bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotype and functional changes of Vγ9/Vδ2 T lymphocytes in Behçet's disease and the effect of infliximab on Vγ9/Vδ2 T cell expansion, activation and cytotoxicity
Authors: Accardo-Palumbo Antonina , Giardina Anna Rita , Ciccia Francesco , Ferrante Angelo , Principato Alfonso , Impastato Rosalia , Giardina Ennio , Triolo Giovanni
Published: June 2010

Introduction

Infliximab is a chimeric monoclonal antibody against tumor necrosis factor alpha (TNF-α) that has been introduced recently for Behçet's disease (BD) patients who were resistant to standard treatment. The aim of this study was to analyse the functional changes of Vγ9/Vδ2 T lymphocytes in both active and inactive disease and the effect of infliximab on Vγ9/Vδ2 T cell expansion, activation and cytotoxicity.

Methods

We investigated 1) cell expansion, 2) expression of TNFRII receptor, 3) perforin and gamma interferon (IFN) content, 4) release of granzyme A (GrA) and 5) phenotype changes, in vitro and in vivo, in Vγ9/Vδ2 T lymphocytes by means of fluorescence-activated cell sorter analysis of lymphocyte cultures from patients with active and inactive BD and healthy subjects.

Results

Cell expansion, expression of TNFRII, perforin and gamma IFN content and release of granzyme A were significantly higher in active patients. In vitro and ex vivo treatment with infliximab resulted in a significant reduction of all parameters together with changes in the phenotype of Vγ9/Vδ2 T cells.

Conclusions

All together these data indicate that infliximab is capable of interfering with Vγ9/Vδ2 T cell function in BD and although cell culture models cannot reliably predict all potential effects of the drug in vivo, our results present the possibility that this drug may find use in a range of immunological disorders, characterized by dysregulated cell-mediated immunity.
Estradiol-17β Stimulates Specific Receptor and Endogenous Nitric Oxide-Dependent Dynamic Endothelial Protein S-Nitrosylation: Analysis of Endothelial Nitrosyl-Proteome
Authors: Zhang Hong-hai , Feng Lin , Livnat Itamar , Hoh Jeong-Kyu , Shim Jae-Yoon , Liao Wu-Xiang , Chen Dong-bao
Published: June 2010

Covalent adduction of a nitrosyl group to cysteines [S-nitrosylation (S-NO)] is emerging as a key route for nitric oxide (NO) to directly modulate protein functions. Here, we studied the effects of estrogens on endothelial protein S-NO and analyzed the nitrosyl-proteomes by biotin/CyDye switch technique combined with two-dimensional fluorescence difference gel electrophoresis and identified nitrosoproteins by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Estradiol-17β (E2) rapidly stimulated protein S-NO in human umbilical vein endothelial cells, maximizing within 10- to 30-min post-E2 (10 nm) exposure. E2-BSA also rapidly stimulated protein S-NO. Both E2 and E2-BSA-induced protein S-NO was blocked by ICI 182,780 and N-nitro-l-arginine-methylester. Human umbilical vein endothelial cells expressed estrogen receptor (ER)α and ERβ; both seemed to be required for E2 stimulation of protein S-NO because: 1) neither ERα or ERβ agonist alone, but their combination, stimulated protein S-NO; and 2) either ERα or ERβ antagonist blocked E2-induced protein S-NO. Numerous nitrosoproteins (spots) were observed on two-dimensional fluorescence difference gel. One hundred spots of interest were picked up; 58 were identified and, of which 15 were novel nitrosoproteins, 28 were up-regulated, 11 were decreased, and the rest were unchanged by E2. Pathway analysis suggested that nitrosoproteins are involved in regulating various endothelial functions, including apoptosis, cell structure and metabolism, redox homeostasis, etc. Thus, estrogens stimulate dynamic endothelial protein S-NO via mechanisms linked to specific ERs possibly on the plasma membrane and endogenous NO. These findings signify a critical next step for the understanding of the biological targets of enhanced NO production by estrogens.
Development of a Technique for Introduction of an Expressed Complementary Deoxyribonucleic Acid into Parathyroid Cells by Direct Injection
Authors: Shiizaki Kazuhiro , Hatamura Ikuji , Fukagawa Masafumi , Nakazawa Eiko , Saji Fumie , Watanabe Yuko , Akizawa Tadao , Kusano Eiji
Published: June 2010

PTH is a major mediator of bone and mineral metabolism. However, physiological and pathological investigations of parathyroid cells (PTCs) have been limited because of the lack of available cell lines and because the organ is too small for detailed studies. Here, we describe a novel method for adenovirus-mediated cDNA transfer into PTCs, and we show the accuracy of the method in a rat model of uremia-induced secondary hyperparathyroidism. Rats underwent a 5/6-nephrectomy and were fed with a high-phosphate diet for 8 wk. The parathyroid glands were surgically exposed and adenoviruses containing LacZ or Ca-sensing receptor (CaSR) were directly injected into the glands under a zoom-stereo microscope. The parathyroid glands were analyzed for infection of adenovirus and immunohistochemically for expression of CaSR. The functional activity of exogenous CaSR in PTCs after this treatment was investigated based on changes of the calcium and PTH curve. A virus concentration of more than 109 plaque-forming units/ml was required for adequate infection of PTCs within 7 d after treatment. Marked increase of CaSR-positive PTCs by 2.39 ± 0.72 times relative to control treatment, and significant colocalization of CaSR overexpression and virus labeling, were observed in glands after gene introduction. The calcium and PTH curve was shifted to the left from the basal position (set point, 1.10 ± 0.09 to 0.76 ± 0.12 mm; P < 0.0001), indicating successful introduction of a functionally active cDNA into the PTCs. This technique may facilitate an elucidation of biological effects through targeting and identification of specific features of PTCs, which may provide the basis for new clinical approaches.
Meeting Report: Nuclear Receptors: Transcription Factors and Drug Targets Connecting Basic Research with Translational Medicine
Authors: Tuckermann Jan , Bourguet William , Mandrup Susanne
Published: June 2010

