuming monoclinic or orthotropic symmetry (which take into account layering and multiple fracture sets), the components of the effective second‐ and fourth‐rank fracture compliance tensors can be used as attributes related to the characteristics of the fractured medium. Synthetic tests indicate that using a priori knowledge of the properties of the unfractured medium, the inversion can be effective on noisy data, with S/N on the order of 2. Monte Carlo simulation was used to test the effect of uncertainties in the a priori information about elastic properties of unfractured rock. Two cases were considered with Wide Azimuth (WAZ) and Narrow Azimuth (NAZ) reflection data and assuming that the fractures have rotationally invariant shear compliance. The relative errors in determination of the components of the fourth‐rank tensor are substantially larger compared to the second‐rank tensor, under the same assumptions.

Elastic properties of background media, consisting in horizontal layers without fractures, do not cause azimuthal changes in the reflection coefficient variation with offset. Thus, due to the different nature of these properties compared to fracture tensor components (which cause azimuthal anomalies), simultaneous inversion for background isotropic properties and fracture tensor components requires additional constraints.

Singular value decomposition (SVD) and resolution matrix analysis can be used to predict fracture inversion efficacy before acquiring data. Therefore, they can be used to determine the optimal seismic survey design for inversion of fracture parameters. However, results of synthetic inversion in some cases are not consistent with resolution matrix results and resolution matrix results are reliable only after one can see a consistent and robust behaviour in inversion of synthetics with different noise levels.
Determining the focal mechanisms and depths of relatively small earthquakes using a few stations by full‐waveform modelling
Authors: Busfar Hussam , Toksöz M. Nafi
Published: January 2013

Determining the focal mechanism of earthquakes helps us to better define faults and understand the stress regime. This technique can be helpful in the oil and gas industry where it can be applied to microseismic events. The objective of this paper is to find double couple focal mechanisms, excluding scalar seismic moments, and the depths of small earthquakes using data from relatively few local stations. This objective is met by generating three‐component synthetic seismograms to match the observed normalized velocity seismograms. We first calculate Green's functions given an initial estimate of the earthquake's hypocentre, the locations of the seismic recording stations and a 1D velocity model of the region for a series of depths. Then, we calculate the moment tensor for different combinations of strikes, dips and rakes for each depth. These moment tensors are combined with the Green's functions and then convolved with a source time function to produce synthetic seismograms. We use a grid search to find the synthetic seismogram with the largest objective function that best fits all three components of the observed velocity seismogram. These parameters define the focal mechanism solution of an earthquake. We tested the method using three earthquakes in Southern California with moment magnitudes of 5.0, 5.1 and 4.4 using the frequency range 0.1–2.0 Hz. The source mechanisms of the events were determined independently using data from a multitude of stations. Our results obtained, from as few as three stations, generally match those obtained by the Southern California Earthquake Data Center. The main advantage of this method is that we use relatively high‐frequency full‐waveforms, including those from short‐period instruments, which makes it possible to find the focal mechanism and depth of earthquakes using as few as three stations when the velocity structure is known.
Analysing 2 × 2 contingency tables: Which test is best?
Authors: Ludbrook John
Published: January 2013

A survey of five journals of physiology or pharmacology for 2011 showed that Fisher's exact test was used three times as frequently as Pearson's Chi‐squared test. I shall argue that neither test is appropriate for analysing 2 × 2 tables of frequency in biomedical research.

Pearson's test requires that random samples are taken from defined populations. The resultant 2 × 2 table is described as unconditional because neither the row nor column marginal totals are fixed in advance.

Fisher's test requires the rare condition that both row and column marginal totals are fixed in advance. The resultant 2 × 2 table is described as doubly conditioned.

However, the most common design of biomedical studies is that a sample of convenience is taken and divided randomly into two groups of predetermined size. The groups are then exposed to different sets of conditions. The binomial outcome is not fixed in advance, but depends on the result of the study. Thus, only the column (group) marginal totals are fixed in advance and the table is described as singly conditioned.

