bluuebunny/crossref_metadata_2025 huggingface dataset:
A Flatness Based Approach to Trajectory Modification of Residual Motion of Cable Transporter Systems
Authors: Pota Hemanshu R. , Agrawal Sunil K. , Zhang Yuhong
Published: September 2004

As high-rise buildings continue to grow, the design and control of elevators to transport passengers safely, quickly, and comfortably still remains a challenging problem. An important issue in ‘elevatoring’ is to transport passengers with minimal residual motion once the elevator has reached its destination floor. A simple and elegant solution of the residual motion control problem can be given using the theory of δ-flatness. First, we present modeling and residual motion control with non-negative inputs of a cable transporter system, consisting of a rigid body (the object) connected by two flexible ropes. Then, we present results for a special case of the general transporter problem, the residual motion control of elevator. A laboratory scale experimental demonstration of the residual motion control is also presented in this paper.
Attitude Vibration Caused by a Stick-Slip Motion for Flexible Solar Array of Advanced Earth Observation Satellite
Authors: Kojima Yasushi , Taniwaki Shigemune , Ohkami Yoshiaki
Published: September 2004

The Advanced Earth Observation Satellite (ADEOS), a remote sensing satellite, was developed by the National Space Development Agency of Japan and launched in 1996. ADEOS had a large flexible solar array, which was made of a membrane-like structure of 23 m in length. During the checkout and subsequent phases of in-orbit operations, it was discovered that the attitude control system was experiencing internal disturbances that had not been anticipated. An intensive investigation based on the down-linked flight data revealed that mechanical vibrations was caused by a stick-slip motion at the tension control mechanism (TCM) of the solar array. The scope of this paper is to present an analytical approach to the stick-slip of the TCM by means of spacecraft attitude responses. The mathematical model utilized assumes that the spacecraft was composed of a main rigid body and flexible appendages, which consist of a number of rigid plates connected by torsional hinges. Key parameters of the hinges are determined by applying the equations of vibration of a uniform cantilever beam with tangible physical parameters. This mathematical model has been evaluated using the ADEOS flight data and ground-based test data. It is concluded that the technical approach and mathematical model utilized have correctly represented actual spacecraft motions.
Error-Tolerant Technique For Catching a Spacecraft With a Spinning Tether
Authors: Lorenzini E. C.
Published: September 2004

This paper presents a novel configuration of a space system which addresses the issue of rendezvous and capture of a spacecraft in a lower (or higher) energy orbit for later injection into a higher (or lower) energy orbit. We first demonstrate that a slender long tether loop in space can maintain its shape while spinning and that the width of its opening depends on the boundary conditions of the loop arms near the center of rotation. Subsequently, we show how the tether loop could be utilized to allow a rendezvous and capture of a spacecraft approaching the loop from a lower (or higher) energy orbit while the natural target area of the loop enables an extended time opportunity for spacecraft capture which is tolerant of errors. We also discuss at the conceptual level a possible device/technique for making a soft contact between the loop and the incoming spacecraft. These results are directly applicable to spinning tether systems for space transportation from low Earth orbit to geotransfer orbit and to escape trajectory or for reentering payloads into the Earth atmosphere (from higher energy orbits) with high Δ V and a predictable reentry trajectory.
Control of Dynamic Systems with Time-Periodic Coefficients via the Lyapunov-Floquet Transformation and Backstepping Technique
Authors: Deshmukh V. S. , Sinha S. C.
Published: September 2004

We address the problem of designing controllers that guarantee asymptotic stability of a class of linear as well as nonlinear dynamical systems with time-periodic coefficients. Using a repeated procedure consisting of the Lyapunov-Floquet transformation, the backstepping technique, and Floquet theory, the asymptotic stability of the closed-loop linearized system is guaranteed. Further, a Lyapunov matrix for the closed-loop asymptotically stable linearized system is constructed. This Lyapunov function is then used to design a combination of linear and nonlinear controllers in order to guarantee the asymptotic stability of the nonlinear system. The methodology is illustrated by designing linear and nonlinear control laws for a system consisting of two statically coupled pendula, each subjected to a time-periodic force acting in the axial direction.
Constant-Gain Linear Feedback Control of Piecewise Linear Structural Systems via Nonlinear Normal Modes
Authors: Butcher E. A. , Lu R.
Published: September 2004