The biannual European Molecular Biology Organization (EMBO) conference on nuclear receptors was organized by Beatrice Desvergne and Laszlo Nagy and took place in Cavtat near Dubrovnik on the Adriatic coast of Croatia September 25–29, 2009. The meeting brought together researchers from all over the world covering a wide spectrum from fundamental mechanistic studies to metabolism, clinical studies, and drug development. In this report, we summarize the recent and exciting findings presented by the speakers at the meeting.
Sweetness and light: perspectives for rodent models of type 1 diabetes
Authors: Avner Philip R.
Published: June 2010

Type 1 diabetes (T1D) is a major disease affecting primarily young children with an incidence in Western societies of around 0.3% by 20 years of age. Although both genetic and environmental factors contribute to the disease aetiology, the precise nature of both the genetic and environmental contribution to human disease onset and progression remains poorly defined. Despite showing some differences from human T1D, rodent models for T1D (Leiter and von Herrath, 2004; von Herrath and Nepom, 2009) and, in particular the nonobese diabetic (NOD) mouse (Atkinson and Leiter, 1999; Kikutani and Makino, 1992), have provided important insights into the disease process, even if they have not yet allowed definitive identification of many of the genetic factors involved in the process. The recent isolation of germline-competent embryonic stem (ES) cells from the NOD mouse strain, and from the rat, will greatly facilitate the functional analysis of T1D in the mouse, and open up the possibility of improved exploitation of rat T1D models. This important technological breakthrough has the potential to remove bottlenecks from the identification of T1D genes, allowing the underlying metabolic pathways to be established and facilitating evaluation of the eventual role of the human homologues in the disease process. The current status and perspectives for an improved mechanistic understanding of the disease process will be addressed.
Normal vaginal delivery in a patient with autosomal recessive limb-girdle muscular dystrophy
Authors: Black Carin , Said Joanne
Published: June 2010

The limb-girdle muscular dystrophies (LGMDs) are a group of genetically determined disorders of skeletal muscle, predominantly affecting the pelvic and shoulder-girdle musculature. The clinical course is variable but steadily progressive. Type 2A LGMD is the most frequent form, accounting for approximately 30% of identified cases. There are few reports of patients with Type 2A LGMD undergoing pregnancy and delivery. This case outlines a successful vaginal delivery in a woman with this condition.
Pheochromocytoma in pregnancy: a case report and review of literature
Authors: George J , Tan J Y L
Published: June 2010

Hypertension is a common problem in pregnancy that can result in significant maternal and fetal morbidity and mortality. The common causes include pre-eclampsia, gestational hypertension and essential hypertension. Although phaeochromocytoma is a rare cause of hypertension in pregnancy, it can lead to potentially life-threatening cardiovascular complications for the mother and increased fetal mortality if left undiagnosed and untreated. The diagnosis can be confirmed by measurement of plasma and urinary catecholamines and their metabolities followed by radiological localization of the tumour. Surgical resection of the tumour after adequate pre-operative control of hypertension using sequential alpha- followed by beta-blockers is the definitive treatment. In pregnancy, depending on the gestation at which diagnosis is made, the optimal timing for surgery is during the late first or early second trimester. When the pregnancy is more advanced, medical management followed by combined caesarean section and tumour resection closer to term is preferred.
Oxygen saturation response to exercise in healthy pregnant women: a simple protocol and normal range
Authors: Langford Edward , Khwanda Ahmad , Langford Kate
Published: June 2010

Measurement of oxygen saturation on excercise, using a pulse oximeter, has been advocated in the assessment of women with shortness of breath in pregnancy. However, there is currently no standard protocol for this. The aims of this study were to determine the normal range for oxygen saturation at rest and on moderate exercise in healthy women from 24 weeks gestation and to evaluate a simple, widely applicable exercise protocol in which women walked at their own pace for 100 metres then up two flights of stairs. The protocol achieved 60–85% maximum predicted heart rate in 99% of women at a median gestation of 31+3 weeks, with a wide range of Hb and BMI. There was a mean 0.3% fall in oxygen saturation on exertion but oxygen saturation did not fall below 95% in any of the women.
Management of inflammatory bowel disease in pregnancy
Authors: Smith M A , Sanderson J D
Published: June 2010

Inflammatory bowel disease (IBD) affects body image, relationships, family planning, fertility and pregnancy outcomes. However, the common misconception that IBD is a contraindication, or serious concern, in pregnancy is essentially a myth. Most patients with IBD can expect to have uneventful pregnancies. We present an overview of the management of IBD during pregnancy, including management in those planning pregnancy, the suitability of relevant medication during pregnancy and breast feeding, investigation and monitoring of IBD during pregnancy, surgical management and considerations relating to delivery. While there are some definite alterations required in the management of IBD during pregnancy, management is essentially unchanged. With close attention to aspects such as nutrition and smoking cessation, and optimal disease control in the run-up to and during pregnancy, we have an opportunity to help our patients with IBD achieve good pregnancy outcomes.
Inappropriate Sexual Behaviors Associated with Donepezil; Metformin-Induced Vitamin B12 Deficiency; Metformin Stinks, Literally; Varenicline-Triggered Pheochromocytoma Crisis; Ranolazine-Related Dyspnea on Exertion; Severe Opioid Withdrawal Due to Misuse of a New Combined Narcotic Agonist/Antagonist Product; A Nearly Overlooked Case of Ziprasidone-Induced Lingual Dystonia
Authors: Shuster Joel
Published: June 2010

