bluuebunny/crossref_metadata_2025 huggingface dataset:
Administrative Data Fail to Accurately Identify Cases of Healthcare-Associated Infection
Authors: Sherman Eileen R. , Heydon Kateri H. , John Keith H. St. , Teszner Eva , Rettig Susan L. , Alexander Sharon K. , Zaoutis Theoklis Z. , Coffin Susan E.
Published: April 2006

Objective.

Some policy makers have embraced public reporting of healthcare-associated infections (HAIs) as a strategy for improving patient safety and reducing healthcare costs. We compared the accuracy of 2 methods of identifying cases of HAI: review of administrative data and targeted active surveillance.

Design, Setting, and Participants.

A cross-sectional prospective study was performed during a 9-month period in 2004 at the Children's Hospital of Philadelphia, a 418-bed academic pediatric hospital. “True HAI” cases were defined as those that met the definitions of the National Nosocomial Infections Surveillance System and that were detected by a trained infection control professional on review of the medical record. We examined the sensitivity and the positive and negative predictive values of identifying HAI cases by review of administrative data and by targeted active surveillance.

Results.

We found similar sensitivities for identification of HAI cases by review of administrative data (61%) and by targeted active surveillance (76%). However, the positive predictive value of identifying HAI cases by review of administrative data was poor (20%), whereas that of targeted active surveillance was 100%.

Conclusions.

The positive predictive value of identifying HAI cases by targeted active surveillance is very high. Additional investigation is needed to define the optimal detection method for institutions that provide HAI data for comparative analysis.
Influenza Immunization in Nursing Homes: Who Does Not Get Immunized and Whose Status Is Unknown?
Authors: Marsteller Jill A. , Tiggle Ronald , Remsburg Robin , Shefer Abigail , Bardenheier Barbara
Published: April 2006

Objective.

To identify nursing home resident and facility characteristics associated with patients not receiving influenza immunization and having unknown immunization status.

Design.

Secondary data analysis using multinomial logistic regression of data from the National Nursing Home Survey, a nationally representative establishment-based survey.

Setting.

A total of 1,423 nursing facilities of all ownerships and certifications systematically sampled with probability proportional to number of beds.

Patients.

A total of 7,350 randomly sampled people aged 65 years or older residing in nursing homes between July and December 1999 (approximately 6 per facility).

Main Outcome Measure.

Immunization status of residents.

Results.

Fifteen percent of residents were not immunized and 19% had unknown immunization status. In multivariate analysis, lack of immunization and unknown immunization status were each separately associated with being newly admitted, with no or unknown pneumococcal immunization, and with facility failures to screen for immunization and to record inoculation in the medical record. High-risk status and staff immunization requirements had no effect. Separate analyses showed that residents with unknown immunization status are statistically significantly different from both those vaccinated and those not vaccinated.

Conclusion.

This study indicates that both resident and facility characteristics are associated with failure to be immunized for influenza. Facilities should consider targeting younger, newly admitted, and residential care residents for influenza immunization, since they are more likely to be missed. Further research into the barriers to immunization specific to nursing home resident choice or opportunity may be warranted.
Identification of Optimal Combinations for Empirical Dual Antimicrobial Therapy of Pseudomonas aeruginosa Infection: Potential Role of a Combination Antibiogram
Authors: Mizuta Mari , Linkin Darren R. , Nachamkin Irving , Fishman Neil O. , Weiner Mark G. , Sheridan Angela , Lautenbach Ebbing
Published: April 2006

To better determine the optimal combinations for empirical dual antimicrobial therapy of Pseudomonas aeruginosa infection, we evaluated the utility of a novel combination antibiogram. Although the combination antibiogram allowed modest fine-tuning of choices for dual antibiotic therapy, selections based on the 2 antibiograms did not differ substantively. Drug combinations with the broadest coverage were consistently composed of an aminoglycoside and a β-lactam.
Outbreak of Infection WithAcinetobacterStrain RUH 1139 in an Intensive Care Unit
Authors: Vegas Elsa Zuleima Salazar De , Nieves Beatriz , Araque Maria , Velasco Elsa , Ruíz Joaquim , Vila Jordi
Published: April 2006

Objective.

To investigate a nosocomial outbreak of infection withAcinetobacterstrain RUH 1139, in the unit of high neonatal risk at University Hospital of The Andes (Mérida, Venezuela).

Methods.

Twenty-eightAcinetobacterstrains were detected by biochemical testing and further identified to the species level by examination of the gene encoding 16S ribosomal DNA, using restriction analysis and gene sequencing. The epidemiological relationship between the strains was established by means of repetitive extragenic palindromic polymerase chain reaction (REP-PCR) and pulsed-field gel electrophoresis (PFGE), and antimicrobial susceptibilities were determined by disk diffusion.

Results.

The spread of an epidemic strain ofAcinetobacterRUH 1139 among 16 patients over a period of 3 months was demonstrated using antimicrobial susceptibility testing, PFGE, and REP-PCR. The epidemic strain was also isolated in 2 of the sampled parenteral nutrition solutions. All the patients involved in the infection outbreak had received parenteral solution. Moreover, strains ofAcinetobacterRUH 1139 with another PFGE pattern and ofA. baumanniiwere sporadically isolated before and during the outbreak.