We present a technique for using constant-gain linear position feedback control to implement eigen-structure assignment of n-degrees-of-freedom conservative structural systems with piecewise linear nonlinearities. We employ three distinct control strategies which utilize methods for approximating the nonlinear normal mode (NNM) frequencies and mode shapes. First, the piecewise modal method (PMM) for approximating NNM frequencies is used to determine n constant actuator gains for eigenvalue (pole) placement. Secondly, eigenvalue placement is accomplished by finding an approximate single-degree-of-freedom reduced model with one actuator gain for the mode to be controlled. The third strategy allows the frequencies and mode shapes (eigenstructure) to be placed by using a full n × n matrix of actuator gains and employing the local equivalent linear stiffness method (LELSM) for approximating NNM frequencies and mode shapes. The techniques are applied to a two-degrees-of-freedom system with two distinct types of nonlinearities: a bilinear clearance nonlinearity and a symmetric deadzone nonlinearity.
The Contribution of Evaluation to Socialization and Externalization of Tacit Knowledge
Authors: Marra Mita
Published: September 2004

International organizations are increasingly focusing on organizational learning. The experience accumulated by development agencies throughout the world has become a source of organizational knowledge, which, according to Nonaka, is transferred through processes of socialization and externalization. Based upon three case studies and in-depth interviewing of World Bank managers and evaluators over two years, this article explores the contribution of evaluation to organizational learning. The study analyses the use patterns of evaluation as a source of knowledge within the World Bank. Findings show that participatory designs and processes favour socialization of tacit knowledge through interaction between organizational members. Theory-driven evaluations help externalize tacit into codified or explicit knowledge. Particular evaluation constructs - i.e. ‘chilling effect’ - provide vocabulary that clarifies discussion and debate for strategic planning. Overall, managers value those evaluation properties associated with (a) first-hand data collection within country case studies, and (b) theory-driven analyses, externalizing tacit insights coming from the field.
Evaluating Partnership
Authors: Halliday Joyce , Asthana Sheena N. M. , Richardson Susan
Published: September 2004

Partnerships are increasingly seeking tools that enable stakeholders to reflect on their own effectiveness, benchmark the status of their partnership and provide a framework for development. Drawing on the evaluation of two Health Action Zones, this article focuses on the use of one such formal assessment tool, adapted from the Nuffield Partnership Assessment Tool and the Verona Benchmark, to explore the contribution of formal tools to our understanding of partnership. It outlines some key methodological limitations and stresses the continued importance of an understanding of context alongside any measurement of partnership effectiveness. It is suggested that formal assessment tools can be extremely valuable in terms of the learning that can result both from the process itself and from the outcomes of the assessment. However, as a stand-alone device they are open to misinterpretation and unlikely to foster development other than in those partnerships prepared to invest the necessary resources in a broad-based evaluation.
Contracting Out Municipal Auditing
Authors: Johnsen Åge , Robertsen Karl , Äsland Dag Yngvar
Published: September 2004

This article evaluates the contracting out of municipal auditing. It draws upon the organizational economics (theory of the firm) tradition, specifically agency theory and transaction cost analysis. In order to systematically assess the effects of contracting out municipal auditing, a conceptual framework of municipal auditing is developed. Some empirical evidence is then discussed in relation to this framework. In general, enhanced competition and contracting out municipal activities seem to lead to an increase in both cost-efficiency and effectiveness. However, there are potential problems related to market contracting of municipal auditing, i.e. the prospect of reduced auditor independence, reduced audit quality and in particular less performance auditing. Finally, the article presents suggestions for future research, indicating the need for further empirical studies, especially on how the contracting out of municipal auditing affects auditor independence and performance auditing, and how mixed ownership/plural governance structures affect audit outcomes.
Evaluating Crime Prevention Scheme Success
Authors: Johnson Shane D. , Bowers Kate J. , Jordan Peter , Mallender Jacqueline , Davidson Norman , Hirschfield Alexander F. G.
Published: September 2004

Research demonstrates that certain crime prevention techniques work. Accordingly, current evaluations focus on what works and where. One of the key elements in assessing crime prevention success is determining the number of crimes prevented. This allows the cost-effectiveness of schemes to be assessed and different schemes to be meaningfully compared. Evaluation studies of what works include a variety of different approaches, some more robust than others. The current article presents two methods for calculating the outcomes of crime prevention interventions. The basic principle behind both approaches involves subtracting the observed number of crimes from an estimate of the number of crimes that would have occurred had the scheme not existed. Importantly, it is acknowledged that area crime rates are influenced both by general trends and more random factors. Thus, each approach produces a range of estimates to attempt to assess the impact of more random influences.
Integrating Data from Multiple Public Sources
Authors: Saunders Robert C. , Heflinger Craig Anne
Published: September 2004