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers.
Prazosin: Benign Prostatic Hyperplasia
Authors: Generali Joyce A. , Cada Dennis J.
Published: June 2010

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a quarterly publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. A summary of the most relevant data is provided, including background, study design, patient population, dosage information, therapy duration, results, safety, and therapeutic considerations. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@kumc.edu .
A Comparison of Automated Infusion Device Technology to Prevent Medication Errors in Pediatric and Adult Intensive Care Unit Patients
Authors: Hennings Steven , Romero Andrew , Erstad Brian L. , Franke Hillary , Theodorou Andreas A.
Published: June 2010

Objective

To compare possible differences in the proportion of medication errors associated with high-risk medications that were avoided by the use of automated infusion device (AID) technology in pediatric and adult intensive care unit (ICU) patients. A secondary purpose was to investigate the number of serious adverse drug events (ADEs) identified by root-cause analyses (RCA).

Method

The study included pediatric and adult patients receiving high-risk medications by continuous infusion in an academic medical center with mixed medical-surgical ICUs. A retrospective evaluation of 1 year's data collected prospectively in an AID database was used to compare the proportion of medication errors avoided based on reprogramming events (2.5 times limit as a low threshold) and overrides (10 times limit as high). Information obtained from RCAs was used to compare the proportion of serious ADEs that occurred during the 5-year periods before and after AID implementation.

Results

The pediatric population was 1.68 times (95% confidence interval [CI], 1.18 to 2.38) more likely to require a reprogramming event than the adult acute care population for all high-risk medications combined. Significantly more reprogramming events occurred in the pediatric patients with potassium (relative risk [RR], 2.77; 95% CI, 1.15 to 6.68) and insulin (RR, 2.73; 95% CI, 1.15 to 6.45) infusions. Additionally, there were more overrides in the pediatric compared to the adult population for the high-risk medications (RR, 1.82; 95% CI, 1.32 to 2.53). The number of serious adverse or sentinel events as identified in RCAs decreased from six before (four deemed preventable by AID technology) to three (zero preventable) after AID implementation.

Conclusions

This study demonstrates that AID technology when properly used leads to reductions in medication errors and possibly serious ADEs in critically ill patients receiving high-risk medications. The technology appears to be particularly beneficial in pediatric patients with weight-based dosing strategies. However, the potential for clinicians to override the alerts remains a concern.
Potential Cost Savings for a Health System–Based Employee Outpatient Pharmacy
Authors: Phillippe Haley M. , Andrus Miranda R. , Sims Matthew , McDaniel Michael R.
Published: June 2010

Abstract

Hospitals everywhere are faced with the same dilemma as other companies, struggling to manage rising health care expenses while providing optimal care for their employees. One of the often overlooked drug expense is the drugs consumed by the facility's employees. Although the average pharmacy department manager has a considerable amount of experience and expertise in dealing with drug expense issues for inpatients or even classic outpatients, the path to optimizing the drug expense investment strategies for their fellow employees can be difficult and elusive to discern. This article should provide a pharmacy manager with a few examples of how to contain costs for employee outpatient pharmacies.
Interaction between Warfarin and Transdermal Selegiline: First Case Report and Literature Review
Authors: Ensor Christopher R. , Dean Stacey R.
Published: June 2010

Abstract

A procoagulant effect may occur when enzymatic inhibitors of CYP2C9, 1A2, or 3A4 are therapeutically coadministered with warfarin. To our knowledge, there have been no case reports of such an interaction between warfarin and selegiline. We describe a case of a 49-year-old female who was taking warfarin for prevention of a venous thromboembolism after orthopedic surgery. During routine follow-up, the patient's international normalized ratio (INR) suddenly elevated to 9.0. Her INR had been subtherapeutic for 2 months prior despite escalating doses of warfarin. The only identifiable change to the patient's lifestyle or medications was the initiation of transdermal selegiline 5 days prior to this supratherapeutic INR. Recent laboratory tests revealed no significant abnormalities, with the exception of slightly depressed serum albumin. Her warfarin was held for 2 days, oral phytonadione 2.5 mg was given, and selegiline was held. The Drug Interaction Probability Scale revealed a probable drug-drug interaction between warfarin and selegiline. The likely mechanism of this interaction is selegiline-mediated moderate inhibition of CYP1A2 and weak or competitive inhibition of 2C9 and 3A4. Clinicians should be hypervigilant to this probable drug-drug interaction when initiating either therapy in a patient maintained on the opposing drug.
When Core Measures Meet Enterprise Performance Management Systems
Authors: Felkey Bill G. , Fox Brent I.
Published: June 2010

In this installment, we address the convergence of several factors that we believe will lead to a dramatically different health care environment. These factors are widespread and are probably already part of the culture at your institution. Health information technology is an important, unifying component of this convergence.
Shall we kill the pixel soldier?: perceptions of trauma and morality in combat video games
Authors: Mukherjee Souvik , Pitchford Jenna
Published: June 2010