Singly conditioned 2 × 2 tables are best analysed by tests of null hypotheses on the odds ratio (OR = 1) or by tests on proportions (p), such as the relative risk (RR = p2/p1 = 1) or the difference between proportions (p2 – p1 = 0). One enormous advantage of these procedures is that they test specific hypotheses. They should be executed in an exact fashion by permutation.
Internal and External Social Capital for Radical Product Innovation: Do They Always Work Well Together?
Authors: Cuevas‐Rodríguez Gloria , Cabello‐Medina Carmen , Carmona‐Lavado Antonio
Published: January 2013

We examine the role of internal and external relational social capital (SC) as determinants of radical product innovation (RPI). By analysing both sides of SC, we provide interesting insights on their relative influence and their interaction effect on this type of innovation. Besides, traditional assumptions on SC and innovation are questioned. In our empirical study using a sample of 142 manufacturing and service companies we found that, of the two types of SC analysed, internal SC is the most relevant predictor of RPI in relation to either technological or market dimensions. The influence of external SC is not as strong as the internal one. Regarding their interaction effect, external SC reduces the positive effect of internal SC on the market dimension of RPI. Interesting implications arise for practitioners, who should pay special attention to the higher impact of internal SC on RPI and the need to carefully manage the difficulties that emerge when it is combined with external SC.
The Audit We Had to Have: The Economic Record, 1960–2009
Authors: Millmow Alex , Tuck Jacqueline
Published: January 2013

The Economic Record, one of the world's oldest economic journals, has a distinguished history. The flagship journal of the Economic Society of Australia and New Zealand was launched in 1925 and is approaching its 100th birthday. We undertake a forensic examination of the journal over the last 50 years, exploring issues like its content, most‐cited articles and most frequent contributors. This article discusses the journal's internationalisation but also identifies how Australia's top economists have, for the most part, faithfully persisted with it. The changing nature of academic publishing is explored through the patterns of collaboration, citations and dry holes.
Biogeographic characteristics of Far Eastern wasps: A case study with eumenine wasps (Hymenoptera: Vespidae: Eumeninae)
Authors: Kim Jeong Kyu
Published: January 2013

A total of 107 forms of 88 eumenine wasp species occurring in the Far East were used to produce a more comprehensive picture of the geographical pattern of wasps in the Far East. All forms occurring in the Far East were biogeographically classified into 22 types in four larger categories, and a summarized table and discussion are presented. The eumenine wasp fauna of the Far East was characterized as a mixture of a fair number of endemic elements, a moderate number of transpalearctic elements, and some Oriental elements. The endemism of the Far East reached 0.71 at the species/subspecies level when the calculation was based on true Palearctic elements occurring in Far Eastern Russia, the Korean peninsula and Japan proper. The relationship between the Far Eastern fauna and the Central/Western Palearctic faunas was also analyzed and discussed. The species occurring in each treated district was counted, and provides evidence for the importance of the Korean fauna in biodiversity evaluation/estimation of Far Eastern fauna. The similarity index between the Korean Peninsula and Japan proper, the Korean Peninsula and the Russian Far East, and the Russian Far East and Japan proper was calculated to explain possible factors for faunal formation in the Far East. The distributional pattern of each form treated in this study and its relatives is tabulated in Appendix I.
Chronic low‐dose radiation inhibits cisplatin‐induced formation of tumorous clones in Drosophila melanogaster wts/ + heterozygotes
Authors: Seong Ki Moon , Kim Cha Soon , Seo Sun Won , Lee Byung‐Sub , Nam Seon Young , Yang Kwang Hee , Kim Ji Young , Min Kyung‐Jin , Jin Young‐Woo
Published: January 2013

Ionizing radiation is one of the most extensively studied carcinogens. In contrast to the detrimental effects of high‐dose radiation in carcinogenesis, the biological effects of low‐dose radiation remains poorly understood. In this study, we introduced adult wts/ + heterozygotes of Drosophila melanogaster as transgenic model organisms to determine the tumorigenic activity of low‐dose radiation. The warts (wts) gene is a tumor suppressor gene in mice and humans that is directly involved in cell cycle regulation. Fruit flies at the first larval stage were subjected to ionizing radiation, and then tumorigenic activity was evaluated as the frequency of observed warts tumorous mosaic clones in adult flies. Low‐dose irradiation alone did not cause tumorigenesis in our system. In combined treatment with a chemical carcinogen, chronic irradiation at 0.2 Gy decreased the frequency of tumorous clones induced by cisplatin. These results suggest that low‐dose radiation alone is not deleterious but beneficial in tumorigenesis induced by a chemical carcinogen.
Novel 3D conformal technique for treatment of choroidal melanoma with external beam photon radiotherapy
Authors: Phillips Claire , Pope Kathy , Hornby Colin , Chesson Brent , Cramb Jim , Bressel Mathias
Published: January 2013