This article aims to inform evaluators about issues involved in using and integrating administrative databases from public agencies. With the growing focus on monitoring and oversight of public programs for health, mental health and substance abuse problems, existing data sets in public agencies became an important source of evaluation and planning information. The focus of this article is on the methods used to find, integrate and analyze multiple existing databases. Primary challenges that confront the evaluator in identifying and accessing data sources and in addressing the technical issues involved are discussed.
Class conflict, state formation and archaism
Authors: Patterson Thomas C.
Published: September 2004

During the last decade, archaeologists have written with steadily increasing frequency about processes of class and state formation that occurred in various precapitalist societies. While some have focused on the origins of states, others have considered the reorganizations that took place in the wake of the expansion of territorially based states. Many acknowledge a causal connection between social stratification and the state, even though they disagree about the nature of the state, social hierarchies and their linkages. While this article adopts an explicitly Marxist interpretation of the interconnections between the processes of class and state formation, on the one hand, and class conflict, on the other, it is also concerned with archaism as a related phenomenon. Its thesis is that archaism - those attempts to imitate or revive past symbols, styles, institutions and practices, to incorporate the old into new contexts - is often an integral feature of class and state formation and the struggles that ensue in such contexts.
Material metaphors
Authors: Brück Joanna
Published: September 2004

This article challenges the traditional assumption that the European Early Bronze Age saw the emergence of an ‘ideology of the individual’. It argues that the Early Bronze Age self was constructed in terms of interpersonal connections rather than the intrinsic attributes of a bounded individual. A discussion of mortuary rites in Britain and Ireland suggests that the objects placed in the grave allowed the mourners to comment metaphorically on the links between the dead and the living, as well as on the changes experienced by a community torn asunder by death. As such, we may argue that identity was a relational attribute; it was people’s relationships with others that made them who they were.
Native American gender politics and material culture in seventeenth-century southeastern New England
Authors: Nassaney Michael S.
Published: September 2004

Scholars have long recognized that European contact had a profound impact on native peoples throughout the Americas. However, subaltern men and women are no longer seen as passive victims in their interactions with the dominant culture but rather as active agents who made their own histories, even as they confronted colonialism on a daily basis. In southeastern New England, population decline and increased commodity exchange created new social opportunities for native men and women by the mid-seventeenth century. These demographic, economic and social conditions contributed to ongoing transformations in gender roles and responsibilities, though they were not experienced uniformly throughout the region. Building on limited and ambiguous documentary and oral accounts, I use archaeological evidence of pipes, pestles, pots, and peage (wampum) to examine gender politics in native New England after European contact.
Mortuary representations of the noble house
Authors: Weiss-Krejci Estella
Published: September 2004

Seventy years of archaeological research in the Maya area have brought to light a series of tombs and crypts that hold more than one individual. The patterns regarding age, completeness and articulation of skeletons and sequence of deposition in some of these tombs suggest different burial traditions. These traditions include the placing of sacrificial victims with a deceased tomb principal, sequential burial of family members, or reburial of curated or exhumed ancestral remains. In medieval and post-medieval Europe, collective tomb burial was also very common. The investigation of tomb formation in the Habsburg dynasty shows that similar patterns can result from mortality, mobility and territorial shifts in a noble house. Maya multiple tombs and crypts simply may have been the final resting-places for the deceased members of noble houses who were deposited and redeposited in both simultaneous and sequential fashion.
Islands and autochthons
Authors: Seirlis Julia Katherine
Published: September 2004

This article, the first in a two-part series, examines the ramifications of the complex relationships between race and space for definitions of the nation and national identity in Rhodesia and Zimbabwe. Most generally, the workings of race and space helped polarize Rhodesia and Zimbabwe between what was set up as ‘white’ and ‘black’, and limit the struggle for power and claims on belonging to those two poles. Racial identity was inscribed into spatial sensibilities and organization so that white space (the city) functioned as a series of islands and black space (the countryside) activated organic assertions of autochthony. More specifically, race and space informed the creation of an intermediate racial category, ‘Coloured’, with no substantive claim to a ‘real’ or ‘full’ identity and with no authoritative claim to the physical soil of the country.
Cheyne-Stokes respiration in patients hospitalised for heart failure
Authors: Mared Lena , Cline Charles , Erhardt Leif , Berg Søren , Midgren Bengt
Published: September 2004

