bluuebunny/crossref_metadata_2025 huggingface dataset:
Individuals with the Dominant Hand Affected following Stroke Demonstrate Less Impairment Than Those with the Nondominant Hand Affected
Authors: Harris Jocelyn E. , Eng Janice J.
Published: August 2006

Objective. The purpose was to determine if upper extremity impairment and function in individuals with chronic stroke is dependent upon whether the dominant or non-dominant hand is affected. Methods. Ninety-three community-dwelling individuals with stroke. The Modified Ashworth Scale (tone), handheld dynamometry (isometric strength), monofilaments (sensation), Brief Pain Inventory (pain), Chedoke Arm and Hand Activity Inventory Motor Activity Log (paretic arm use), and Reintegration to Normal Living Index (participation) were used to form impairment and function models. Results. Multivariate analysis models (Dominance × Severity) were created for impairment and function variables. There was a significant interaction and main effect of Dominance for the impairment model ( P = 0.01) but not the function model ( P = 0.75). The dependent variables of tone, grip strength, and pain were all significantly affected by Dominance, indicating less impairment if the dominant hand was affected. All dependent variables except pain were affected by Severity. Conclusion. This study looked at the effect of the dominant hand being affected versus the nondominant in individuals with chronic stroke. Individuals with the dominant hand affected demonstrated less impairment than those with the nondominant hand affected. However, there was no effect of dominance on paretic arm use or performance in activities of daily living. Prospective studies to further explore the issue of hand dominance and poststroke function are suggested.
Outcomes of Physical Therapy, Speech Pathology, and Occupational Therapy for People with Motor Neuron Disease: A Systematic Review
Authors: Morris Meg E. , Perry Alison , Bilney Belinda , Curran Andrea , Dodd Karen , Wittwer Joanne E. , Dalton Gregory W.
Published: August 2006

This article describes a systematic review and critical evaluation of the international literature on the effects of physical therapy, speech pathology, and occupational therapy for people with motor neuron disease (PwMND). The results were interpreted using the framework of the International Classification of Functioning, Disability and Health. This enabled us to summarize therapy outcomes at the level of body structure and function, activity limitations, participation restrictions, and quality of life. Databases searched included MEDLINE, PUBMED, CINAHL, PSYCInfo, Data base of Abstracts of Reviews of Effectiveness (DARE), The Physiotherapy Evidence data base (PEDro), Evidence Based Medicine Reviews (EMBASE), the Cochrane database of systematic reviews, and the Cochrane Controlled Trials Register. Evidence was graded according to the Harbour and Miller classification. Most of the evidence was found to be at the level of “clinical opinion” rather than of controlled clinical trials. Several nonrandomized small group and “observational studies” provided low-level evidence to support physical therapy for improving muscle strength and pulmonary function. There was also some evidence to support the effectiveness of speech pathology interventions for dysarthria. The search identified a small number of studies on occupational therapy for PwMND, which were small, noncontrolled pre-post-designs or clinical reports.
Longitudinal Changes in Cerebral Response to Proprioceptive Input in Individual Patients after Stroke: An fMRI Study
Authors: Ward Nick S. , Brown Martin M. , Thompson Alan J. , Frackowiak Richard S. J.
Published: August 2006

Objective. Functional magnetic resonance imaging (fMRI) provides an opportunity to study the relationship between cerebral reorganization and functional recovery after stroke. The authors set out to demonstrate the feasibility of using fMRI to investigate mechanisms of recovery in individual patients presenting with severe motor impairment. Methods. fMRI was performed during passive movement at both affected and unaffected wrists separately in 2 patients with pure motor stroke. Six scanning sessions were performed in each patient over the first 4 months after stroke. Seven control subjects were also studied, 1 of them over 6 sessions. The authors examined for longitudinal changes in cerebral responses to proprioceptive afferent input that correlated with motor recovery. Results. In control subjects, passive movement of either wrist led to relative increases in brain activation in the contralateral sensorimotor cortex and supplementary motor area, the bilateral inferior parietal cortex and secondary somatosensory areas, and the ipsilateral cerebellum. Increases in brain activation correlating with motor recovery were observed in both the ipsilesional primary sensory and primary motor cortex in 1 patient with good motor recovery but not in another patient with poor recovery. No longitudinal changes were seen in the control subject. Conclusions. These 2 case reports demonstrate that functionally relevant changes in cerebral organization can be identified in individual patients.
Prediction of Driving after Stroke: A Prospective Study
Authors: Akinwuntan A. E. , Feys H. , De Weerdt W. , Baten G. , Arno P. , Kiekens C.
Published: August 2006