The western media has been eager to construct an apparent link between the so-called moral desensitization of soldiers in the 2003 Iraq War and their experience of video game combat. Commentators assert that games have avoided engaging the real-life issues to which they are responding
(Zacny 2008), including the issue of combat trauma. Contrary to such positions, many video games already simulate the trauma in their gameplay experience; this article explores this concept from Brown's definition of trauma as outside the range of human experience (1995: 101). This evokes
recent work in games studies on in-game involvement and identity-formation and raises questions about the role of morality in gameplay, especially in multi-player combat games like Counter-Strike, Call of Duty 4 and America's Army. Working from these hitherto overlooked aspects
of trauma in gameplay experiences, this article challenges the oversimplified association of video games with the desensitization of US troops in recent conflicts.
Reviews
Authors: Mullen Mark , Ruch Adam , Devers Deirdre
Published: June 2010

IN DECISION VERITAS: THE WITCHER AND GAMEPLAY CHOICE
The Witcher Enhanced Edition, CD Projekt Red (2008), New York: Atari, $29.99 (USD)

INTERPRETATIONS OF FREEDOM AND CONTROL IN BIOSHOCK

BIOSHOCK, 2K Boston & 2K Australia (2007)
Novato, CA: 2K Games

ACADEMIC EXPERIENCE: ENGAGING WITH VIDEO GAMES AND THEIR PLEASURES
Video game, Player, Text, Barry Atkins and Tanya Krzywinska (eds) (2008) Manchester: Manchester University Press, 320 pp. ISBN 978-0_7190-7401-1, Paperback, $26.00 (USD)
The imagination and the imaginary in games and virtual worlds
Authors: Maccallum-Stewart Esther , Doyle Denise
Published: June 2010

This special issue of Journal of Gaming and Virtual Worlds seeks to demonstrate the potential for depth and broadness of interpretation within one single concept, and to present a variety of articles that interpret this theme in different ways. The Imagination and the role of
Imaginary, a topic that both editors have studied in different ways, seemed also to be a subject that has crossed the various debates in gaming and virtual worlds studies, engaging many different philosophical, ludological, aesthetic and practice-based fields. This issue has therefore also
been designed to reflect the growing maturity of games and virtual worlds studies, and to suggest ways in which one concept can provide extremely disparate readings of each medium.
An Experimental Technique for Determining the Hydraulic Properties of Unsaturated Pyroclastic Soils
Authors: Nicotera Marco Valerio , Papa Raffaele , Urciuoli Gianfranco
Published: June 2010

The experimental technique proposed in the paper was designed to rapidly and reliably determine both the water retention curve and the permeability function of undisturbed natural pyroclastic soil samples. The technique was developed in the framework of an experimental research project on mudflows in pyroclastic soils in the southern Italian region of Campania (Italy). Grain-size distribution and void ratio of the particular pyroclastic soils suggested investigation of the hydraulic behavior for matric suction values in the range between 0 and 100 kPa. Our experimental technique consisted of a sequence of testing phases to be conducted on a single undisturbed soil sample: A constant head permeation test, a forced evaporation test, and finally a drying test in a pressure plate apparatus. Interpretation of the experimental data was based on inverse modelling and allowed both water retention curves and permeability functions to be determined. The six parameters of the Mualem–van Genuchten model were adopted to describe the hydraulic behavior of the tested soils. Each testing phase supplied experimental data to be used in the interpretation procedure: The permeation phase provided a matching data point for the permeability function near saturation; the forced evaporation test was related to the hydraulic behavior for matric suction values ranging from a few kPa to less than 80–90 kPa (i.e., mini-tensiometer functioning range); and the drying steps in the pressure plate apparatus provided information about the retention properties for matric suction values up to 1 MPa. The results shown in the paper clearly confirm the goodness of the experimental design and the interpretation procedure.
Fractography of ASTM D2512 Tested Polymeric Isotropic Material Residuals Generated External to the Impacting Indenter
Authors: Gerzeski Roger
Published: June 2010

An examination of the fracture surfaces found on residuals originating external to the specimen contacting indenter of a ASTM D2512 tested isotropic polymeric material has been conducted for the first time. The repeated appearance and interrelationship of a select series of distinct features was identified. Cracks which plunge from the surface into the bulk of the tested specimen were routinely observed. They are developed by the independent mechanism of sliding Hertzian fracture. Radial cracks, propagating through the entire thickness of the tested specimen, from the most central portion of the original specimen through to its back edge were always observed. They were developed by the independent mechanism of tensile hoop failure. This tensile hoop mechanism also caused the point loaded backside impact damage feature occasionally observed. Shield shaped cracks and indications of secondary point loaded impacts were also routinely observed. Extrinsically generated, finely crushed granular and/or flake powder was commonly found tenaciously adhering to the fractured and top edges of many of these residuals. This powder feature always exhibited indications of having flowed onto the residual and frequently indications of having experienced intense heating. The forced flow of the powder caused the powder’s surface to be heated by the mechanism of kinetic friction heating. While kinetic friction heating did generate features indicative of exposure to intense heat, there were effectively no lasting indications that ignition had originated on these external residuals.
Design and Use of Expansion Joints in New and Existing Clay Masonry Wall Systems
Authors: Farmer Matthew C. , Gerns Edward A.
Published: June 2010