Background

Previous studies showing a strong relationship between Cheyne-Stokes respiration and the severity of left ventricular systolic dysfunction have usually been done in selected patient populations with lower age and a higher proportion of males than the "typical" in-hospital patient with heart failure. The purpose of the present study was test the strength of this relationship in unselected patients admitted to hospital due to decompensated chronic heart failure.

Methods

We evaluated 191 patients (32% women), mean age 73 years, ready for discharge from the heart failure unit in the University Hospital of Malmö, Sweden. The patients underwent echocardiography for determination of left ventricular ejection fraction and left ventricular inner diastolic diameter. A respiratory investigation during sleep was performed the last night before discharge.

Results

We found that 66% of the patients had Cheyne-Stokes respiration more than 10% of the total recording time. Only 7 (3.6%) of the patients had predominantly obstructive apnoeas. There was a significant but very weak relationship between left ventricular ejection fraction and left ventricular inner diastolic diameter on one hand and Cheyne-Stokes respiration on the other. Age was a stronger determinant of Cheyne-Stokes respiration than any of the cardiac or other clinical variables.

Conclusion

Although presence of Cheyne-Stokes respiration indicates left ventricular dysfunction, its severity seems only weakly related to the severity of heart failure. Age was found to be a stronger determinant, which may reflect the underlying age-dependency found also in healthy subjects. Due to age restrictions or other selection criteria, the importance of age may have been underestimated in many previous studies on factors associated with Cheyne-Stokes respiration.
Regulation of signaling genes by TGFβ during entry into dauer diapause in C. elegans
Authors: Liu Tao , Zimmerman Karen K , Patterson Garth I
Published: September 2004

Background

When resources are scant, C. elegans larvae arrest as long-lived dauers under the control of insulin/IGF- and TGFβ-related signaling pathways. However, critical questions remain regarding the regulation of this developmental event. How do three dozen insulin-like proteins regulate one tyrosine kinase receptor to control complex events in dauer, metabolism and aging? How are signals from the TGFβ and insulin/IGF pathways integrated? What gene expression programs do these pathways regulate, and how do they control complex downstream events?

Results

We have identified genes that show different levels of expression in a comparison of wild-type L2 or L3 larvae (non-dauer) to TGFβ mutants at similar developmental stages undergoing dauer formation. Many insulin/IGF pathway and other known dauer regulatory genes have changes in expression that suggest strong positive feedback by the TGFβ pathway. In addition, many insulin-like ligand and novel genes with similarity to the extracellular domain of insulin/IGF receptors have altered expression. We have identified a large group of regulated genes with putative binding sites for the FOXO transcription factor, DAF-16. Genes with DAF-16 sites upstream of the transcription start site tend to be upregulated, whereas genes with DAF-16 sites downstream of the coding region tend to be downregulated. Finally, we also see strong regulation of many novel hedgehog- and patched-related genes, hormone biosynthetic genes, cell cycle genes, and other regulatory genes.

Conclusions

The feedback regulation of insulin/IGF pathway and other dauer genes that we observe would be predicted to amplify signals from the TGFβ pathway; this amplification may serve to ensure a decisive choice between "dauer" and "non-dauer", even if environmental cues are ambiguous. Up and down regulation of insulin-like ligands and novel genes with similarity to the extracellular domain of insulin/IGF receptors suggests opposing roles for several members of these large gene families. Unlike in adults, most genes with putative DAF-16 binding sites are upregulated during dauer entry, suggesting that DAF-16 has different activity in dauer versus adult metabolism and aging. However, our observation that the position of putative DAF-16 binding sites is correlated with the direction of regulation suggests a novel method of achieving gene-specific regulation from a single pathway. We see evidence of TGFβ-mediated regulation of several other classes of regulatory genes, and we discuss possible functions of these genes in dauer formation.
Development of a perioperative medicine research agenda: a cross sectional survey
Authors: Khan Nadia A , Taher Taha , McAlister Finlay A , Ferland Andre , Campbell Norman R , Ghali William A ,   for the Canadian Perioperative Research Group
Published: September 2004

Background

Post-operative complications are a significant source of morbidity and mortality for patients undergoing surgery. However, there is little research in the emerging field of perioperative medicine beyond cardiac risk stratification. We sought to determine the research priorities for perioperative medicine using a cross sectional survey of Canadian and American general internists.