Conclusion.

This is the first description of an outbreak of infection with this genospecies ofAcinetobacterin which parenteral nutrition solution was potentially the infection source.
Sampling for Collection of Central Line–Day Denominators in Surveillance of Healthcare-Associated Bloodstream Infections
Authors: Klevens R. M. , Tokars J. I. , Edwards J. , Horan T. ,   National Nosocomial Infections Surveillance (NNIS) System
Published: April 2006

Objective.

To determine the feasibility of estimating the number of central line-days at a hospital from a sample of months or individual days in a year, for surveillance of healthcare-associated bloodstream infections.

Design.

We used data reported to the National Nosocomial Infections Surveillance system in the adult and pediatric intensive care unit component for 1995-2003 and data from a sample of hospitals' daily counts of device use for 12 consecutive months. We calculated the percentile error as the central line-associated bloodstream infection percentile based on rates per line-days minus the percentile based on rates per estimated line-days.

Setting and Participants.

A total of 247 hospitals were used for sampling whole months and 12 hospitals were used for sampling individual days.

Results.

For a 1-month sample of central line–days data, the median percentile error was 3.3 (75th percentile, 7.9; 90th percentile, 15.4). The percentile error decreased with an increase in the number of months sampled. For a 3-month sample, the median percentile error was 1.4 (75th percentile, 4.3; 95th percentile, 8.3). Sampling individual days throughout the year yielded lower percentile errors than sampling an equivalent fraction of whole months. With 1 weekday sampled per week, the median percentile error ranged from 0.65 to 1.40, and the 90th percentile ranged from 2.8 to 5.0. Thus, for 90% of units, collecting data on line-days once a week provides an estimate within ± 5 percentile points of the true line-day rate.

Conclusion.

Sample-based estimates of central line-days can yield results that are acceptable for surveillance of healthcare-associated bloodstream infections.
Analysis and Presentation of Cumulative Antimicrobial Susceptibility Data (Antibiograms): Substantial Variability Across Medical Centers in the United States
Authors: Lautenbach Ebbing , Nachamkin Irving
Published: April 2006

We found substantial variability in approaches to constructing antibiograms at 65 United States medical centers. Laboratories in teaching hospitals and those with more personnel were significantly more likely to offer sophisticated antibiogram approaches, including the compiling of unit-specific susceptibility data and the reporting of temporal trends in susceptibility data.
Device-Associated Nosocomial Infection Rates in Turkish Medical-Surgical Intensive Care Units
Authors: Inan Dilara , Saba Rabin , Yalcin Ata Nevzat , Yilmaz Murat , Ongut Gozde , Ramazanoglu Atilla , Mamikoglu Latife
Published: April 2006

Objective.

To describe the incidence of device-associated nosocomial infections in medical-surgical intensive care units (MS ICUs) in a university hospital in Turkey and compare it with National Nosocomial Infections Surveillance (NNIS) system rates.

Design.

Prospective surveillance study during a period of 27 months. Device utilization ratios and device-associated infection rates were calculated using US Centers for Disease Control and Prevention and NNIS definitions.

Setting.

Two separate MS ICUs at Akdeniz University Hospital, Antalya, Turkey.

Patients.

All patients were included who presented with no signs and symptoms of infection within the first 48 hours after admission.

Results.

Data on 1,985 patients with a total of 16,892 patient-days were analyzed. The mean overall infection rate per 100 patients was 29.1 infections, and the mean infection rate per 1,000 patient-days was 34.2 infections. The rate of ventilator-associated pneumonia was 20.76 infections per 1,000 ventilator-days, the rate of catheter-associated urinary tract infection was 13.63 infections per 1,000 urinary catheter–days, and the rate of catheter-associated bloodstream infection was 9.69 infections per 1,000 central line–days. The most frequently isolated pathogens were Pseudomonas species among patients with ventilator-associated pneumonias (35.8% of cases), Candida species among patients with catheter-associated urinary tract infections (37.1% of cases), and coagulase-negative staphylococci among patients with catheter-associated bloodstream infections (20.0% of cases).

Conclusion.

We found both higher device-associated infection rates and higher device utilization ratios in our MS ICUs than those reported by the NNIS system. To reduce the rate of infection, implementation of infection control practices and comprehensive education are required, and an appropriate nationwide nosocomial infection and control system is needed in Turkey.
Test to Determine Sterile Integrity of Wrapped Medical Products at a Probability of Recontamination of 1: 1,000,000
Authors: Dunkelberg Hartmut , Rohmann Susanne
Published: April 2006

Objective.

We developed a microbiological test to detect the penetration of airborne microorganisms through the packaging of medical products after sterilization, to meet the requirements of European standard EN 556. We applied this test method to transparent pouches.

Design.

The microbial-barrier properties of the transparent pouches were determined using the microbial challenge test, in which the package was placed inside an exposure chamber and exposed to a defined aerosol of Saccharomyces cerevisiae. The atmospheric pressure in the chamber was periodically reduced by 0-75 millibars, to simulate weather-dependent pressure changes. Thermoresistant petri dishes filled with nutrient agar were integrated into the transparent pouches before sterilization. The packages were incubated after exposure. They were then opened and examined for colony growth.