In modern masonry wall construction, integration of expansion joints (both vertical and horizontal) has become commonplace, but the rationale behind their width, placement, detailing, and maintenance is often misunderstood. With restoration projects and older wall systems it is often not clear whether expansion joints are needed and should be added as part of a restoration. Older structures in particular offer unique challenges. Damage of masonry wall systems can occur as a result of volume changes in the masonry materials despite the presence of expansion joints; this is frequently because joints are placed or installed inappropriately for the construction of the wall system, the particular wall geometry, or other factors related to the placement of joints designed to accommodate movement. This paper attempts to clarify and expand on the reasoning behind many of the standard guidelines commonly used for joint placement, size, and spacing. In addition, suggestions are provided for joint placement and detailing in several atypical situations, such as existing buildings, parapets, solid masonry wall systems, and window lintels. Factors leading to the need for expansion joints are reviewed, along with several lesser known concepts regarding expansion joint implementation. Also addressed are common problems with installation and maintenance of existing expansion joints.
Loading Mixity on the Interfacial Failure Mode in Lead-Free Solder Joint
Authors: Gao Feng , Jing Jianping , Liang Frank Z. , Williams Richard L. , Qu Jianmin
Published: June 2010

In this paper, single solder joints (SSJs) were subjected to moderate speed loading (5 mm/s) in different directions, from pure tensile mixity mode to pure shear. Fracture surfaces from different loading directions were examined both experimentally and numerically. The intermetallic compound (IMC) is formed between the solder alloy and the Cu pad, and the failure typically occurs at or near the solder/IMC/Cu interfaces of the board side. Pure tensile loading typically leads to interfacial fracture along the IMC/Cu interface. Mixity mode loading usually results in a mixture of interfacial and cohesive failure with damage propagating in a zigzag fashion between the solder/IMC interface and the solder alloy. Loading with higher shear component tends to result in more cohesive failure of the solder alloy near the solder/IMC interface. Under pure shear loading, failure is almost always cohesive within the solder alloy near the solder/IMC interface.
Using Environmental Correlations to Identify Loci Underlying Local Adaptation
Authors: Coop Graham , Witonsky David , Di Rienzo Anna , Pritchard Jonathan K
Published: June 2010

Loci involved in local adaptation can potentially be identified by an unusual correlation between allele frequencies and important ecological variables or by extreme allele frequency differences between geographic regions. However, such comparisons are complicated by differences in sample sizes and the neutral correlation of allele frequencies across populations due to shared history and gene flow. To overcome these difficulties, we have developed a Bayesian method that estimates the empirical pattern of covariance in allele frequencies between populations from a set of markers and then uses this as a null model for a test at individual SNPs. In our model the sample frequencies of an allele across populations are drawn from a set of underlying population frequencies; a transform of these population frequencies is assumed to follow a multivariate normal distribution. We first estimate the covariance matrix of this multivariate normal across loci using a Monte Carlo Markov chain. At each SNP, we then provide a measure of the support, a Bayes factor, for a model where an environmental variable has a linear effect on the transformed allele frequencies compared to a model given by the covariance matrix alone. This test is shown through power simulations to outperform existing correlation tests. We also demonstrate that our method can be used to identify SNPs with unusually large allele frequency differentiation and offers a powerful alternative to tests based on pairwise or global FST. Software is available at http://www.eve.ucdavis.edu/gmcoop/.
The Consequences of Regulation of desat1 Expression for Pheromone Emission and Detection inDrosophila melanogaster
Authors: Houot Benjamin , Bousquet François , Ferveur Jean-François
Published: June 2010

Sensory communication depends on the precise matching between the emission and the perception of sex- and species-specific signals; understanding both the coevolutionary process and the genes involved in both production and detection is a major challenge. desat1 determines both aspects of communication—a mutation in desat1 simultaneously alters both sex pheromone emission and perception in Drosophila melanogaster flies. We investigated whether the alteration of pheromonal perception is a consequence of the altered production of pheromones or if the two phenotypes are independently controlled by the same locus. Using several genetic tools, we were able to separately manipulate the two pheromonal phenotypes, implying that desat1 is the sole gene responsible, exerting a pleiotropic effect on both transmission and detection. The levels of the five desat1 trancripts, measured in the head and body of manipulated flies, were related to variation in pheromone production. This suggests that the pleiotropic action of desat1 on pheromonal communication depends on the fine regulation of its transcriptional activity.
Detecting Selection in Population Trees: The Lewontin and Krakauer Test Extended
Authors: Bonhomme Maxime , Chevalet Claude , Servin Bertrand , Boitard Simon , Abdallah Jihad , Blott Sarah , SanCristobal Magali
Published: June 2010

Detecting genetic signatures of selection is of great interest for many research issues. Common approaches to separate selective from neutral processes focus on the variance of FST across loci, as does the original Lewontin and Krakauer (LK) test. Modern developments aim to minimize the false positive rate and to increase the power, by accounting for complex demographic structures. Another stimulating goal is to develop straightforward parametric and computationally tractable tests to deal with massive SNP data sets. Here, we propose an extension of the original LK statistic (TLK), named TF–LK, that uses a phylogenetic estimation of the population's kinship ($\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{\mathcal{F}}\) \end{document}$) matrix, thus accounting for historical branching and heterogeneity of genetic drift. Using forward simulations of single-nucleotide polymorphisms (SNPs) data under neutrality and selection, we confirm the relative robustness of the LK statistic (TLK) to complex demographic history but we show that TF–LK is more powerful in most cases. This new statistic outperforms also a multinomial-Dirichlet-based model [estimation with Markov chain Monte Carlo (MCMC)], when historical branching occurs. Overall, TF–LK detects 15–35% more selected SNPs than TLK for low type I errors (P < 0.001). Also, simulations show that TLK and TF–LK follow a chi-square distribution provided the ancestral allele frequencies are not too extreme, suggesting the possible use of the chi-square distribution for evaluating significance. The empirical distribution of TF–LK can be derived using simulations conditioned on the estimated $\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(\mathrm{\mathcal{F}}\) \end{document}$ matrix. We apply this new test to pig breeds SNP data and pinpoint outliers using TF–LK, otherwise undetected using the less powerful TLK statistic. This new test represents one solution for compromise between advanced SNP genetic data acquisition and outlier analyses.
The gypsy Insulator of Drosophila melanogaster, Together With Its Binding Protein Suppressor of Hairy-Wing, Facilitate High and Precise Expression of Transgenes in Arabidopsis thaliana
Authors: She Wenjing , Lin Weiqiang , Zhu Yubin , Chen Yong , Jin Weiyuan , Yang Yanjun , Han Ning , Bian Hongwu , Zhu Muyuan , Wang Junhui
Published: June 2010