Methods

Surveys were electronically sent to 312 general internists from the Canadian Society of Internal Medicine and 130 internists from the perioperative medicine research interest group within the US based Society of General Internal Medicine. The questionnaire contained thirty research questions and respondents were asked to rate the priority of these questions for future study.

Results

The research topics with the highest ratings included: the need for tight control of diabetes mellitus postoperatively and the value of starting aspirin on patients at increased risk for postoperative cardiac events. Research questions evaluating the efficacy and safety of perioperative interventions had higher ratings than questions relating to the prediction of postoperative risk. Questions relating to the yield of preoperative diagnostic tests had the lowest ratings (p < 0.001 for differences across these categories).

Conclusion

The results of this survey suggest that practicing general internists believe that interventions studies are a priority within perioperative medicine. These findings should help prioritize research in this emerging field.
UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research based review
Authors: Breuckmann Frank , Gambichler Thilo , Altmeyer Peter , Kreuter Alexander
Published: September 2004

Background

Broad-band UVA, long-wave UVA1 and PUVA treatment have been described as an alternative/adjunct therapeutic option in a number of inflammatory and malignant skin diseases. Nevertheless, controlled studies investigating the efficacy of UVA irradiation in connective tissue diseases and related disorders are rare.

Methods

Searching the PubMed database the current article systematically reviews established and innovative therapeutic approaches of broad-band UVA irradiation, UVA1 phototherapy and PUVA photochemotherapy in a variety of different connective tissue disorders.

Results

Potential pathways include immunomodulation of inflammation, induction of collagenases and initiation of apoptosis. Even though holding the risk of carcinogenesis, photoaging or UV-induced exacerbation, UVA phototherapy seems to exhibit a tolerable risk/benefit ratio at least in systemic sclerosis, localized scleroderma, extragenital lichen sclerosus et atrophicus, sclerodermoid graft-versus-host disease, lupus erythematosus and a number of sclerotic rarities.

Conclusions

Based on the data retrieved from the literature, therapeutic UVA exposure seems to be effective in connective tissue diseases and related disorders. However, more controlled investigations are needed in order to establish a clear-cut catalogue of indications.
Consumers as tutors – legitimate teachers?
Authors: Owen Cathy , Reay Rebecca E
Published: September 2004

Background

The aim of this study was to research the feasibility of training mental health consumers as tutors for 4th year medical students in psychiatry.

Methods

A partnership between a consumer network and an academic unit in Psychological Medicine was formed to jointly develop a training package for consumer tutors and a curriculum in interviewing skills for medical students. Student attitudes to mental health consumers were measured pre and post the program. All tutorial evaluation data was analysed using univariate statistics. Both tutors and students evaluated the teaching program using a 4 point rating scale. The mean scores for teaching and content for both students and tutors were compared using an independent samples t-test.

Results

Consumer tutors were successfully trained and accredited as tutors and able to sustain delivery of tutorials over a 4 year period. The study found that whilst the medical students started with positive attitudes towards consumers prior to the program, there was a general trend towards improved attitude across all measures. Other outcomes for tutors and students (both positive and negative) are described.

Conclusions

Consumer tutors along with professional tutors have a place in the education of medical students, are an untapped resource and deliver largely positive outcomes for students and themselves. Further possible developments are described.
A preliminary report of an educational intervention in practice management
Authors: Crites Gerald E , Schuster Richard J
Published: September 2004

Background

Practice management education continues to evolve, and little information exists regarding its curriculum design and effectiveness for resident education. We report the results of an exploratory study of a practice management curriculum for primary care residents.

Methods

After performing a needs assessment with a group of primary care residents at Wright State University, we designed a monthly seminar series covering twelve practice management topics. The curriculum consisted of interactive lectures and practice-based application, whenever possible. We descriptively evaluated two cognitive components (practice management knowledge and skills) and the residents' evaluation of the curriculum.

Results

The mean correct on the knowledge test for this group of residents was 74% (n = 12) and 91% (n = 12) before and after the curriculum, respectively. The mean scores for the practice management skill assessments were 2.62 before (n = 12), and 3.65 after (n = 12) the curriculum (modified Likert, 1 = strongly disagree, 5 = strongly agree). The residents rated the curriculum consistently high.