Results.

The number of recontaminated packages per test group (n = 50) depended on the microbial bioload (defined as the number of colony-forming units per plate) to which the packages were exposed and on the size and number of decreases in atmospheric pressure. Results of multiple regression analysis showed a significant increase in the number of recontaminated packages in correlation with the product of the values for microbial bioload and the size and number of decreases in atmospheric pressure. When we analyzed the probability of recontamination of wrapped medical devices after 2 reductions in atmospheric pressure (30 millibars each) and with a surface microbial load of 10 colony-forming units per 64 cm2, we estimated that the frequency of recontamination was 1: 100,000.

Conclusion.

Multiple regression analysis showed that the proposed microbial challenge test is suitable to determine the probability of package recontamination at the 1: 1,000,000 level.
Pyrogenic Reactions in Hemodialysis Patients, Hanoi, Vietnam
Authors: Archibald Lennox K. , Khoi Nguyen Nguyen , Jarvis William R. , Reller L. Barth , Cam Phung Dac , Thu Truong Anh , Hung Nguyen Viet
Published: April 2006

Of 33,111 patients admitted to a large hospital in Vietnam from November 2000 through July 2001, a total of 303 were undergoing hemodialysis and had pyrogenic reactions (ie, fever and/or rigors). Ten case patients (3.3%) had documented bacteremia; pathogens were largely waterborne microorganisms. Pyrogenic reactions in case patients might have occurred because of suboptimal water quality or inadequate dialyzer reprocessing procedures.
Inappropriate Antibiotic Use in a Tertiary Care Center in Thailand: An Incidence Study and Review of Experience in Thailand
Authors: Apisarnthanarak Anucha , Danchaivijitr Somwang , Bailey Thomas C. , Fraser Victoria J.
Published: April 2006

The incidence and patterns of and factors associated with inappropriate antibiotic use were studied in a tertiary care center in Thailand. The incidence of inappropriate antibiotic use was 25%. Admission to the surgical department (adjusted odds ratio, 2.0; P = .02) and to the obstetrics and gynecology department (adjusted odds ratio, 2.0; P = .03) were associated with inappropriate antibiotic use, whereas consultation with an infectious diseases specialist was protective against inappropriate antibiotic use (adjusted odds ratio, 0.15; P = .01).
Epidemiology ofAcinetobacter baumanniiin a University Hospital in Turkey
Authors: Akalin Halis , Özakin Cüneyt , Gedikoğlu Suna
Published: April 2006

Objective.

Molecular epidemiologic surveillance ofAcinetobacter baumanniiby polymerase chain reaction-randomly amplified polymorphic DNA analysis in a university hospital for 3 consecutive study periods.

Results.

Twelve differentAcinetobacter baumanniigenotypes (A-L) were detected. Although only 2 genotypes were detected during the first period and genotype A appeared to be the most common genotype, genotype D was included in these genotypes during the second study period. Genotype A completely disappeared during the third period. Although the presence of genotype C and the genotype D continued during the third period, 9 new genotypes were detected during this period. Genotype A appeared to be the most common genotype in the hospital (detected in 19 different clinics). The distribution of genotypes in clinical samples correlated with patient traffic between them. Some genotypes were found in both clinical and environmental samples. Seventeen different antibiotypes were detected, according to antibiotic susceptibility profiles.

Conclusions.

Environmental contamination, airborne transmission, patient transfer, and cross-contamination play important roles in epidemics caused byA. baumanniiin our hospital. The distribution of genotypes can change over time, so antibiotyping is not appropriate for the epidemiological analysis ofA. baumaniiinfection.
Prevalence of Nosocomial Infections in High-Risk Units in the University Clinical Center of Kosova
Authors: Raka L. , Zoutman D. , Mulliqi G. , Krasniqi S. , Dedushaj I. , Raka N. , Ahmeti S. , Shala M. , Vishaj A. , Elezi Y.
Published: April 2006

A point-prevalence study was performed to determine the prevalence of nosocomial infections in University Clinical Center of Kosova. Of 167 surveyed patients, 27 had a total of 29 nosocomial infections, with an overall prevalence rate of 17.4%. Nosocomial bloodstream infections were most prevalent (62%). The prevalence was highest among neonates in intensive-care units (77.8%).
MAP Kinase Pathway–dependent Phosphorylation of the L1-CAM Ankyrin Binding Site Regulates Neuronal Growth
Authors: Whittard John D. , Sakurai Takeshi , Cassella Melanie R. , Gazdoiu Mihaela , Felsenfeld Dan P.
Published: April 2006