Introduction

To report a 3D conformal radiotherapy (3D‐CRT) technique that utilises a specific eye immobilisation and treatment set‐up method as an alternative to stereotactic radiotherapy (SRT), for treatment of juxtapapillary choroidal melanoma (CM) and report early treatment outcomes of this technique.

Methods

A contact lens and rod system was designed to provide eye immobilisation and a treatment reference point for 3D‐CRT. The technique is described in detail in the body of the paper. A retrospective chart review was conducted to report freedom from local progression (FFLP) and radiation toxicity in a cohort of patients treated with a dose of 50 Gy in five fractions.

Results

Eleven eligible patients with juxtapapillary CM were treated between 2003 and 2009. The median follow‐up was 3.2 years (range 1.2–5.3). The FFLP was 100% (95% confidence interval 71.5–100). The reproducibility of the set‐up and eye immobilisation for fractionation was excellent. The mean dose to the planning target volume was 51.4 Gy (interquartilic range 51.0–51.9). Normal tissue dose constraints were achieved; however, the quality of the 3D‐CRT plan was variable. The highest acute radiation toxicity score was Common Toxicity Criteria version 3 grade 1. Vision outcomes were poor.

Conclusion

In this small series, a novel non‐stereotactic technique was found to be an accurate method for the treatment of CM with a high rate of freedom from tumour progression, in keeping with the SRT series. The quality of the conformal plan was variable. Investigation of the optimal dose‐fractionation schedule to minimise late radiation toxicity without compromise of tumour control is the focus of ongoing clinical research at our centre.
Overview of airway involvement in tuberculosis
Authors: Arora Arundeep , Bhalla Ashu Seith , Jana Manisha , Sharma Raju
Published: January 2013

Pulmonary tuberculosis is a ubiquitous infection and a re‐emerging medical and socioeconomic problem resulting in increasing mortality and morbidity, especially in Asian countries. We aim to review the spectrum of imaging findings in airway involvement in tuberculosis through characteristic radiological images and to assess the role of computed tomography and image‐guided interventions in the diagnosis and management of pulmonary tuberculosis.
Improved method of double‐J ureteric stenting
Authors: H'ng Martin Weng Chin , Ilin Lei , Wong Kai‐Ping
Published: January 2013

Double‐J ureteral stents and antegrade stenting have been performed by radiologists for years. Various methods have been described, dependent on available equipment as well as technical expertise. As such, there is no definite consensus with regards to deployment of these stents. We describe an innovative technique, which would improve this procedure and highlight its advantages.
Impact of a physician‐staffed helicopter on a regional trauma system: a prospective, controlled, observational study
Authors: HESSELFELDT R. , STEINMETZ J. , JANS H. , JACOBSSON M.‐L. B , ANDERSEN D. L. , BUGGESKOV K. , KOWALSKI M. , PRÆST M. , ØLLGAARD L. , HÖIBY P. , RASMUSSEN L. S.
Published: January 2013

Introduction

This study aims to compare the trauma system before and after implementing a physician‐staffed helicopter emergency medical service (PS‐HEMS). Our hypothesis was that PS‐HEMS would reduce time from injury to definitive care for severely injured patients.

Methods

This was a prospective, controlled, observational study, involving seven local hospitals and one level I trauma centre using a before and after design. All patients treated by a trauma team within a 5‐month period (1 December 2009–30 April 2010) prior to and a 12‐month period (1 May 2010–30 April 2011) after implementing a PS‐HEMS were included.

We compared time from dispatch of the first ground ambulance to arrival in the trauma centre for patients with Injury Severity Score (ISS) > 15. Secondary end points were the proportion of secondary transfers and 30‐day mortality.