Conclusions

This exploratory study suggests that this curriculum may be useful in developing knowledge and skills in practice management for primary care residents. This study suggests further research into evaluation of this curriculum may be informative for practice-based education.
The contrast-enhanced Doppler ultrasound with perfluorocarbon exposed sonicated albumin does not improve the diagnosis of renal artery stenosis compared with angiography
Authors: Teixeira Odila UN , Bortolotto Luiz A , Silva Hélio Bernardes
Published: September 2004

There are no studies investigating the effect of the contrast infusion on the sensitivity and specificity of the main Doppler criteria of renal artery stenosis (RAS). Our aim was to evaluate the accuracy of these Doppler criteria prior to and following the intravenous administration of perfluorocarbon exposed sonicated albumin (PESDA) in patients suspected of having RAS. Thirty consecutive hypertensive patients (13 males, mean age of 57 ± 10 years) suspected of having RAS by clinical clues, were submitted to ultrasonography (US) of renal arteries before and after enhancement using continuous infusion of PESDA. All patients underwent angiography, and haemodynamically significant RAS was considered when ≥50%. At angiography, it was detected RAS ≥50% in 18 patients, 5 with bilateral stenosis. After contrast, the examination time was slightly reduced by approximately 20%. In non-enhanced US the sensitivity was better when based on resistance index (82.9%) while the specificity was better when based on renal aortic ratio (89.2%). The predictive positive value was stable for all indexes (74.0%–88.0%) while negative predictive value was low (44%–51%). The specificity and positive predictive value based on renal aortic ratio increased after PESDA injection respectively, from 89 to 97.3% and from 88 to 95%. In hypertensives suspected to have RAS the sensitivity and specificity of Duplex US is dependent of the criterion evaluated. Enhancement with continuous infusion of PESDA improves only the specificity based on renal aortic ratio but do not modify the sensitivity of any index.
Multimorbidity and quality of life in primary care: a systematic review
Authors: Fortin Martin , Lapointe Lise , Hudon Catherine , Vanasse Alain , Ntetu Antoine L , Maltais Danielle
Published: September 2004

Background

Many patients with several concurrent medical conditions (multimorbidity) are seen in the primary care setting. A thorough understanding of outcomes associated with multimorbidity would benefit primary care workers of all disciplines. The purpose of this systematic review was to clarify the relationship between the presence of multimorbidity and the quality of life (QOL) or health-related quality of life (HRQOL) of patients seen, or likely to be seen, in the primary care setting.

Methods

Medline and Embase electronic databases were screened using the following search terms for the reference period 1990 to 2003: multimorbidity, comorbidity, chronic disease, and their spelling variations, along with quality of life and health-related quality of life. Only descriptive studies relevant to primary care were selected.

Results

Of 753 articles screened, 108 were critically assessed for compliance with study inclusion and exclusion criteria. Thirty of these studies were ultimately selected for this review, including 7 in which the relationship between multimorbidity or comorbidity and QOL or HRQOL was the main outcome measure. Major limitations of these studies include the lack of a uniform definition for multimorbidity or comorbidity and the absence of assessment of disease severity. The use of self-reported diagnoses may also be a weakness. The frequent exclusion of psychiatric diagnoses and presence of potential confounding variables are other limitations. Nonetheless, we did find an inverse relationship between the number of medical conditions and QOL related to physical domains. For social and psychological dimensions of QOL, some studies reveal a similar inverse relationship in patients with 4 or more diagnoses.

Conclusions

Our findings confirm the existence of an inverse relationship between multimorbidity or comorbidy and QOL. However, additional studies are needed to clarify this relationship, including the various dimensions of QOL affected. Those studies must employ a clear definition of multimorbidity or comorbidity and valid ways to measure these concepts in a primary care setting. Pursuit of this research will help to better understand the impact of chronic diseases on patients.
Evaluating the cytotoxicity of innate immune effector cells using the GrB ELISPOT assay
Authors: Shafer-Weaver Kimberly A , Sayers Thomas , Kuhns Douglas B , Strobl Susan L , Burkett Mark W , Baseler Michael , Malyguine Anatoli
Published: September 2004

Background

This study assessed the Granzyme B (GrB) ELISPOT as a viable alternative to the 51Cr-release assay for measuring cytotoxic activity of innate immune effector cells. We strategically selected the GrB ELISPOT assay because GrB is a hallmark effector molecule of cell-mediated destruction of target cells.