The process of determining whether patients with stroke should drive again often involves off-road evaluations and road tests that usually take about 2 to 3 h to complete. Objectives. This prospective study sought to identify the combination of tests that best predicts fitness to drive after stroke. The main aim was to develop a short and predictive predriving assessment battery. Methods. Sixty-eight consecutive stroke patients were studied who performed a mandatory predriving assessment at the Belgian Road Safety Institute, Brussels, within 18 months. Performance in a predriving assessment included medical examination (when needed), visual and neuropsychological evaluations, and an on-road test. Based on these assessments, a physician, psychologist, and the driving safety expert who administered the tests decided if a subject was either “fit to drive,”“temporarily unfit to drive,” or “unfit to drive.” Results. Logistic regression analysis revealed a combination of visual neglect, figure of Rey, and on-road tests as the model that best predicted ( R2 = 0.73) fitness to drive after stroke. Using a discriminant function that included the 3 tests of the logistic model, the fitness to drive judgments of 59 (86.8%) subjects were correctly predicted. The sensitivity and specificity of the predictions were 79.4% and 94.1%, respectively. Conclusion. Fitness to drive after stroke can be predicted from performance on a few road-related tests with a high degree of accuracy. However, some individuals require extended assessments and further tests.
Primary Motor Area Activation during Precision-Demanding versus Simple Finger Movement
Authors: Carey James R. , Greer Kristine R. , Grunewald Tiffany K. , Steele Jennifer L. , Wiemiller Jeff W. , Bhatt Ela , Nagpal Ashima , Lungu Ovidiu , Auerbach Edward J.
Published: August 2006

The authors used functional magnetic resonance imaging to explore whether the primary motor area (M1) serves a processing role in a finger-movement tracking task, emphasizing attention to accuracy, beyond its execution role of simple movements, with no attention to accuracy. Twenty healthy subjects performed alternating conditions: Rest, involving no finger movement; Track, involving careful control of a cursor along a target pathway with finger extension/flexion movements; and Move, involving finger extension/flexion movements without careful control. The authors compared volume of activated voxels in the M1, blood-oxygen-level-dependent (BOLD) signal intensity of activated voxels in the M1, and BOLD signal intensity of all voxels in the M1 between the Track and Move conditions. The results showed greater volume and signal intensity in both the contralateral and ipsilateral M1 during Track than during Move. Overall, the results suggest that the M1 is engaged not only in the execution of movements but also in spatial and temporal processing to produce accurately controlled movements. These findings invite further work exploring whether precision-demanding movements, such as tracking, form a more potent stimulus for promoting helpful brain reorganization in the M1 during the recovery from stroke than simple repetitive movements.
A Multicenter Trial of a Footdrop Stimulator Controlled by a Tilt Sensor
Authors: Stein Richard B. , Chong SuLing , Everaert Dirk G. , Rolf Robert , Thompson Aiko K. , Whittaker Maura , Robertson Jenny , Fung Joyce , Preuss Richard , Momose Kimito , Ihashi Kouji
Published: August 2006

Objectives. To test the efficacy and acceptance of a footdrop stimulator controlled by a tilt sensor. Methods. A nonrandomized, test-retest study of 26 subjects with footdrop of more than 1 year’s duration, resulting from various central nervous system disorders, was performed in 4 centers for at least 3 months. Speed of walking in a straight line, speed around a figure of 8, and physiological cost index (PCI) were measured with and without the device. Hours/day and steps/day using the device were recorded. Results.All but 2 subjects used the tilt sensor at home, rather than a foot switch. Walking speed increased by 15% after 3 months ( n = 26; P < 0.01), 32% after 6 months ( n = 16; P < 0.01), and 47% after 12 months ( n = 8; P < 0.05), while PCI decreased. The number of steps taken per day of use increased significantly over time, and increased speed was directly correlated with usage. Walking speed also increased with the stimulator off, but to a lesser extent, indicating a training effect. Subject feedback from a questionnaire indicated satisfaction with the stimulator. Conclusions. Both efficacy and acceptance of the stimulator were good in a population of subjects with chronic footdrop.
The Dag Hammarskjöld Library 1965–2005: Modernization and Outreach
Authors: Dickstein Phyllis
Published: August 2006

This article, by a long-time staff member and former Head Librarian, details the process of modernization of the Dag Hammarskjöld Library at United Nations Headquarters, New York, 1965–2005. It covers the Library's outreach efforts both to its primary clientele and worldwide, development of its databases, adoption of standard software packages to manage operations, the Library's website, online searching and contracting for electronic services, digitization of hard-copy materials, collaboration with other United Nations libraries, knowledge management, multilingualism. Analyses why various approaches were adopted, particularly with respect to the Library's databases, why they succeeded or did not succeed, and the extent to which the Library's efforts live up to the vision of the late Secretary-General Dag Hammarskjöld.
Protein tyrosine phosphatase receptor–type O truncated (PTPROt) regulates SYK phosphorylation, proximal B-cell–receptor signaling, and cellular proliferation
Authors: Chen Linfeng , Juszczynski Przemyslaw , Takeyama Kunihiko , Aguiar Ricardo C. T. , Shipp Margaret A.
Published: August 2006