The variation of expression pattern exhibited by a transgene as a result of random integration, known as position effect, is, among other mechanisms, a particular challenge to reverse genetics. We present a strategy to counteract position effect in Arabidopsis thaliana by flanking the transgenes with the gypsy insulator from Drosophila melanogaster. In addition, Suppressor of Hairy-wing [Su(Hw)], the binding protein of the gypsy insulator, was coexpressed. Results indicated that the gypsy insulators could efficiently improve the expression levels of reporter genes driven by various kinds of promoters by 8- to 13-fold. Coexpression of the Su(Hw) protein led to a more uniform expression level of transgenes, as the coefficient of variation of expression levels was reduced further. The gypsy-Su(Hw) system enhanced expression levels, but did not alter the specificity of promoter activities, as experimentally evidenced by the promoters of the PIN and the AFB gene families. Interestingly, the gypsy insulator was also able to improve the expression of a selectable marker gene outside the insulated region, which facilitated the screen of transformants. Our system will likely decrease the number of lines that experimenters need to create and examine for a given transgene by contributing to relatively high and precise expression of transgenes in plants. Certain features of the gypsy insulator in Arabidopsis also provide new perspectives on the insulator field.
A High Frequency of Beneficial Mutations Across Multiple Fitness Components inSaccharomyces cerevisiae
Authors: Hall David W , Joseph Sarah B
Published: June 2010

Mutation-accumulation experiments are widely used to estimate parameters of spontaneous mutations affecting fitness. In many experiments only one component of fitness is measured. In a previous study involving the diploid yeast Saccharomyces cerevisiae, we measured the growth rate of 151 mutation-accumulation lines to estimate parameters of mutation. We found that an unexpectedly high frequency of fitness-altering mutations was beneficial. Here, we build upon our previous work by examining sporulation efficiency, spore viability, and haploid growth rate and find that these components of fitness also show a high frequency of beneficial mutations. We also examine whether mutation-acycumulation (MA) lines show any evidence of pleiotropy among accumulated mutations and find that, for most, there is none. However, MA lines that have zero fitness (i.e., lethality) for any one fitness component do show evidence for pleiotropy among accumulated mutations. We also report estimates of other parameters of mutation based on each component of fitness.
Comparative Transcriptome Analysis of the CO2 Sensing Pathway Via Differential Expression of Carbonic Anhydrase in Cryptococcus neoformans
Authors: Kim Min Su , Ko Young-Joon , Maeng Shinae , Floyd Anna , Heitman Joseph , Bahn Yong-Sun
Published: June 2010

Carbon dioxide (CO2) sensing and metabolism via carbonic anhydrases (CAs) play pivotal roles in survival and proliferation of pathogenic fungi infecting human hosts from natural environments due to the drastic difference in CO2 levels. In Cryptococcus neoformans, which causes fatal fungal meningoencephalitis, the Can2 CA plays essential roles during both cellular growth in air and sexual differentiation of the pathogen. However the signaling networks downstream of Can2 are largely unknown. To address this question, the present study employed comparative transcriptome DNA microarray analysis of a C. neoformans strain in which CAN2 expression is artificially controlled by the CTR4 (copper transporter) promoter. The PCTR4∷CAN2 strain showed growth defects in a CO2-dependent manner when CAN2 was repressed but resumed normal growth when CAN2 was overexpressed. The Can2-dependent genes identified by the transcriptome analysis include FAS1 (fatty acid synthase 1) and GPB1 (G-protein β subunit), supporting the roles of Can2 in fatty acid biosynthesis and sexual differentiation. Cas3, a capsular structure designer protein, was also discovered to be Can2-dependent and yet was not involved in CO2-mediated capsule induction. Most notably, a majority of Can2-dependent genes were environmental stress-regulated (ESR) genes. Supporting this, the CAN2 overexpression strain was hypersensitive to oxidative and genotoxic stress as well as antifungal drugs, such as polyene and azole drugs, potentially due to defective membrane integrity. Finally, an oxidative stress-responsive Atf1 transcription factor was also found to be Can2-dependent. Atf1 not only plays an important role in diverse stress responses, including thermotolerance and antifungal drug resistance, but also represses melanin and capsule production in C. neoformans. In conclusion, this study provides insights into the comprehensive signaling networks orchestrated by CA/CO2-sensing pathways in pathogenic fungi.
Hepatocellular carcinoma – from macroscopy to molecular pathology
Authors: Schaff Zsuzsa , Kovalszky Ilona , Lotz Gábor , Kiss András
Published: June 2010