The growth of neuronal processes depends critically on the function of adhesion proteins that link extracellular ligands to the cytoskeleton. The neuronal adhesion protein L1-CAM serves as a receptor for nerve growth–promoting proteins, a process that is inhibited by the interaction between L1-CAM and the cytoskeleton adaptor ankyrin. Using a novel reporter based on intramolecular bioluminescence resonance energy transfer, we have determined that the MAP kinase pathway regulates the phosphorylation of the FIGQY motif in the adhesion protein L1-CAM and its interaction with ankyrin B. MAP kinase pathway inhibitors block L1-CAM–mediated neuronal growth. However, this blockade is partially rescued by inhibitors of L1-CAM–ankyrin binding. These results demonstrate that the MAP kinase pathway regulates L1-CAM–mediated nerve growth by modulating ankyrin binding, suggesting that nerve growth can be regulated at the level of individual receptors.
A fast coarse filtering method for peptide identification by mass spectrometry
Authors: Ramakrishnan Smriti R. , Mao Rui , Nakorchevskiy Aleksey A. , Prince John T. , Willard Willard S. , Xu Weijia , Marcotte Edward M. , Miranker Daniel P.
Published: April 2006

Motivation: We reformulate the problem of comparing mass-spectra by mapping spectra to a vector space model. Our search method leverages a metric space indexing algorithm to produce an initial candidate set, which can be followed by any fine ranking scheme.

Results: We consider three distance measures integrated into a multi-vantage point index structure. Of these, a semi-metric fuzzy-cosine distance using peptide precursor mass constraints performs the best. The index acts as a coarse, lossless filter with respect to the SEQUEST and ProFound scoring schemes, reducing the number of distance computations and returned candidates for fine filtering to about 0.5% and 0.02% of the database respectively. The fuzzy cosine distance term improves specificity over a peptide precursor mass filter, reducing the number of returned candidates by an order of magnitude. Run time measurements suggest proportional speedups in overall search times. Using an implementation of ProFound's Bayesian score as an example of a fine filter on a test set of Escherichia coli protein fragmentation spectra, the top results of our sample system are consistent with that of SEQUEST.

Contact:  smriti@cs.utexas.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Global dynamics of biological systems from time-resolved omics experiments
Authors: Grigorov Martin G.
Published: April 2006

The emergent properties of biological systems, organized around complex networks of irregularly connected elements, limit the applications of the direct scientific method to their study. The current lack of knowledge opens new perspectives to the inverse scientific paradigm where observations are accumulated and analysed by advanced data-mining techniques to enable a better understanding and the formulation of testable hypotheses about the structure and functioning of these systems. The current technology allows for the wide application of omics analytical methods in the determination of time-resolved molecular profiles of biological samples. Here it is proposed that the theory of dynamical systems could be the natural framework for the proper analysis and interpretation of such experiments. A new method is described, based on the techniques of non-linear time series analysis, which is providing a global view on the dynamics of biological systems probed with time-resolved omics experiments.

Contact:  martin.grigorov@rdls.nestle.com
Identification of biochemical networks by S-tree based genetic programming
Authors: Cho Dong-Yeon , Cho Kwang-Hyun , Zhang Byoung-Tak
Published: April 2006

Motivation: Most previous approaches to model biochemical networks have focused either on the characterization of a network structure with a number of components or on the estimation of kinetic parameters of a network with a relatively small number of components. For system-level understanding, however, we should examine both the interactions among the components and the dynamic behaviors of the components. A key obstacle to this simultaneous identification of the structure and parameters is the lack of data compared with the relatively large number of parameters to be estimated. Hence, there are many plausible networks for the given data, but most of them are not likely to exist in the real system.

Results: We propose a new representation named S-trees for both the structural and dynamical modeling of a biochemical network within a unified scheme. We further present S-tree based genetic programming to identify the structure of a biochemical network and to estimate the corresponding parameter values at the same time. While other evolutionary algorithms require additional techniques for sparse structure identification, our approach can automatically assemble the sparse primitives of a biochemical network in an efficient way. We evaluate our algorithm on the dynamic profiles of an artificial genetic network. In 20 trials for four settings, we obtain the true structure and their relative squared errors are <5% regardless of releasing constraints about structural sparseness. In addition, we confirm that the proposed algorithm is robust within ±10% noise ratio. Furthermore, the proposed approach ensures a reasonable estimate of a real yeast fermentation pathway. The comparatively less important connections with non-zero parameters can be detected even though their orders are below 10−2. To demonstrate the usefulness of the proposed algorithm for real experimental biological data, we provide an additional example on the transcriptional network of SOS response to DNA damage in Escherichia coli. We confirm that the proposed algorithm can successfully identify the true structure except only one relation.

Availability: The executable program and data are available from the authors upon request.

Contact:  ckh-sb@snu.ac.kr or btzhang@snu.ac.kr
PowQ: a user-friendly package for the design of variance component multipoint linkage analysis studies
Authors: Falchi Mario , Borlino Cesare Cappio
Published: April 2006

Summary: A user-friendly, graphical package for power evaluation and enhancement planning through variance component linkage analysis in a multipoint framework.