The strength and duration of B-cell–receptor (BCR) signaling depends upon the balance between protein tyrosine kinase (PTK) activation and protein tyrosine phosphatase (PTP) inhibition. BCR-dependent activation of the SYK PTK initiates downstream signaling events and amplifies the original BCR signal. Although BCR-associated SYK phosphorylation is clearly regulated by PTPs, SYK has not been identified as a direct PTP substrate. Herein, we demonstrate that SYK is a major substrate of a tissue-specific and developmentally regulated PTP, PTP receptor–type O truncated (PTPROt). PTPROt is a member of the PTPRO family (also designated GLEPP, PTP-Ø, PTP-oc, and PTPu2), a group of highly conserved receptor-type PTPs that are thought to function as tumor suppressor genes. The overexpression of PTPROt inhibited BCR-triggered SYK tyrosyl phosphorylation, activation of the associated adaptor proteins SHC and BLNK, and downstream signaling events, including calcium mobilization and mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) activation. PTPROt overexpression also inhibited lymphoma cell proliferation and induced apoptosis in the absence of BCR cross-linking, suggesting that the phosphatase modulates tonic BCR signaling.
CXCR4 is a prognostic marker in acute myelogenous leukemia
Authors: Spoo Anke C. , Lübbert Michael , Wierda William G. , Burger Jan A.
Published: August 2006

CXCR4 chemokine receptors retain hematopoietic progenitors and leukemia cells within the marrow microenvironment. We prospectively evaluated the prognostic implication of CXCR4 in 90 consecutive patients with acute myelogenous leukemia (AML) by flow cytometry. Patients were divided into groups with low (n = 32), intermediate (n = 26), or high (n = 32) CXCR4 expression, as defined by CXCR4 mean fluorescence intensity ratio thresholds of less than 5, 5 to 10, or more than 10, respectively. We found that low CXCR4 expression on AML cells correlated with a better prognosis, resulting in a longer relapse-free and overall survival of 24.3 ± 2.9 months for low CXCR4-expressing patients, compared with 17.4 ± 3.4 months for intermediate and 12.8 ± 2 months (mean ± SEM) for patients with high expression. In univariate analyses, CXCR4 expression, cytogenetics, white blood cell count, and serum lactate dehydrogenase (LDH) predicted for shorter survival. Multivariate analysis revealed CXCR4 expression and unfavorable cytogenetics as independent prognostic factors. We conclude that CXCR4 expression in AML is an independent prognostic predictor for disease relapse and survival that can rapidly and easily be determined at disease presentation. These findings warrant further investigation into the role of CXCR4 in AML and suggest that CXCR4 should be incorporated into the risk assessment of AML patients.
Acetylation of GATA-1 is required for chromatin occupancy
Authors: Lamonica Janine M. , Vakoc Christopher R. , Blobel Gerd A.
Published: August 2006

All 3 hematopoietic GATA transcription factors, GATA-1, GATA-2, and GATA-3, are acetylated, although the in vivo role of this modification remains unclear. We examined the functions of an acetylation-defective mutant of GATA-1 in maturing erythroid cells. We found that removal of the acetylation sites in GATA-1 does not impair its nuclear localization, steady-state protein levels, or its ability to bind naked GATA elements in vitro. However, chromatin immunoprecipitation (ChIP) experiments revealed that mutant GATA-1 was dramatically impaired in binding to all examined cellular target sites in vivo, including genes that are normally activated and repressed by GATA-1. Together, these results suggest that acetylation regulates chromatin occupancy of GATA-1. These findings point to a novel function for transcription factor acetylation, perhaps by facilitating protein interactions required for stable association with chromatin templates in vivo.
C. elegansfeeding defective mutants have shorter body lengths and increased autophagy
Authors: Mörck Catarina , Pilon Marc
Published: August 2006

Background

Mutations that cause feeding defects in the nematode C. elegans are known to increase life span. Here we show that feeding defective mutants also have a second general trait in common, namely that they are small.

Results

Our measurements of the body lengths of a variety of feeding defective mutants, or of a variety of double mutants affecting other pathways that regulate body length in C. elegans, i.e. the DBL-1/TGFβ, TAX-6/calcineurin and the SMA-1/βH-spectrin pathways, indicate that food uptake acts as a separate pathway regulating body length. In early stages, before eating begins, feeding defective worms have no defect in body length or, in some cases, have only slightly smaller body length compared to wild-type. A significant difference in body length is first noticeable at later larval stages, a difference that probably correlates with increasing starvation. We also show that autophagy is induced and that the quantity of fat is decreased in starved worms.

Conclusion

Our results indicate that the long-term starvation seen in feeding-defective C. elegans mutants activates autophagy, and leads to depletion of fat deposits, small cell size and small body size.
Single and multiple dose pharmacokinetics of maritime pine bark extract (Pycnogenol) after oral administration to healthy volunteers
Authors: Grimm Tanja , Skrabala Roswitha , Chovanová Zuzana , Muchová Jana , Sumegová Katarína , Liptáková Anna , Ďuračková Zdeňka , Högger Petra
Published: August 2006

Background

Since plant extracts are increasingly used as phytotherapeutics or dietary supplements information on bioavailability, bioefficacy and safety are warranted. We elucidated the plasma kinetics of genuine extract components and metabolites after single and multiple ingestion of the standardized maritime pine bark extract Pycnogenol (USP quality) by human volunteers.

Methods

Eleven volunteers received a single dose of 300 mg pine bark extract, five volunteers ingested 200 mg daily for five days to reach steady state concentrations. Plasma samples were obtained before and at defined time points after intake of the extract. Samples were analyzed by HPLC with ion-pair reagents and simultaneous UV and electrochemical detection.