A hepatocellularis carcinoma (HCC) igen rossz prognózisú daganat, azonban diagnosztikája és kezelése területén az utóbbi években jelentős előrehaladás történt. Mindehhez hozzájárult a HCC molekuláris patogenezisének mélyebb megismerése. A cirrhosis talaján kialakult HCC praemalignus elváltozásai a nagy regeneratív nodulus, az alacsony („low”) és magas („high”) fokozatú diszplasztikus nodulus. Mikroszkóposan a WHO trabecularis (micro-, macrotrabecularis), acinaris (pseudoglandularis,), scirrhosus és szolid formát különít el, speciális altípusként a világos sejtes, fibrolamellaris és kevert cholangiohepatocellularis szöveti forma ismert. Ezen szövettani típusok prognosztikai jelentősége vitatott. A fibrolamellaris, fiatalokban előforduló, nem cirrhoticus HCC-t jobb prognózisúnak tartják, bár valószínű, hogy ez annak a következménye, hogy ezen típust cirrhosis nem kíséri. A diagnózist segíthetik egyes, a szérumban és a daganatban is kimutatható tumormarkerek, így a jól ismert alfa-fetoprotein (AFP) mellett a glipikán-3 és a survivin, az újabban leírt agrin és claudinok, valamint a májsejteredetet bizonyító hepatocytaspecifikus antigén (HSA). Újabban az úgynevezett mikro-RNS-ek diagnosztikus jelentősége, elsősorban a májsejtspecifikus mir-122-é is felmerült. A HCC molekuláris osztályozása, a kezelés irányait is megszabó barcelonai beosztás (BCLC) mellett, kulcsfontosságú molekuláris eltérések alapján csoportosítja a HCC-t. Számos olyan molekuláris alteráció észlelhető, amely minden HCC-ben megfigyelhető, míg egyes eltérések csak bizonyos tumorokban detektálhatók.
Th17 cells in rheumatoid arthritis
Authors: Himer Leonóra , Balog Attila , Szebeni Beáta , Nagy Szakál Dorottya , Sziksz Erna , Reusz György , Tulassay Tivadar , Vannay Ádám
Published: June 2010

A T helper 17 (Th17) populáció a CD4+T-lymphocyták újonnan felfedezett csoportja. Az aktivált Th17 sejtek az őket leginkább jellemző interleukin (IL) -17A mellett számos más proinflammatorikus citokint is termelnek. Az IL-17A epithel- és endothelsejteken, fibroblastokon és a leukocytákon található sejtfelszíni receptorán keresztül további gyulladásos mediátorok felszabadításával és neutrophil granulocyták aktiválásával vesz részt az immunválasz szabályozásában. Az immunreguláció érzékeny egyensúlyának megbomlása gyulladásos és autoimmun betegségekhez vezet. A Th17 sejtek és az általuk termelt citokinek kiemelt szerepét számos humán autoimmun kórképben, köztük a rheumatoid arthritisben is igazolták. Terápiás célpontként való felhasználásuk napjaink immunológiai kutatásainak egyik ígéretes területe.
Biological and social predictors of smoking and perception of health
Authors: Bácskai Erika , Czobor Pál , Gerevich József
Published: June 2010

Világszerte jelentős figyelmet fordítottak a dohányzás biológiai (biológiai nem, életkor) és szociális (iskolai végzettség, foglalkoztatottság, lakóhely) jellemzőiben megmutatkozó egyenlőtlenségek vizsgálatára. Magyarországon ugyanakkor kevés elemzés történt ebben a témában. A dohányzással összefüggő morbiditási és mortalitási adatok hazai emelkedése ellenére a magyar lakosság egészségészlelése indokolatlanul optimista. Jelen tanulmányban a dohányzás biológiai és szociális prediktorjellemzőit a napi dohányzás prevalenciájával való összefüggésében, az általános egészség percepcióját pedig abban az összefüggésben vizsgáltuk, hogy a vizsgálati személyek milyennek tartották az egészségi állapotukat, és a vizsgálat időpontjában dohányoztak-e, valamint hány éves korukban kezdtek el dohányozni. A vizsgálati időszak 1990–2008 volt. A vizsgálat empirikus adatai 15, dohányzásra irányuló reprezentatív kutatás egyéni szintű adatbázisából származtak. A minta nagysága 30 352 személyt ölelt fel. GLIMMIX, GLM és logisztikus regressziós elemzést alkalmaztunk metaanalízis keretében. Az eredmények szerint a dohányzás prevalenciája a vizsgálati időszakban emelkedést mutatott. A nőknél lényegesen nagyobb volt a napi dohányzás prevalenciájának emelkedése, mint a férfiaknál. Az alacsony iskolai végzettség, a munkanélküliség és az egy lakásban élők magas száma megnövelte a napi dohányzás, a dohányzás ténye és korai kezdete pedig megnövelte a megkérdezettek saját egészségükről vallott rossz véleményének a valószínűségét. Az eredményekben megmutatkozó dohányzási tendenciák felhívják a figyelmet az eddigi hazai dohányzáspolitikák és prevenciós gyakorlat elégtelenségére, és azonnali szakmai, politikai intervenciót sürgetnek átfogó nemzeti stratégia keretében.
Pathomechanism of diabetic neuropathy: background of the pathogenesis-oriented therapy
Authors: Winkler Gábor , Kempler Péter
Published: June 2010