Availability: The package is made available at:

Contact:  mario.falchi@kcl.ac.uk
Smooth solution to the one-dimensional inhomogeneous non-automorphic Landau–Lifshitz equation
Authors: Lin Junyu , Ding Shijin
Published: April 2006

Using the differential–difference method and viscosity vanishing approach, we obtain the existence and uniqueness of the global smooth solution to the periodic initial-value problem of the inhomogeneous, non-automorphic Landau–Lifshitz equation without Gilbert damping terms in one dimension. To establish the uniform estimates, we use some identities resulting from the fact

and the fact that the vectors

form an orthogonal base of the space

.
Wolbachiainfection reduces sperm competitive ability in an insect
Authors: Champion de Crespigny Fleur E , Wedell Nina
Published: April 2006

The maternally inherited bacteriumWolbachia pipientisimposes significant fitness costs on its hosts. One such cost is decreased sperm production resulting in reduced fertility of maleDrosophila simulansinfected with cytoplasmic incompatibility (CI) inducingWolbachia. We tested the hypothesis thatWolbachiainfection affects sperm competitive ability and found thatWolbachiainfection is indeed associated with reduced success in sperm competition in non-virgin males. In the second male role, infected males sired 71% of the offspring whereas uninfected males sired 82% of offspring. This is the first empirical evidence indicating thatWolbachiainfection deleteriously affects sperm competition and raises the possibility that polyandrous females can utilize differential sperm competitive ability to bias the paternity of broods and avoid the selfish manipulations ofWolbachia. This suggests a relationship betweenWolbachiainfection and host reproductive strategies. These findings also have important consequences forWolbachiapopulation dynamics because the transmission advantage ofWolbachiais likely to be undermined by sperm competition.
Regional heterogeneity and gene flow maintain variance in a quantitative trait within populations of lodgepole pine
Authors: Yeaman Sam , Jarvis Andy
Published: April 2006

Genetic variation is of fundamental importance to biological evolution, yet we still know very little about how it is maintained in nature. Because many species inhabit heterogeneous environments and have pronounced local adaptations, gene flow between differently adapted populations may be a persistent source of genetic variation within populations. If this migration–selection balance is biologically important then there should be strong correlations between genetic variance within populations and the amount of heterogeneity in the environment surrounding them. Here, we use data from a long-term study of 142 populations of lodgepole pine (Pinus contorta) to compare levels of genetic variation in growth response with measures of climatic heterogeneity in the surrounding region. We find that regional heterogeneity explains at least 20% of the variation in genetic variance, suggesting that gene flow and heterogeneous selection may play an important role in maintaining the high levels of genetic variation found within natural populations.
Short RNAs in environmental adaptation
Authors: Dalmay Tamas
Published: April 2006

Non-coding small RNAs (19–24 nucleotide long) have recently been recognized as the important regulator of gene expression in both plants and animals. Several classes of endogenous short RNAs have partial or near perfect complementarity to mRNAs and a protein complex is guided by short RNAs to target mRNAs. The targeted mRNA is either cleaved or its translation is suppressed. Initially, short RNAs were believed to primarily regulate the normal development of plants and animals, but recent advances implicate short RNAs in environmental adaptation.
Modelling transcriptional feedback loops: the role of Gro/TLE1 in Hes1 oscillations
Authors: Bernard Samuel , Čajavec Branka , Pujo-Menjouet Laurent , Mackey Michael C , Herzel Hanspeter
Published: April 2006

The transcriptional repressor Hes1, a basic helix-loop-helix family protein, periodically changes its expression in the presomitic mesoderm. Its periodic pattern of expression is retained in a number of cultured murine cell lines. In this paper, we introduce an extended mathematical model for Hes1 oscillatory expression that includes regulation of Hes1 transcription by Drosophila Groucho (Gro) or its vertebrate counterpart, the transducine-like enhancer of split/Groucho-related gene product 1 (TLE1). Gro/TLE1 is a necessary corepressor required by a number of DNA-binding transcriptional repressors, including Hes1. Models of direct repression via Hes1 typically display an expression overshoot after transcription initiation which is not seen in the experimental data. However, numerical simulation and theoretical predictions of our model show that the cofactor Gro/TLE1 reduces the overshoot and is thus necessary for a rapid and finely tuned response of Hes1 to activation signals. Further, from detailed linear stability and numerical bifurcation analysis and simulations, we conclude that the cooperativity coefficient (
h
) for Hes1 self-repression should be large (i.e.
h
≥4). Finally, we introduce the characteristic turnaround duration, and show that for our model the duration of the repression loop is between 40 and 60 min.
Acidosis in models of cardiac ventricular myocytes
Authors: Crampin Edmund J , Smith Nicolas P , Langham A. Elise , Clayton Richard H , Orchard Clive H
Published: April 2006

The effects of acidosis on cardiac electrophysiology and excitation–contraction coupling have been studied extensively. Acidosis decreases the strength of contraction and leads to altered calcium transients as a net result of complex interactions between protons and a variety of intracellular processes. The relative contributions of each of the changes under acidosis are difficult to establish experimentally, however, and significant uncertainties remain about the key mechanisms of impaired cardiac function.