Results

We quantified total plasma concentrations of catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (δ-(3,4-dihydroxy-phenyl)-γ-valerolactone). Additionally, we describe plasma time courses and steady state appearance of ten so far unknown compounds, U1 to U10. After single ingestion, compounds derived from the extract were rapidly absorbed and the majority of them were detectable over whole experimental period of 14 h. The analysis of steady state plasma samples revealed significant phase II metabolism.

Conclusion

We present the first systematic pharmacokinetic analysis of compounds derived from maritime pine bark extract. Beyond the known constituents and metabolites we uncovered the plasma time courses of ten unknown compounds. In concert with our previous detection of anti-inflammatory bioefficacy of these plasma samplesex vivowe suggest that constituents and metabolites of Pycnogenol bear potential for disclosure of novel active principles.
Cross sectional study of performance indicators for English Primary Care Trusts: testing construct validity and identifying explanatory variables
Authors: Brown Celia , Lilford Richard
Published: August 2006

Background

The performance of Primary Care Trusts in England is assessed and published using a number of different performance indicators. Our study has two broad purposes. Firstly, to find out whether pairs of indicators that purport to measure similar aspects of quality are correlated (as would be expected if they are both valid measures of the same construct). Secondly, we wanted to find out whether broad (global) indicators correlated with any particular features of Primary Care Trusts, such as expenditure per capita.

Methods

Cross sectional quantitative analysis using data from six 2004/05 PCT performance indicators for 303 English Primary Care Trusts from four sources in the public domain: Star Rating, aggregated Quality and Outcomes Framework scores, Dr Foster mortality index, Dr Foster equity index (heart by-pass and hip replacements), NHS Litigation Authority Risk Management standards and Patient Satisfaction scores from the Star Ratings. Forward stepwise multiple regression analysis to determine the effect of Primary Care Trust characteristics on performance.

Results

Star Rating and Quality and Outcomes Framework total, both summary measures of global quality, were not correlated with each other (F = 0.66, p = 0.57). There were however positive correlations between Quality and Outcomes Framework total and patient satisfaction (r = 0.61, p < 0.001) and between screening/'additional services' indicators on the Star Ratings and Quality and Outcomes Framework (F = 24, p < 0.001). There was no correlation between different measures of access to services. Likewise we found no relationship between either Star Rating or Litigation Authority Standards and hospital mortality (F = 0.61, p = 0.61; F = 0.31, p = 0.73).

Conclusion

Performance assessment in healthcare remains on the Government's agenda, with new core and developmental standards set to replace the Star Ratings in 2006. Yet the results of this analysis provide little evidence that the current indicators have sufficient construct validity to measure the underlying concept of quality, except when the specific area of screening is considered.
Service utilization in community health centers in China: a comparison analysis with local hospitals
Authors: Pan Xilong , Dib Hassan H , Wang Xiaohang , Zhang Hong
Published: August 2006

Background

Being an important part of China's Urban Health Care Reform System, Community Health Centers (CHCs) have been established throughout the entire country and are presently undergoing substantial reconstruction. However, the services being delivered by the CHCs are far from reaching their performance targets. In order to assess the role of the CHCs, we examined their performance in six cities located in regions of South-East China. The purpose of this investigation was to identify the utilization and the efficiency of community health resources that are able to provide basic medical and public health services.

Methods

The study was approved by Peking University Health Science Center Institutional Reviewing Board (NO: IRB00001052-T1). Data were collected from all the local health bureaux and processed using SPSS software. Methods of analysis mainly included: descriptive analysis, paired T-test and one-way ANOVA.

Results

The six main functions of the CHCs were not fully exploited and the surveys that were collected on their efficiency and utilization of resources indicate that they have a low level of performance and lack the trust of local communities. Furthermore, the CHCs seriously lack funding support and operate under difficult circumstances, and residents have less positive attitudes towards them.

Conclusion

The community health service must be adjusted according to the requirements of urban medical and health reform, taking into account communities' health needs. More research is required on the living standards and health needs of residents living within the CHC's range, taking into consideration the users' needs in expanding the newly implemented service, and at the same time revising the old service system so as to make the development of CHCs realistic and capable of providing a better service to patients. Several suggestions are put forward for an attainable scheme for developing a community health service.
Japanese version of the Dermatology Life Quality Index: validity and reliability in patients with acne
Authors: Takahashi Natsuko , Suzukamo Yoshimi , Nakamura Motonobu , Miyachi Yoshiki , Green Joseph , Ohya Yukihiro , Finlay Andrew Y , Fukuhara Shunichi ,   the Acne QOL Questionnaire Development Team
Published: August 2006

Background

Patient-reported quality of life is strongly affected by some dermatologic conditions. We developed a Japanese version of the Dermatology Life Quality Index (DLQI-J) and used psychometric methods to examine its validity and reliability.