Results

We included 1788 patients, of which 204 had an ISS > 15. The PS‐HEMS transported 44 severely injured directly to the trauma centre resulting in a reduction of secondary transfers from 50% before to 34% after implementation (P = 0.04). Median delay for definitive care for severely injured patients was 218 min before and 90 min after implementation (P < 0.01). The 30‐day mortality was reduced from 29% (16/56) before to 14% (21/147) after PS‐HEMS (P = 0.02). Logistic regression showed PS‐HEMS had an odds ratio (OR) for survival of 6.9 compared with ground transport.

Conclusions

Implementation of a PS‐HEMS was associated with significant reduction in time to the trauma centre for severely injured patients. We also observed significantly reduced proportions of secondary transfers and 30‐day mortality.
The dopamine beta‐hydroxylase inhibitor nepicastat increases dopamine release and potentiates psychostimulant‐induced dopamine release in the prefrontal cortex
Authors: Devoto Paola , Flore Giovanna , Saba Pierluigi , Bini Valentina , Gessa Gian Luigi
Published: January 2013

The dopamine‐beta‐hydroxylase inhibitor nepicastat has been shown to reproduce disulfiram ability to suppress the reinstatement of cocaine seeking after extinction in rats. To clarify its mechanism of action, we examined the effect of nepicastat, given alone or in association with cocaine or amphetamine, on catecholamine release in the medial prefrontal cortex and the nucleus accumbens, two key regions involved in the reinforcing and motivational effects of cocaine and in the reinstatement of cocaine seeking.

Nepicastat effect on catecholamines was evaluated by microdialysis in freely moving rats.

Nepicastat reduced noradrenaline release both in the medial prefrontal cortex and in the nucleus accumbens, and increased dopamine release in the medial prefrontal cortex but not in the nucleus accumbens. Moreover, nepicastat markedly potentiated cocaine‐ and amphetamine‐induced extracellular dopamine accumulation in the medial prefrontal cortex but not in the nucleus accumbens. Extracellular dopamine accumulation produced by nepicastat alone or by its combination with cocaine or amphetamine was suppressed by the α2‐adrenoceptor agonist clonidine.

It is suggested that nepicastat, by suppressing noradrenaline synthesis and release, eliminated the α2‐adrenoceptor mediated inhibitory mechanism that constrains dopamine release and cocaine‐ and amphetamine‐induced dopamine release from noradrenaline or dopamine terminals in the medial prefrontal cortex.
Genomic Signatures of a Global Fitness Index in a Multi‐Ethnic Cohort of Women
Authors: Rampersaud Evadnie , Nathanson Lubov , Farmer Jeffrey , Meshbane Karyn , Belton Richard L. , Dressen Amy , Cuccaro Michael , Musto Anthony , Daunert Sylvia , Deo Sapna , Hudson Natasha , Vance Jeffery M. , Seo David , Mendez Armando , Dykxhoorn Derek M. , Pericak‐Vance Margaret A. , Goldschmidt‐Clermont Pascal J.
Published: January 2013

The rates of obesity and sedentary lifestyle are on a dramatic incline, with associated detrimental health effects among women in particular. Although exercise prescriptions are useful for overcoming these problems, success can be hampered by differential responsiveness among individuals in cardiovascular fitness indices (i.e. improvements in strength, lipids, VO2max). Genomic factors appear to play an important role in determining this inter‐individual variation. We performed microarray analyses on mRNA in whole blood from 60 sedentary women from a multi‐ethnic cohort who underwent 12 weeks of exercise, to identify gene subsets that were differentially expressed between individuals who experienced the greatest and least improvements in fitness. We identified 43 transcripts in 39 unique genes (FDR<10%; FC>1.5) whose expression increased the most in “high” versus “low” pre‐menopausal female responders. These 39 genes were enriched in six biological pathways, including oxidative phosphorylation (p = 8.08 × 10−3). Several of the 39 genes (i.e. TIGD7, UQCRH, PSMA6, WDR12, TFB2M, USP15) have previously reported associations with fitness‐related phenotypes. In summary, we identified gene signatures based on mRNA analysis that define responsiveness to exercise in a largely minority‐based female cohort. Importantly, this study validates several genes/pathways previously associated with exercise responsiveness and extends these findings with additional novel genes.
Regulatory T Cells are Baby′s Best Friends
Authors: Teles Ana , Zenclussen Ana Claudia , Schumacher Anne
Published: January 2013