Methods

We optimized the GrB ELISPOT assay using the human-derived TALL-104 cytotoxic cell line as effectors against K562 target cells. Titration studies were performed to assess whether the ELISPOT assay could accurately enumerate the number of GrB-secreting effector cells. TALL-104 were treated with various secretion inhibitors and utilized in the GrB ELISPOT to determine if GrB measured in the ELISPOT was due to degranulation of effector cells. Additionally, CD107a expression on effector cells after effector-target interaction was utilized to further confirm the mechanism of GrB release by TALL-104 and lymphokine-activated killer (LAK) cells. Direct comparisons between the GrB ELISPOT, the IFN-γ ELISPOT and the standard 51Cr-release assays were made using human LAK cells.

Results

Titration studies demonstrated a strong correlation between the number of TALL-104 and LAK effector cells and the number of GrB spots per well. GrB secretion was detectable within 10 min of effector-target contact with optimal secretion observed at 3–4 h; in contrast, optimal IFN-γ secretion was not observed until 24 h. The protein secretion inhibitor, brefeldin A, did not inhibit the release of GrB but did abrogate IFN-γ production by TALL-104 cells. GrB secretion was abrogated by BAPTA-AM (1,2-bis-(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid tetra(acetoxymethyl) ester), which sequesters intracellular Ca2+, thereby preventing degranulation. The number of effector cells expressing the degranulation associated glycoprotein CD107a increased after interaction with target cells and correlated with the stimulated release of GrB measured in the ELISPOT assay.

Conclusions

Because of its high sensitivity and ability to estimate cytotoxic effector cell frequency, the GrB ELISPOT assay is a viable alternative to the 51Cr-release assay to measure MHC non-restricted cytotoxic activity of innate immune cells. Compared to the IFN-γ ELISPOT assay, the GrB ELISPOT may be a more direct measure of cytotoxic cell activity. Because GrB is one of the primary effector molecules in natural killer (NK) cell-mediated killing, detection and enumeration of GrB secreting effector cells can provide valuable insight with regards to innate immunological responses.
Normal histone modifications on the inactive X chromosome in ICF and Rett syndrome cells: implications for methyl-CpG binding proteins
Authors: Gartler Stanley M , Varadarajan Kartik R , Luo Ping , Canfield Theresa K , Traynor Jeff , Francke Uta , Hansen R Scott
Published: September 2004

Background

In mammals, there is evidence suggesting that methyl-CpG binding proteins may play a significant role in histone modification through their association with modification complexes that can deacetylate and/or methylate nucleosomes in the proximity of methylated DNA. We examined this idea for the X chromosome by studying histone modifications on the X chromosome in normal cells and in cells from patients with ICF syndrome (Immune deficiency, Centromeric region instability, and Facial anomalies syndrome). In normal cells the inactive X has characteristic silencing type histone modification patterns and the CpG islands of genes subject to X inactivation are hypermethylated. In ICF cells, however, genes subject to X inactivation are hypomethylated on the inactive X due to mutations in the DNA methyltransferase (DNMT3B) genes. Therefore, if DNA methylation is upstream of histone modification, the histones on the inactive X in ICF cells should not be modified to a silent form. In addition, we determined whether a specific methyl-CpG binding protein, MeCP2, is necessary for the inactive X histone modification pattern by studying Rett syndrome cells which are deficient in MeCP2 function.

Results

We show here that the inactive X in ICF cells, which appears to be hypomethylated at all CpG islands, exhibits normal histone modification patterns. In addition, in Rett cells with no functional MeCP2 methyl-CpG binding protein, the inactive X also exhibits normal histone modification patterns.