Methods

The Japanese version of the DLQI was created from the original (English) version, using a standard method. The DLQI-J was then completed by 197 people, to examine its validity and reliability. Some participants completed the DLQI-J a second time, 3 days later, to examine the reproducibility of their responses. In addition to the DLQI-J, the participants completed parts of the SF-36 and gave data on their demographic and clinical characteristics. Their physicians provided information on the location and clinical severity of the skin disease.

Results

The participants reported no difficulties in answering the DLQI-J items. Their mean age was 24.8 years, 77.2% were female, and 78.7% had acne vulgaris. The mean score of DLQI was 3.99(SD: 3.99). The responses were found to be reproducible and stable. Results of principal-component and factor analysis suggested that this scale measured one construct. The correlations of DLQI-J scores with sex or age were very poor, but those with SF-36 scores and with clinical severity were high.

Conclusion

The DLQI-J provides valid and reliable data despite having only a small number of items.
Raman spectroscopy: the gateway into tomorrow's virology
Authors: Lambert Phelps J , Whitman Audy G , Dyson Ossie F , Akula Shaw M
Published: August 2006

In the molecular world, researchers act as detectives working hard to unravel the mysteries surrounding cells. One of the researchers' greatest tools in this endeavor has been Raman spectroscopy. Raman spectroscopy is a spectroscopic technique that measures the unique Raman spectra for every type of biological molecule. As such, Raman spectroscopy has the potential to provide scientists with a library of spectra that can be used to unravel the makeup of an unknown molecule. However, this technique is limited in that it is not able to manipulate particular structures without disturbing their unique environment. Recently, a novel technology that combines Raman spectroscopy with optical tweezers, termed Raman tweezers, evades this problem due to its ability to manipulate a sample without physical contact. As such, Raman tweezers has the potential to become an incredibly effective diagnostic tool for differentially distinguishing tissue, and therefore holds great promise in the field of virology for distinguishing between various virally infected cells. This review provides an introduction for a virologist into the world of spectroscopy and explores many of the potential applications of Raman tweezers in virology.
Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants
Authors: Sun Dongxiao , Chen Gang , Dellinger Ryan W , Duncan Kimberly , Fang Jia-Long , Lazarus Philip
Published: August 2006

Introduction

Tamoxifen (TAM) is an antiestrogen widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism of TAM and one of its major active metabolites, 4-hydroxytamoxifen (4-OH-TAM), is via glucuronidation. In the present study, the glucuronidating activities of three common variant isoforms encoded by the human UDP-glucuronosyltransferase (UGT) 1A4 gene were examined against TAM,trans-4-OH-TAM andcis-4-OH-TAM.

Methods

HPLC was used to detect glucuronide conjugates in microsomes from UGT1A4-overexpressing HK293 cells. The UGT1A4 wild-type cDNA was synthesized by RT-PCR using normal human liver total RNA. The UGT1A424Thr/48Leuand UGT1A424Pro/48Valvariants were generated by site-directed mutagenesis of the pcDNA3.1/V5-His-TOPO plasmid expressing wild-type UGT1A424Pro/48Leu. Levels of UGT1A4 expression in UGT-overexpressing cell lines were measured by western blot analysis.

Results

Microsomes from wild-type UGT1A424Pro/48Leu-overexpressing HK293 cells exhibited significant levels of activity against TAM,trans-4-OH-TAM andcis-4-OH-TAM, forming exclusively the tamoxifen quaternary ammonium glucuronide (TAM-N+-glucuronide) and the 4-hydroxytamoxifen quaternary ammonium glucuronides (trans-4-OH-TAM-N+-glucuronide andcis-4-OH-TAM-N+-glucuronide) with apparentKmvalues of 2.0 μM, 2.2 μM, and 2.1 μM, respectively. Higher glucuronidation activities were found by kinetic analysis for microsomes from the variant UGT1A424Pro/48Val-overexpressing cell line as compared with microsomes from wild-type UGT1A424Pro/48Leu-overexpressing cells against TAM and against both thetransandcisisomers of 4-OH-TAM. A significantly (P< 0.02) lowerKmvalue (~1.6-fold to 1.8-fold) was observed for both 4-OH-TAM isomers, while a near-significant (P= 0.053) decrease inKmwas observed for TAM for the UGT1A424Pro/48Valvariant as compared with wild-type UGT1A4. TheVmax/Kmratio for the UGT1A424Pro/48Valvariant was significantly (P≤ 0.005) higher than that observed for the wild-type UGT1A4 isoform for both thetransandcisisomers of 4-OH-TAM after normalization for UGT1A4 expression by western blotting. No significant effect on enzyme kinetics was observed for the UGT1A424Thr/48Leuvariant against either isomer of 4-OH-TAM or with TAM.

Conclusion

These data suggest that the UGT1A4 codon 48 Leu>Val polymorphism significantly alters glucuronidation rates against TAM and its active hydroxylated metabolites, and that this polymorphism may play an important role in individual pharmacological response to TAM therapy.
Primate-specific evolution of an LDLR enhancer
Authors: Wang Qian-fei , Prabhakar Shyam , Wang Qianben , Moses Alan M , Chanan Sumita , Brown Myles , Eisen Michael B , Cheng Jan-Fang , Rubin Edward M , Boffelli Dario
Published: August 2006

Background

Sequence changes in regulatory regions have often been invoked to explain phenotypic divergence among species, but molecular examples of this have been difficult to obtain.