Regulatory T cells (Treg) are one of the most and best studied immune cell population during human and murine pregnancy, and there is a general consent about their expansion during pregnancy. However, the identification of new and more reliable Treg markers during the last years resulted in some controversies about the kinetics of various Treg subsets at different pregnancy stages. No doubt exists regarding the importance of Treg for a normal pregnancy as pregnancy complications like spontaneous abortion and preeclampsia could be associated with a reduced Treg number and activity. In future, more attention should be paid to bring established data from the bench to the bedside to force the development of adequate therapies for treatment of pregnancy complications. In this article, we summarize previous and recent data on several aspects of Treg biology during human and murine pregnancy.
B7 Costimulation and Intracellular Indoleamine‐2,3‐Dioxygenase Expression in Peripheral Blood of Healthy Pregnant and Pre‐Eclamptic Women
Authors: Toldi Gergely , Vásárhelyi Barna , Biró Enikő , Fügedi Gergely , Rigó János , Molvarec Attila
Published: January 2013

Problem

We determined the frequency of activated (CD11b+) monocytes expressing B7‐1, B7‐2, B7‐H1, and B‐7H2, and that of T cells and T helper cells expressing CD28, CTLA‐4, PD‐1, and ICOS in peripheral blood samples from normal pregnant (NP) and pre‐eclamptic (PE) women. We also examined the intracellular expression of indoleamine‐2,3‐dioxygenase (IDO).

Method of study

We measured the expression of the above markers using flow‐cytometry in peripheral blood samples from 20 NP and 20 PE women in the third trimester.

Results

The frequency of B7‐1 and B7‐2 expressing activated monocytes and that of IDO expressing T‐lymphocytes was lower in PE than in NP.

Conclusion

Lower expression of B7‐1 and B7‐2 proteins on peripheral monocytes in PE might indicate a secondary regulatory mechanism in response to the ongoing systemic maternal inflammation. IDO plays an important role in the pregnancy‐specific immune tolerance, and might be a contributing factor in the pathogenesis of PE.
Techniques for Visualization of Cell–Cell Contact at the Fetal‐Maternal Interface
Authors: Olivieri David N. , Tadokoro Carlos E.
Published: January 2013

Historically, several in vitro/ex vivo microscopy imaging techniques have been used to study cellular interactions within the uterus and the placenta. As these experimental methods have revealed compelling facts about the biologic phenomena of cell–cell contacts in these organs, they cannot be used to study complex dynamic behavior of living cells inside their physiologic environment. For this, recent advances in intravital imaging techniques, together with two‐photon microscopy, offer an exciting opportunity to study such dynamic immunologic processes at the cellular level in the complex uterine and placental tissues. In this article, we review experimental imaging techniques that have been used for studying the uterus and placenta. In particular, we describe the advantages of intravital techniques and discuss novel procedures that can be used in reproductive immunology. We also describe several technical details involved in image sequence post‐processing required to extract useful data. Finally, we conclude by discussing how the reproductive immunology field may benefit from the broad use of these intravital techniques.
Serum I‐FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies
Authors: Adriaanse M. P. M. , Tack G. J. , Passos V. Lima , Damoiseaux J. G. M. C. , Schreurs M. W. J. , van Wijck K. , Riedl R. G. , Masclee A. A. M. , Buurman W. A. , Mulder C. J. J. , Vreugdenhil A. C. E.
Published: January 2013

Background

Enterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I‐FABP) is a sensitive marker to study enterocyte damage.

Aims

To evaluate the severity of enterocyte damage in adult‐onset CD and its course upon a gluten‐free diet (GFD). Furthermore, the correlation among enterocyte damage, CD autoantibodies and histological abnormalities during the course of disease is studied.

Methods

Serum I‐FABP levels were determined in 96 biopsy‐proven adult CD patients and in 69 patients repeatedly upon a GFD. A total of 141 individuals with normal antitissue transglutaminase antibody (IgA‐tTG) levels served as controls. I‐FABP levels were related to the degree of villous atrophy (Marsh grade) and IgA‐tTG.