In this paper, we review the experimental findings concerning the effects of acidosis on the action potential and calcium handling in the cardiac ventricular myocyte, and we present a modelling study that establishes the contribution of the different effects to altered Ca
2+
transients during acidosis. These interactions are incorporated into a dynamical model of pH regulation in the myocyte to simulate respiratory acidosis in the heart.
Modelling Cl
−
homeostasis and volume regulation of the cardiac cell
Authors: Terashima K , Takeuchi A , Sarai N , Matsuoka S , Shim E.B , Leem C.H , Noma A
Published: April 2006

We aim at introducing a Cl
−
homeostasis to the cardiac ventricular cell model (Kyoto model), which includes the sarcomere shortening and the mitochondria oxidative phosphorylation. First, we examined mechanisms underlying the cell volume regulation in a simple model consisting of Na
+
/K
+
pump, Na
+
–K
+
–2Cl
−
cotransporter 1 (NKCC1), cystic fibrosis transmembrane conductance regulator, volume-regulated Cl
−
channel and background Na
+
, K
+
and Cl
−
currents. The high intracellular Cl
−
concentration of approximately 30 mM was achieved by the balance between the secondary active transport via NKCC1 and passive currents. Simulating responses to Na
+
/K
+
pump inhibition revealed the essential role of Na
+
/K
+
pump in maintaining the cellular osmolarity through creating the negative membrane potential, which extrudes Cl
−
from a cell, confirming the previous model study in the skeletal muscle. In addition, this model well reproduced the experimental data such as the responses to hypotonic shock in the presence or absence of β-adrenergic stimulation. Finally, the volume regulation via Cl
−
homeostasis was successfully incorporated to the Kyoto model. The steady state was well established in the comprehensive cell model in respect to both the intracellular ion concentrations and the shape of the action potential, which are all in the physiological range. The source code of the model, which can reproduce every result, is available from
http://www.sim-bio.org/
.
Derepression of the Her-2 uORF is mediated by a novel post-transcriptional control mechanism in cancer cells
Authors: Mehta Anuradha , Trotta Christopher R. , Peltz Stuart W.
Published: April 2006

Transcripts harboring 5′ upstream open reading frames (uORFs) are often found in genes controlling cell growth including receptors, oncogenes, or growth factors. uORFs can modulate translation or RNA stability and mediate inefficient translation of these potent proteins under normal conditions. In dysregulated cancer cells, where the gene product, for example Her-2 receptor, is overexpressed, post-transcriptional processes must exist that serve to override the inhibitory effects of the uORFs. The 5′ untranslated region (UTR) of Her-2 mRNA contains a short uORF that represses translation of the downstream coding region. We demonstrate that in Her-2 overexpressing breast cancer cells, the 3′ UTR of the Her-2 mRNA can override translational inhibition mediated by the Her-2 uORF. Within this 3′ UTR, a translational derepression element (TDE) that binds to a 38-kDa protein was identified. These results define a novel biological mechanism in which translational control of genes harboring a 5′ uORF can be modulated by elements in their 3′ UTRs.
PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein
Authors: Lee Hansol , Quinn John C. , Prasanth Kannanganattu V. , Swiss Victoria A. , Economides Kyriakos D. , Camacho Marie M. , Spector David L. , Abate-Shen Cory
Published: April 2006

The mechanisms by which homeoproteins bind selectively to target genes in vivo have long remained unresolved. Here we report that PIAS1 confers DNA-binding specificity on the Msx1 homeoprotein by regulating its subnuclear localization and proximity to target genes. We demonstrate that the interaction of Msx1 with PIAS1, but not its sumoylation, is required for Msx1 to function as an inhibitor of myoblast differentiation through repression of myogenic regulatory genes, such as MyoD. We find that PIAS1 enables Msx1 to bind selectively to a key regulatory element in MyoD, the CER, in myoblast cells and to distinguish the CER from other nonregulatory TAAT-containing sequences. We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells. Furthermore, we demonstrate that myogenic regulatory genes that are repressed by Msx1, namely MyoD and Myf5, are located at the nuclear periphery in myoblast cells. We propose that a key regulatory event for DNA-binding specificity by homeoproteins in vivo is their appropriate targeting to subnuclear compartments where their target genes are located, which can be achieved by cofactors such as PIAS1.
The Drosophila P68 RNA helicase regulates transcriptional deactivation by promoting RNA release from chromatin
Authors: Buszczak Michael , Spradling Allan C.
Published: April 2006

Terminating a gene’s activity requires that pre-existing transcripts be matured or destroyed and that the local chromatin structure be returned to an inactive configuration. Here we show that the Drosophila homolog of the mammalian P68 RNA helicase plays a novel role in RNA export and gene deactivation. p68 mutations phenotypically resemble mutations in small bristles (sbr), the Drosophila homolog of the human mRNA export factor NXF1. Full-length hsp70 mRNA accumulates in the nucleus near its sites of transcription following heat shock of p68 homozygotes, and hsp70 gene shutdown is delayed. Unstressed mutant larvae show similar defects in transcript accumulation and gene repression at diverse loci, and we find that p68 mutations are allelic to Lighten-up, a known suppressor of position effect variegation. Our observations reveal a strong connection between transcript clearance and gene repression. P68 may be needed to rapidly remove transcripts from a gene before its activity can be shut down and its chromatin reset to an inactive state.
Role of heat-shock factor 2 in cerebral cortex formation and as a regulatorof p35 expression
Authors: Chang Yunhua , Östling Päivi , Åkerfelt Malin , Trouillet Diane , Rallu Murielle , Gitton Yorick , El Fatimy Rachid , Fardeau Vivienne , Le Crom Stéphane , Morange Michel , Sistonen Lea , Mezger Valérie
Published: April 2006

Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2−/− cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2−/− cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2−/− cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.
Directed evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide‐MHC without increasing apparent cross‐reactivity
Authors: Dunn Steven M. , Rizkallah Pierre J. , Baston Emma , Mahon Tara , Cameron Brian , Moysey Ruth , Gao Feng , Sami Malkit , Boulter Jonathan , Li Yi , Jakobsen Bent K.
Published: April 2006

The mammalian α/β T cell receptor (TCR) repertoire plays a pivotal role in adaptive immunity by recognizing short, processed, peptide antigens bound in the context of a highly diverse family of cell‐surface major histocompatibility complexes (pMHCs). Despite the extensive TCR–MHC interaction surface, peptide‐independent cross‐reactivity of native TCRs is generally avoided through cell‐mediated selection of molecules with low inherent affinity for MHC. Here we show that, contrary to expectations, the germ line‐encoded complementarity determining regions (CDRs) of human TCRs, namely the CDR2s, which appear to contact only the MHC surface and not the bound peptide, can be engineered to yield soluble low nanomolar affinity ligands that retain a surprisingly high degree of specificity for the cognate pMHC target. Structural investigation of one such CDR2 mutant implicates shape complementarity of the mutant CDR2 contact interfaces as being a key determinant of the increased affinity. Our results suggest that manipulation of germ line CDR2 loops may provide a useful route to the production of high‐affinity TCRs with therapeutic and diagnostic potential.
Guanidinium derivatives bind preferentially and trigger long‐distance conformational changes in an engineered T4 lysozyme
Authors: Yousef Mohammad S. , Bischoff Nicole , Dyer Collin M. , Baase Walter A. , Matthews Brian W.
Published: April 2006

The binding of guanidinium ion has been shown to promote a large‐scale translation of a tandemly duplicated helix in an engineered mutant of T4 lysozyme. The guanidinium ion acts as a surrogate for the guanidino group of an arginine side chain. Here we determine whether methyl‐ and ethylguani‐dinium provide better mimics. The results show that addition of the hydrophobic moieties to the ligand enhances the binding affinity concomitant with reduction in ligand solubility. Crystallographic analysis confirms that binding of the alternative ligands to the engineered site still drives the large‐scale conformational change. Thermal analysis and NMR data show, in comparison to guanidinium, an increase in protein stability and in ligand affinity. This is presumably due to the successive increase in hydrophobicity in going from guanidinium to ethylguanidinium. A fluorescence‐based optical method was developed to sense the ligand‐triggered helix translation in solution. The results are a first step in the de novo design of a molecular switch that is not related to the normal function of the protein.
TOPOGRAPHY OF CELL DIVISION IN THE STRUCTURALLY COMPLEX DINOFLAGELLATE GENUS ORNITHOCERCUS1
Authors: Taylor F. J. R.
Published: April 2006

The dinophysoid dinoflagellates (to which Ornithocercus belongs) achieve growth both by increase in size of individual wall elements and, during rapid lateral expansion associated with cell division, by the formation of a semimeridional band of material termed the megacytic zone (MZ). The MZ maintains mother cell wall integrity during complete cytokinesis of the cell body and enclosure with new wall elements. The lists, extensive wing‐like extensions of the wall, can only be reformed after dissolution of the MZ. Beginning near the ventral region (which is the last region of the wall to be duplicated), the MZ dislocates and its material is apparently resorbed. The last region of attachment is invariably dorsal and in several, but not all species, the daughter cells may remain attached during early list formation by a special remnant of the MZ, termed here the dorsal megacytic bridge (DMB). After full separation of daughter cells remnants of the DMB persist for an unknown but presumably short period.

The topography of this process, involving radical ontogenetic alterations in the appearance of the daughter cells and some wall surfaces, is illustrated here by the scanning electron microscope. In addition 2 aberrant types of division are shown, one of which results in a double individual, termed a geminoid.
FERTILIZATION IN OEDOGONIUM. I. PLASMOGAMY12
Authors: Hoffman Larry R.
Published: April 2006