Results

In this study we identified an anthropoid primate-specific sequence element that contributed to the regulatory evolution of the low-density lipoprotein receptor. Using a combination of close and distant species genomic sequence comparisons coupled with in vivo and in vitro studies, we found that a functional cholesterol-sensing sequence motif arose and was fixed within a pre-existing enhancer in the common ancestor of anthropoid primates.

Conclusion

Our study demonstrates one molecular mechanism by which ancestral mammalian regulatory elements can evolve to perform new functions in the primate lineage leading to human.
Combinatorial RNA interference in Caenorhabditis elegans reveals that redundancy between gene duplicates can be maintained for more than 80 million years of evolution
Authors: Tischler Julia , Lehner Ben , Chen Nansheng , Fraser Andrew G
Published: August 2006

Background

Systematic analyses of loss-of-function phenotypes have been carried out for most genes in Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster. Although such studies vastly expand our knowledge of single gene function, they do not address redundancy in genetic networks. Developing tools for the systematic mapping of genetic interactions is thus a key step in exploring the relationship between genotype and phenotype.

Results

We established conditions for RNA interference (RNAi) in C. elegans to target multiple genes simultaneously in a high-throughput setting. Using this approach, we can detect the great majority of previously known synthetic genetic interactions. We used this assay to examine the redundancy of duplicated genes in the genome of C. elegans that correspond to single orthologs in S. cerevisiae or D. melanogaster and identified 16 pairs of duplicated genes that have redundant functions. Remarkably, 14 of these redundant gene pairs were duplicated before the divergence of C. elegans and C. briggsae 80-110 million years ago, suggesting that there has been selective pressure to maintain the overlap in function between some gene duplicates.

Conclusion

We established a high throughput method for examining genetic interactions using combinatorial RNAi in C. elegans. Using this technique, we demonstrated that many duplicated genes can retain redundant functions for more than 80 million years of evolution. This provides strong support for evolutionary models that predict that genetic redundancy between duplicated genes can be actively maintained by natural selection and is not just a transient side effect of recent gene duplication events.
Statistical assessment of the global regulatory role of histone acetylation in Saccharomyces cerevisiae
Authors: Yuan Guo-Cheng , Ma Ping , Zhong Wenxuan , Liu Jun S
Published: August 2006

Background

Histone acetylation plays important but incompletely understood roles in gene regulation. A comprehensive understanding of the regulatory role of histone acetylation is difficult because many different histone acetylation patterns exist and their effects are confounded by other factors, such as the transcription factor binding sequence motif information and nucleosome occupancy.

Results

We analyzed recent genomewide histone acetylation data using a few complementary statistical models and tested the validity of a cumulative model in approximating the global regulatory effect of histone acetylation. Confounding effects due to transcription factor binding sequence information were estimated by using two independent motif-based algorithms followed by a variable selection method. We found that the sequence information has a significant role in regulating transcription, and we also found a clear additional histone acetylation effect. Our model fits well with observed genome-wide data. Strikingly, including more complicated combinatorial effects does not improve the model's performance. Through a statistical analysis of conditional independence, we found that H4 acetylation may not have significant direct impact on global gene expression.

Conclusion

Decoding the combinatorial complexity of histone modification requires not only new data but also new methods to analyze the data. Our statistical analysis confirms that histone acetylation has a significant effect on gene transcription rates in addition to that attributable to upstream sequence motifs. Our analysis also suggests that a cumulative effect model for global histone acetylation is justified, although a more complex histone code may be important at specific gene loci. We also found that the regulatory roles among different histone acetylation sites have important differences.
Comparative inflammatory properties of staphylococcal superantigenic enterotoxins SEA and SEG: implications for septic shock
Authors: Dauwalder Olivier , Thomas Damien , Ferry Tristan , Debard Anne-Lise , Badiou Cédric , Vandenesch François , Etienne Jerome , Lina Gerard , Monneret Guillaume
Published: August 2006

The severity of Staphylococcus aureus sepsis is positively associated with staphylococcal enterotoxin A (SEA) and negatively associated with the enterotoxin gene cluster (egc), which encodes five staphylococcal enterotoxins [1]. We postulated that the variable, clinical severity of S. aureus sepsis might be a result of differences in the inflammatory properties of staphylococcal superantigens. We therefore compared the inflammatory properties of SEA with those of staphylococcal entérotoxin G (SEG), a member of the five egc superantigens. We found that SEA and SEG had similar superantigenic properties, as they induced CD69 expression on T lymphocytes and selective expansion of Vβ subpopulations. Contrary to SEG, however, SEA induced a strong proinflammatory/Th1 response, including TNF-α and MIP-1α production. These results suggest that the association of SEA with the severity of S. aureus septic shock, characterized by a deleterious, inflammatory cascade, may be explained partly by the specific proinflammatory properties of this superantigen.
5-Hydroxyeicosatetraenoic acid is a key intermediate of the arachidonate-dependent protective signaling in monocytes/macrophages exposed to peroxynitrite
Authors: Tommasini Ilaria , Guidarelli Andrea , Palomba Letizia , Cerioni Liana , Cantoni Orazio
Published: August 2006