Results

I‐FABP levels were elevated in untreated CD (median 691 pg/mL) compared with controls (median 178 pg/mL, P < 0.001) and correlated with Marsh grade (r = 0.265, P < 0.05) and IgA‐tTG (r = 0.403, P < 0.01). Upon a GFD serum levels decreased significantly, however, not within the range observed in controls, despite the common observed normalisation of IgA‐tTG levels and Marsh grade. CD patients with elevated I‐FABP levels nonresponding to GFD showed persistent histological abnormalities.

Conclusions

Enterocyte damage assessed by serum I‐FABP correlates with the severity of villous atrophy in coeliac disease at the time of diagnosis. Although enterocyte damage improves upon treatment, substantial enterocyte damage persists despite absence of villous atrophy and low IgA‐tTG levels in the majority of cases. Elevated I‐FABP levels nonresponding to gluten‐free diet are indicative of histological abnormalities and warrant further evaluation.
Psychiatric co‐morbidity is associated with increased risk of surgery in Crohn's disease
Authors: Ananthakrishnan A. N. , Gainer V. S. , Perez R. G. , Cai T. , Cheng S.‐C. , Savova G. , Chen P. , Szolovits P. , Xia Z. , De Jager P. L. , Shaw S. Y. , Churchill S. , Karlson E. W. , Kohane I. , Perlis R. H. , Plenge R. M. , Murphy S. N. , Liao K. P.
Published: January 2013

Background

Psychiatric co‐morbidity, in particular major depression and anxiety, is common in patients with Crohn's disease (CD) and ulcerative colitis (UC). Prior studies examining this may be confounded by the co‐existence of functional bowel symptoms. Limited data exist examining an association between depression or anxiety and disease‐specific endpoints such as bowel surgery.

Aims

To examine the frequency of depression and anxiety (prior to surgery or hospitalisation) in a large multi‐institution electronic medical record (EMR)‐based cohort of CD and UC patients; to define the independent effect of psychiatric co‐morbidity on risk of subsequent surgery or hospitalisation in CD and UC, and to identify the effects of depression and anxiety on healthcare utilisation in our cohort.

Methods

Using a multi‐institution cohort of patients with CD and UC, we identified those who also had co‐existing psychiatric co‐morbidity (major depressive disorder or generalised anxiety). After excluding those diagnosed with such co‐morbidity for the first time following surgery, we used multivariate logistic regression to examine the independent effect of psychiatric co‐morbidity on IBD‐related surgery and hospitalisation. To account for confounding by disease severity, we adjusted for a propensity score estimating likelihood of psychiatric co‐morbidity influenced by severity of disease in our models.

Results

A total of 5405 CD and 5429 UC patients were included in this study; one‐fifth had either major depressive disorder or generalised anxiety. In multivariate analysis, adjusting for potential confounders and the propensity score, presence of mood or anxiety co‐morbidity was associated with a 28% increase in risk of surgery in CD (OR: 1.28, 95% CI: 1.03–1.57), but not UC (OR: 1.01, 95% CI: 0.80–1.28). Psychiatric co‐morbidity was associated with increased healthcare utilisation.

Conclusions

Depressive disorder or generalised anxiety is associated with a modestly increased risk of surgery in patients with Crohn's disease. Interventions addressing this may improve patient outcomes.
Meta‐analysis: the diagnostic accuracy of critical flicker frequency in minimal hepatic encephalopathy
Authors: Torlot F. J. , McPhail M. J. W. , Taylor‐Robinson S. D.
Published: January 2013

Background

Minimal hepatic encephalopathy (MHE) reduces quality of life, increases the risk of road traffic incidents and predicts progression to overt hepatic encephalopathy and death. Current psychometry‐based diagnostic methods are effective, but time‐consuming and a universal ‘gold standard’ test has yet to be agreed upon. Critical Flicker Frequency (CFF) is a proposed language‐independent diagnostic tool for MHE, but its accuracy has yet to be confirmed.

Aim

To assess the diagnostic accuracy of CFF for MHE by performing a systematic review and meta‐analysis of all studies, which report on the diagnostic accuracy of this test.