Events prior to, during, and immediately following plasmogamy have been investigated in Oedogonium cardiacum using combined techniques of light and electron microscopy. Maturation of the oogonium involves the formation of an oogonial pore and the differentiation of the single egg from the larger oogonial protoplast from which it is formed. The fine structure of the sperm cell at the time of plasmogamy is described as well as the nature of its entrance into the oogonium. Cinematographic films were used to analyze the movements of the spermatozoids prior to plasmogamy and, similarly, 26 complete acts of gametic fusion were recorded and analyzed. Prior to plasmogamy the flagella‐bearing anterior extremity of the spermatozoid typically becomes elongate and is thereafter capable of flexible movements and rapid changes in shape which appear more or less independent of the rest of the cell. The sperm cell always makes initial contact with the egg surface by means of this agile, proboscis‐like, anterior end. Contact results through a combination of thrusting movements of the entire sperm cell and rapid, lateral sweeping movements of its flagellated anterior extremity against the egg surface. Gametic fusion is initiated with violent, vibrational movements of the sperm cell accompanied by loss of its flagella. Apparent fusion of the gamete membranes unites their protoplasts by a narrow cytoplasmic bridge which gradually increases in size as the sperm cell cytoplasm flows into the egg. An average time of 30.5 sec was required for complete fusion as determined from 25 typical sequences of plasmogamy recorded cinematographically. Fusion occurs even more rapidly when diploid oogonia are substituted for daploid oogonia. The entire sperm cell, with the exception of the flagella, fuses with the egg during plasmogamy. The dissimilar gamete nuclei are clearly distinguished ultrastructurally in the binucleate fusion cell. Concentrations of sperm cell mitochondria and remains of the flagellar apparatus (but no flagella) are readily recognized in the fusion cell. The fate of these and other cytoplasmic constituents of the sperm cell is discussed. Immediately after plasmogamy, and prior to karyogamy, a thin, finely fibrous layer is formed us an investment exterior to the fusion cell. Karyogamy follows shortly after plasmogamy, and both events may take place within 15 min after mixing eggs and spermatozoids.
PHOTOASSIMILATION OF 14C‐ACETATE BY ULVA LACTUCA1
Authors: Gemmill Eldon R. , Galloway Raymond A.
Published: April 2006

The effect of light on the uptake of 14C‐labeled acetate, glucose, α‐ketoglutarate, mannitol, and glycine was investigated in Ulva lactuca var. rigida. Uptake in the light over that in the dark of 14C‐acetale (8‐fold) was far higher than that of the other compounds tested. Further study of the phenomenon showed that (1) an increase in light intensity from 60 through 1000 ft‐c results in increased 14C‐acetate uptake, the kinetics of which differ from that of 14CO2 uptake versus light intensity over the same range: (2) the action spectrum of acetate uptake, between 450 and 730 nm conforms to the action spectrum for photosynthesis in Ulva; (3) the acetate uptake process is sensitive to photosynthetic poisons including N'‐ (3‐4, dichlorophenyl)‐N, N‐dimethyl urea (DCMU), and phenazine methosulfate (PMS), and inhibitors of the Krebs cycle including sodium monofluoroacetate (MFA) and malonate; (4) uptake of acetate is favored by low CO2 concentrations; (5) uptake of acetate is not sensitive to 10−4 M uranyl nitrate; (6) continuous white light, with and without far‐red radiation, indicates no significant phytochrome involvement in the process.

These results point to an intracellular dependence of the assimilation of acetate on the Krebs cycle in some manner (possibly in cooperation with the glyoxylate cycle) other than simply releasing CO2 from the acetate moiety with subsequent fixation via the Calvin cycle, and on some product(s) of photo‐system 2, eg, NADPH+, reduced ferredoxin, or O2.
Contact allergy to herbal teas derived from Asteraceae plants
Authors: Lundh Kerstin , Hindsén Monica , Gruvberger Birgitta , Möller Halvor , Svensson Åke , Bruze Magnus
Published: April 2006

Contact allergy to herbal teas derived from the Asteraceae plant family was investigated in patients allergic to sesquiterpene lactones (SLs). 20 patients with a known contact allergy to SLs were recalled and patch tested with aqueous extracts of 8 different herbal teas based on Asteraceae plants as well as with parthenolide and other SLs. In 18 of 20 patients with SL allergy, there were positive test reactions to the Asteraceae teas, mainly to those based on German chamomile, dandelion and wormwood. Among the SLs, parthenolide was the most frequent co‐reactor. Obviously, most patients with a contact allergy to SLs are allergic to commercial teas derived from the Asteraceae plant family as well.
Rosemary contact dermatitis and cross‐reactivity with other labiate plants
Authors: González‐Mahave I , Lobesa T , Del Pozo M. D , Blasco A. , Venturini M
Published: April 2006

Rosemary, a plant belonging to the labiate family, is frequently used in the making of cosmetics and also for medicinal purposes. There are few reported cases of contact dermatitis due to this plant. Here we present 1 case and asses the existence of cross‐reactivity with plants from the same family. 53‐year‐old man with several episodes of a pruritic and erythematous eruption that resulted in peeling of the skin, after applying rosemary alcohol, on the chest reported. Epicutaneous tests were done with the standard European series (GEIDC), with the commercial plant series (Bial‐Aristegui) and with plants from the labiate family. Results were positive for 3 of 4 labiate species tested. we present a case of rosemary contact dermatitis, where we have found cross‐reactivity with 3 of 4 species tested from the same family.
Community Partnerships: Integrating Early Education with Childcare
Authors: Broadhead Pat , Armistead Jo
Published: April 2006

This study reports on research into a Local Authority initiative in York, in North Yorkshire which aimed to establish early education and childcare partnerships between its 51 primary schools and local early‐years providers from the community‐voluntary and private sectors in close geographical proximity to the schools. The initiative was named Shared Foundation Community Partnerships.