Endogenous generation of arachidonic acid via selective activation of cytosolic phospholipase A2 has been implicated in the mechanism of monocytes/macrophage survival in the presence of peroxynitrite. In particular, the lipid messenger was shown to prevent the otherwise rapid onset of a mitochondrial permeability-transition (MPT)-dependent necrosis by causing the mitochondrial translocation of protein kinase Cα (PKCα) and the ensuing cytosolic accumulation of the Bcl-2-antagonist of cell death (Bad), an event promoting the anti-MPT function of Bcl-2 (or Bcl-XL). Here, we show that the effects on PKCα are not mediated directly by arachidonate but rather, by downstream products of the enzyme 5-lipoxygenase (5-LO). Peroxynitrite elicited the nuclear membrane translocation of 5-LO and enhanced its enzymatic activity via a mechanism sensitive to low concentrations of inhibitors of 5-LO or the 5-LO-activating protein, as well as to genetic depletion of the latter enzyme. Inhibition of 5-LO activity was invariably associated with the cytosolic localization of PKCα, the mitochondrial accumulation of Bad, and a rapid MPT-dependent necrosis. All these events were prevented by nanomolar concentrations of the 5-LO product 5-hydroxyeicosatetraenoic acid.
Ultimate attainment in interlanguage grammars: a prosodic approach
Authors: Goad Heather , White Lydia
Published: August 2006

In this article, we argue against the Representational Deficit Hypothesis, according to which second language (L2) speakers can never acquire functional categories or features that are absent in the first language (L1), suggesting that fossilization is inevitable. Instead, we support the Prosodic Transfer Hypothesis, which argues that the ultimate attainment of L2 speakers is constrained by L1 prosodic representations; these representations can, however, be minimally adapted to accommodate the needs of the L2 under certain conditions. We investigate the L2 acquisition of English by 10 Mandarin speakers, by means of an experiment involving judgement and production of tense and participial morphology. Mandarin lacks overt tense inflection, while English inflection is represented by adjunction to the Prosodic Word, an option not available in Mandarin. We show that Mandarin speakers have few problems interpreting English tense appropriately, contrary to the predictions of the Representational Deficit Hypothesis. A detailed analysis is offered of their production of the morphology, which motivates the claim that the prosodic representation required for regular inflection in English can be built by combining licensing relations available in Mandarin. We conclude that target-like prosodic representations are ultimately attainable for at least some functional material which is absent from the L1.
Interpretation of English multiple wh-questions by Japanese speakers: a missing uninterpretable feature account
Authors: Hawkins Roger , Hattori Hajime
Published: August 2006

In recent work by Tsimpli (2003) and Tsimpli and Dimitrakopoulou (to appear) an explicit claim is made about the nature of end-state grammars in older second language (L2) learners: uninterpretable syntactic features that have not been selected during first language (L1) acquisition will not be available for L2 grammar construction. Interpretable syntactic features, on the other hand, remain available (as well as the computational procedures and principles of the language faculty), even those not selected by the L1. The present study investigates this hypothesis in relation to the acquisition of the uninterpretable feature that forces wh-movement in interrogatives in English. Nineteen L1 speakers of Japanese (a wh-in-situ language that lacks the movement-forcing feature) who are highly proficient speakers of English were asked to interpret bi-clausal multiple wh-questions in English (like Where did the professor say the students studied when?). Their responses were compared with those of a native speaker control group. It is argued that the results are consistent with the unavailability of the uninterpretable feature. Two conclusions are drawn: first, that there is a critical period for the selection of uninterpretable syntactic features for the construction of mental grammars; second, that despite the observation of target-like performance by L1 Japanese speakers on English wh-interrogatives reported in a number of existing studies, caution is required in interpreting target-like performance as evidence that L2 speakers have the same underlying grammatical representations as native speakers.
Is there a critical period for semantics?
Authors: Slabakova Roumyana
Published: August 2006

This article reviews recent research on the second language acquisition of meaning with a view of establishing whether there is a critical period for the acquisition of compositional semantics. It is claimed that the functional lexicon presents the most formidable challenge, while syntax and phrasal semantics pose less difficulty to learners. Findings from the neurofunctional imaging (PET, fMRI) and electrophysiology (ERPs) of L2 comprehension are reviewed and critically examined. Since it is argued that experimental tasks suggesting differential acquisition of L2 syntax and semantics are in need of linguistic refinement, further evidence is marshalled from behavioural studies of L2 acquisition of semantics to fill in the current gap in L2 comprehension modelling. The 15 studies reviewed here point to no apparent barrier to ultimate success in the acquisition of phrasal semantics.
Anaphora resolution in near-native speakers of Italian
Authors: Sorace Antonella , Filiaci Francesca
Published: August 2006