Methods

A systematic literature search was performed to locate all publications reporting on the diagnostic accuracy of CFF for MHE. Data were extracted from 2 × 2 tables or calculated from reported accuracy data. Collated data were meta‐analysed for sensitivity, specificity, diagnostic odds ratio (DOR) and summary receiver operator curve (sROC) analysis. Prespecified subgroup analysis and meta‐regression were also performed.

Results

Nine studies with data for 622 patients were included. Summary sensitivity was 61% (95% CI: 55–67), specificity 79% (95% CI: 75–83) and DOR 10.9 (95% CI: 4.2–28.3). A symmetrical sROC gave an area under the receiver operator curve of 0.84 (SE = 0.06). The heterogeneity of the DOR was 74%.

Conclusions

Critical Flicker Frequency has a high specificity and moderate sensitivity for diagnosing minimal hepatic encephalopathy. Given the advantages of language independence and being both simple to perform and interpret, we suggest the use of critical flicker frequency as an adjunct (but not replacement) to psychometric testing.
Absolute and relative contraindications to pegylated‐interferon or ribavirin in the US general patient population with chronic hepatitis C: results from a US database of over 45 000 HCV‐infected, evaluated patients
Authors: Talal A. H. , LaFleur J. , Hoop R. , Pandya P. , Martin P. , Jacobson I. , Han J. , Korner E. J.
Published: January 2013

Background

Chronic hepatitis C (HCV) treatment with pegylated‐interferon (PEG‐IFN)/ribavirin (RBV) is often limited by preexisting medical, psychiatric and psychosocial contraindications. However, limited data exist in general patient populations.

Aim

To evaluate the percentage of HCV‐infected patients in the general US population who may have contraindications to PEG‐IFN/RBV.

Methods

The General Electric (GE) Centricity dataset was used to screen the US population between 2004 and 2009 for HCV infection and contraindications to PEG‐IFN/RBV. HCV diagnosis and contraindications were identified using ICD‐9‐CM codes or laboratory values. Only patients with an encounter 180 days prior to HCV diagnosis were included. Demographic differences were calculated using Pearson's chi‐squared test. Frequencies and percentages for absolute and relative contraindications to PEG‐IFN and/or RBV were determined and proportions and rates/1000 person‐months were calculated.

Results

A total of 15 561 021 patients were screened, and 45 690 (0.3%) were HCV‐positive and were evaluated. Those with contraindications were significantly younger, female, White, not currently married and receiving Medicare or Medicaid coverage (all P < 0.0001). 17.3% had at least one contraindication to PEG‐IFN/RBV (5.5 events/1000 person‐months); bipolar disorder (6.5%), anaemia (Hgb < 10 g/dL; 5.9%), pregnancy (1.9%) and neutropenia (neutrophils <750 cells/mm3; 1.2%) were most frequently cited.

Conclusions

Approximately, 17% of HCV‐infected patients in the general US population had at least one contraindication to PEG‐IFN/RBV. Most contraindications were relative and potentially modifiable. Clinical assessment of contraindications as relative and/or modifiable should be considered and used to determine if patients could benefit from current PEG‐IFN–containing triple therapy or future PEG‐IFN– or RBV‐free regimens.
Diffusion‐weighted magnetic resonance imaging for detecting and assessing ileal inflammation in Crohn's disease
Authors: Buisson A. , Joubert A. , Montoriol P.‐F. , Ines D. D. , Hordonneau C. , Pereira B. , Garcier J.‐M. , Bommelaer G. , Petitcolin V.
Published: January 2013

Background

Whether diffusion‐weighted imaging (DWI)‐MRI is of value in detecting and assessing inflammation of ileal Crohn's disease (CD) remains poorly investigated.

Aim

To compare DWI‐MR enterography (MRE) with conventional MRE in estimating inflammation in small bowel CD, to determine an apparent diffusion coefficient (ADC) threshold to differentiate active from non‐active lesions and to assess inter‐observer agreement.