A cukorbetegséghez társuló idegrendszeri károsodás kialakulásának mechanizmusa ma sem teljes mértékben tisztázott, bár az utóbbi évtizedben számos, részben terápiás konzekvenciával járó adat vált ismertté. Az endoneuralis véráramlás csökkenése részben a primer haemostasis károsodásának, a koagulációs rendszer trombogén irányú elmozdulásának következménye. A hyperglykaemia a szuperoxid-anion fokozott képződése révén a glikolízisben kulcsszerepet játszó glicerin-aldehid-3-foszfát-dehidrogenáz aktivitásának csökkenéséhez, alternatív anyagcsereutak (poliol-, hexóz-amin-, diacil-glicerol-, proteinkináz-C anyagcsereút, fehérjeglikáció) aktiválódásához vezet. A végglikációs fehérjék fokozzák a nukleáris faktor κ-B aktivitását, vazoaktív tényezők és citokinek (interleukin-1, -6, tumornekrózis-faktor-α) termelődését. A patogenetikai alapon nyugvó oki kezelés célja a neuropathiás károsodás progressziójának lassítása, megállítása vagy visszafordítása. Az oki kezelés legfontosabb összetevői: a szénhidrátanyagcsere-helyzet optimális beállítása, a rizikófaktorok kezelése, valamint benfotiamin és alfa-liponsav adása. A transzketoláz-aktivátor benfotiamin egyrészt gátolja a hyperglykaemia következményeként előtérbe kerülő legfontosabb alternatív anyagcsereutak (fehérjeglikáció, diacil-glicerol-, proteinkináz-C-aktiváció, poliol- és hexóz-amin-anyagcsereút) aktivitását, másrészt fokozza a pentóz-foszfát-sönt aktivitását. A benfotiamin klinikai hatékonyságát számos hazai és nemzetközi tanulmány igazolta. Az antioxidáns hatású alfa-liponsav az oxidatív stressz csökkentése révén elősegíti a glicerin-aldehid-3-foszfát-dehidrogenáz aktivitásának fokozódását. Az alfa-liponsav mind infúzióban, mind per os adagolva csökkenti a neuropathiával összefüggő tüneteket és mérsékli a neuropathiás károsodást. Összességében a neuropathia diabetica jól illusztrálja, hogy a patomechanizmussal kapcsolatos ismereteink bővülése számottevően hozzájárulhat a terápia sikeréhez is.
2009 Nobel Prize in Medicine and an interesting message: telomerase activity is associated with lifestyle
Authors: Falus András , Marton István , Borbényi Erika , Tahy Ádám , Karádi Pál , Aradi János , Stauder Adrienne , Kopp Mária
Published: June 2010

A 2009. évi orvosi Nobel-díjat a telomerák és a telomeráz enzim felfedezéséért és az ezekkel kapcsolatos úttörő kutatásokért három, Amerikában dolgozó tudós kapta megosztva. Nem régóta az is ismert, hogy bizonyos életmód- és táplálkozásbeli változások (Ornish-féle életmódváltozás), magatartásbeli, pszichológiai tényezők, valamint a telomerarövidülés között bizonyított kapcsolat létezik. Az összefoglalóban ezen összefüggések molekuláris, sejtbiológiai, életmódbeli és magatartási vonatkozásait, valamint ezek lehetséges összefüggéseit mutatják be.
Laparoscopic endoscopy: experiences with the new type of rendezvous technique
Authors: Völgyi Zoltán , Fischer Tünde , Szenes Mária , Tüske György , Vattay Péter , Gasztonyi Beáta
Published: June 2010

A szerzők egy, a kórházukban új módszer bevezetéséről és annak egyéves tapasztalatairól számolnak be. Epehólyagkő esetén az esetek egy részében epeúti kő is fennáll egyidejűleg. Utóbbi diagnózisa időnként könnyű, más esetekben azonban igen nehéz. A diagnózis felállításában az új képalkotók (endoszkópos ultrahang, mágneses rezonancia cholangiopancreatographia) segítségül szolgálhatnak. Amennyiben a choledochuskő gyanúja miatt végzett preoperatív endoszkópos retrográd cholangiopancreatographia (ERCP) sikertelen, randevú-ERCP-t, azaz laparoendoszkópiát végeztek. A szerzők a módszer nemzetközi irodalmának áttekintése és annak technikai leírását követően 10 saját esetről számolnak be, amelyek minden esetben sikeresek voltak. Hangsúlyozzák az új módszer előnyeit bizonyos betegcsoportban a hagyományos, szekvenciális módszerrel (preoperatív ERCP, majd laparoszkópos cholecystectomia) szemben, és felhívják a figyelmet azokra a technikai trükkökre, amelyekre szert tettek az eddigi műtétek során. Végül kiemelik a teammunka jelentőségét, amely a beavatkozás indikációjában, megszervezésében és kivitelezésében is feltételezi a gasztroenterológus, sebész és aneszteziológus együttműködését.
A new therapeutic class for the therapy of type 2 diabetes: DPP-4 inhibitors (sitagliptin)
Authors: Ábel Tatjána , Fehér† János
Published: June 2010

A 2-es típusú diabetes világszerte egyre terjedő megbetegedés. A rendezett vércukorkontroll csökkenti a microvascularis és feltehetően a macrovascularis szövődményeket is. A dipeptidil-peptidáz-4- (DPP-4-) gátlók, mint a sitagliptin is, a 2-es típusú diabeteses betegek kezelése során úgynevezett inkretin alapú, glükózdependens hatást fejtenek ki, anélkül, hogy hypoglykaemiát vagy testsúlyemelkedést okoznának.