This study presents data from an experiment on the interpretation of intrasentential anaphora in Italian by native Italian speakers and by English speakers who have learned Italian as adults and have reached a near-native level of proficiency in this language. The two groups of speakers were presented with complex sentences consisting of a main clause and a subordinate clause, in which the subordinate clause had either an overt pronoun or a null subject pronoun. In half of the sentences the main clause preceded the subordinate clause (forward anaphora) and in the other half the subordinate clause preceded the main clause (backward anaphora). Participants performed in a picture verification task in which they had to indicate the picture(s) that corresponded to the meaning of the subordinate clause, thus identifying the possible antecedents of the null or overt subject pronouns. The patterns of responses of the two groups were very similar with respect to the null subject pronouns in both the forward and backward anaphora conditions. Compared to native monolingual speakers, however, the near-natives had a significantly higher preference for the subject of the matrix clause as a possible antecedent of overt subject pronouns, particularly in the backward anaphora condition. The results indicate that near-native speakers have acquired the syntactic constraints on pronominal subjects in Italian, but may have residual indeterminacy in the interface processing strategies they employ in interpreting pronominal forms.
Syntactic features and reanalysis in near-native processing
Authors: Hopp Holger
Published: August 2006

In order to investigate second language (L2) processing at ultimate attainment, 20 first language (L1) English and 20 L1 Dutch advanced to near-native speakers of German as well as 20 native Germans were tested in two experiments on subject-object ambiguities in German. The results from a self-paced reading task and a speeded acceptability judgement task show that the lower-proficient advanced learners in this study display the same processing preferences as natives in reading accuracy yet fail to demonstrate differential response latencies associated with native syntactic reanalysis. By contrast, near-native speakers of either L1 converge on incremental native reanalysis patterns. Together, the findings highlight the role of proficiency for processing the target language since it is only at near-native levels of proficiency that non-natives converge on native-like parsing. The results support the view that endstate non-native processing and native processing are qualitatively identical.
Reconceptualizing fossilization in second language acquisition: a review
Authors: Fidler Ashley
Published: August 2006

In recent fossilization literature, two problems have been raised repeatedly (e.g. Han, 2003; Long, 2003; Birdsong, 2004). First, the term ‘fossilization’ lacks a unified definition and, second, it has not been adequately described empirically. The works reviewed here seek to address this situation. Han (2004) describes a conceptual framework within which to understand existing work on fossilization, and Han and Odlin (2005) present a collection of empirical and analytical studies that help to ameliorate both the definitional and empirical shortcomings of contemporary fossilization research. Taken together, these volumes provide an admirable synthesis of existing research and problems, as well as noteworthy analyses of how to move forward empirically. For the moment, however, idiosyncratic perspectives on fossilization still prevail.
Contaminating fat in pericardial suction blood: a clinical, technical and scientific challenge
Authors: Engström Karl Gunnar
Published: August 2006

Stroke and diffuse brain damage after cardiac surgery are too common. It is important to find means to reduce the incidence in view of future competition to surgery from less invasive procedures. Stroke is fairly well defined in clinical terms and with several identified mechanisms. Diffuse brain damage is less well defined and more complex in nature. One suggested mechanism is from cerebral fat microembolization of retrieved pericardial suction blood (PSB). The present study aimed to describe a simple method to measure fat content of PSB, how experimental artefacts interfere with the results, and how the unstable character of a fat-blood suspension can be used to design a simple fat-separation system. The quantity of small amounts of fat can be amplified by centrifugation to the tapered tip of a standard glass pipette. The coefficient of variation after repeated experiments was 9.5%. PSB after coronary bypass surgery contained 0.22±0.04% fat of which 15±3% was bound to the surface of the plastic collecting bag. Experimentation requires standardized routines. Static incubation, blood-fat mixing routines, and transfer steps of blood samples between syringes induce substantial artefacts from spontaneous density separation and surface-adhesion of fat. Soya oil is a common reference substance replacing human fat in technical laboratory science, but is associated with artefacts of its own. These artefacts cause problems during experimentation but the oil is a good resource in the design of a simple fat-separation system
Methodological approach in adopting off-pump coronary artery bypass surgery in a British cardiothoracic unit: Harefield experience
Authors: Al-Ruzzeh Sharif , Athanasiou Thanos , George Shane , Amrani Mohamed
Published: August 2006

The theoretical and practical disadvantages of coronary artery bypass graft surgery using cardiopulmonary bypass with cardioplegic arrest are well reported in the literature. Encouraged by our work and others, we adopted a systematic approach to the application of off-pump coronary artery bypass surgery. We aimed to validate the non-selective use of the off-pump technique in all patients and assess the outcome in specific patient groups including: patients with ischaemic left ventricular dysfunction, female and high-risk patients. We investigated specific technical details related to off-pump surgery including: the potential effect of the distortion of the mitral valve on haemodynamic stability intraoperatively and the feasibility of sequential coronary artery bypass grafting using the off-pump technique. We also compared the outcome to the national United Kingdom performance in a risk-stratified manner. An extensive retrospective data review for comparative analysis of outcome was carried out at both local and multi-centre levels. This showed that off-pump surgery was feasible for all patients, and provided a better outcome in patients with ischaemic left ventricular dysfunction, female and high-risk patients. The distortion of the mitral valve contributed to the haemodynamic instability. In conclusion, off-pump surgery is safe and provides better outcome in specific patient groups.