Methods

Thirty‐one CD patients from the Clermont‐Ferrand IBD unit with ileal involvement were consecutively and prospectively included between April and June 2011. All patients underwent DWI‐MRI to detect the digestive segment with the most severe lesions, which was then used to calculate the ADC. Qualitative and quantitative results were compared with conventional MRE including MaRIA (Magnetic Resonance Index of Activity) score calculation and independent activity predictors (wall thickening, oedema, ulcers). Each examination was interpreted independently by two radiologists blinded for clinical assessment.

Results

Seventeen patients (54.8%) had active CD as defined by the MaRIA score ≥7. DWI hyperintensity was highly correlated with disease activity evaluated using conventional MRE (P = 0.001). Qualitative analysis of DW sequences determined sensitivity, specificity, positive predictive value and negative predictive value as 100%, 92.9%, 94.4% and 100% respectively. Quantitative analysis using a cut‐off of 1.6 × 10−3 mm²/s for ADC yielded sensitivity and specificity values of, respectively, 82.4% and 100%. Inter‐observer agreement was high with regard to DWI hyperintensity (κ = 0.69, accuracy rate = 85.7%) and ADC (correlation = 0.74, P < 0.001, and concordance = 0.71, P < 0.001).

Conclusion

DWI‐MR enterography is a well‐tolerated, non‐time‐consuming and accurate tool for detecting and assessing inflammation in small bowel Crohn's disease.
Gaze, goals and growing up: Effects on imitative grasping
Authors: Brubacher Sonja P. , Roberts Kim P. , Obhi Sukhvinder S.
Published: January 2013

Developmental differences in the use of social‐attention cues to imitation were examined among children aged 3 and 6 years old (n = 58) and adults (n = 29). In each of 20 trials, participants watched a model grasp two objects simultaneously and move them together. On every trial, the model directed her gaze towards only one of the objects. Some object pairs were related and had a clear functional relationship (e.g., flower, vase), while others were functionally unrelated (e.g., cardboard square, ladybug). Owing to attentional effects of eye gaze, it was expected that all participants would more faithfully imitate the grasp on the gazed‐at object than the object not gazed‐at. Children were expected to imitate less faithfully on trials with functionally related objects than those without, due to goal‐hierarchy effects. Results support effects of eye gaze on imitation of grasping. Children's grasping accuracy on functionally related and functionally unrelated trials was similar, but they were more likely to only use one hand on trials where the object pairs were functionally related than unrelated. Implications for theories of imitation are discussed.
Transfusion of prion‐filtered red cells does not increase the rate of alloimmunization or transfusion reactions in patients: results of the UK trial of prion‐filtered versus standard red cells in surgical patients (PRISM A)
Authors: Elebute Modupe O. , Choo Louise , Mora Ana , MacRury Coral , Llewelyn Charlotte , Purohit Shilpi , Hicks Vicky , Casey Caroline , Malfroy Moira , Deary Alison , Reed Tania , Meredith Sarah , Manson Lynn , Williamson Lorna M.
Published: January 2013

This study, conducted for the UK Blood Transfusion Services (UKBTS), evaluated the clinical safety of red cells filtered through a CE‐marked prion removal filter (P‐Capt™). Patients requiring blood transfusion for elective procedures in nine UK hospitals were entered into a non‐randomized open trial to assess development of red cell antibodies to standard red cell (RCC) or prion‐filtered red cell concentrates (PF‐RCC) at eight weeks and six months post‐transfusion. Patients who received at least 1 unit of PF‐RCC were compared with a control cohort given RCC only. About 917 PF‐RCC and 1336 RCC units were transfused into 299 and 291 patients respectively. Twenty‐six new red cell antibodies were detected post‐transfusion in 10 patients in each arm, an overall alloimmunization rate of 4·4%. Neither the treatment arm [odds ratio (OR) 0·93, 95% confidence interval (CI) 0·3, 2·5] nor number of units transfused (OR 0·95, 95% CI 0·8, 1·1) had a significant effect on the proportion of patients who developed new alloantibodies. No pan‐reactive antibodies or antibodies specifically against PF‐RCC were detected. There was no difference in transfusion reactions between arms, and no novel transfusion‐related adverse events clearly attributable to PF‐RCC were seen. These data suggest that prion filtration of red cells does not reduce overall transfusion safety. This finding requires confirmation in large populations of transfused patients.