Conclusions

These data suggest that DNA methylation and the associated methyl-DNA binding proteins may not play a critical role in determining histone modification patterns on the mammalian inactive X chromosome at the sites analyzed.
Divergence of the mRNA targets for the Ssb proteins of bacteriophages T4 and RB69
Authors: Borjac-Natour Jamilah M , Petrov Vasiliy M , Karam Jim D
Published: September 2004

The single-strand binding (Ssb) protein of phage T4 (T4 gp32, product of gene 32) is a mRNA-specific autogenous translational repressor, in addition to being a sequence-independent ssDNA-binding protein that participates in phage DNA replication, repair and recombination. It is not clear how this physiologically essential protein distinguishes between specific RNA and nonspecific nucleic acid targets. Here, we present phylogenetic evidence suggesting that ssDNA and specific RNA bind the same gp32 domain and that plasticity of this domain underlies its ability to configure certain RNA structures for specific binding. We have cloned and characterized gene 32 of phage RB69, a relative of T4 We observed that RB69 gp32 and T4 gp32 have nearly identical ssDNA binding domains, but diverge in their C-terminal domains. In T4 gp32, it is known that the C-terminal domain interacts with the ssDNA-binding domain and with other phage-induced proteins. In translation assays, we show that RB69 gp32 is, like T4 gp32, an autogenous translational repressor. We also show that the natural mRNA targets (translational operators) for the 2 proteins are diverged in sequence from each other and yet can be repressed by either gp32. Results of chemical and RNase sensitivity assays indicate that the gp32 mRNA targets from the 2 related phages have similar structures, but differ in their patterns of contact with the 2 repressors. These and other observations suggest that a range of gp32-RNA binding specificities may evolve in nature due to plasticity of the protein-nucleic acid interaction and its response to modulation by the C-terminal domain of this translational repressor.
Expression analysis of three isoforms of hyaluronan synthase and hyaluronidase in the synovium of knees in osteoarthritis and rheumatoid arthritis by quantitative real-time reverse transcriptase polymerase chain reaction
Authors: Yoshida Mamoru , Sai Shigaku , Marumo Keishi , Tanaka Takaaki , Itano Naoki , Kimata Koji , Fujii Katsuyuki
Published: September 2004

Hyaluronan is a major molecule in joint fluid and plays a crucial role in joint motion and the maintenance of joint homeostasis. The concentration and average molecular weight of hyaluronan in the joint fluids are reduced in osteoarthritis and rheumatoid arthritis. To elucidate the underlying mechanism, we analyzed the message expression of three isoforms of hyaluronan synthase and hyaluronidase from knee synovium, using real-time reverse transcriptase polymerase chain reaction. Synovia were obtained from 17 patients with osteoarthritis, 14 patients with rheumatoid arthritis, and 20 healthy control donors. The message expression of hyaluronan synthase-1 and -2 in the synovium of both types of arthritis was significantly less than in the control synovium, whereas that of hyaluronidase-2 in the synovium of both arthritides was significantly greater than in the control synovium. The decreased expression of the messages for hyaluronan synthase-1 and -2 and/or the increased expression of the message for hyaluronidase-2 may be reflected in the reduced concentration and decreased average molecular weight of hyaluronan in the joint fluids of patients with osteoarthritis and rheumatoid arthritis.
Genetic polymorphism in the manganese superoxide dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study
Authors: Cai Qiuyin , Shu Xiao-Ou , Wen Wanqing , Cheng Jia-Rong , Dai Qi , Gao Yu-Tang , Zheng Wei
Published: September 2004

Introduction

It has been suggested that oxidative stress and mitochondrial DNA damage play important roles in breast cancer carcinogenesis. Manganese superoxide dismutase (MnSOD) is a major enzyme that is responsible for the detoxification of reactive oxygen species in the mitochondria. A T → C substitution in the MnSOD gene results in a Val → Ala change at the -9 position of the mitochondrial targeting sequence (Val-9Ala), which alters the protein secondary structure and thus affects transport of MnSOD into the mitochondria.

Methods

We evaluated this genetic polymorphism in association with breast cancer risk using data from the Shanghai Breast Cancer Study, a population-based case–control study conducted in urban Shanghai from 1996 to 1998. The MnSOD Val-9Ala polymorphism was examined in 1125 breast cancer cases and 1197 age-frequency-matched control individual.

Results

Breast cancer risk was slightly elevated in women with Ala/Ala genotype (odds ratio [OR] 1.3, 95% confidence interval [CI] 0.7–2.3), particularly among premenopausal women (OR 1.8, 95% CI 0.9–3.7), as compared with those with Val/Val genotype. The increased risk with the Ala/Ala genotype was stronger among premenopausal women with a higher body mass index (OR 2.5, 95% CI 0.9–7.0) and more years of menstruation (OR 2.6, 95% CI 0.8–8.0). The risk among premenopausal women was further increased twofold to threefold among those with a low intake of fruits, vegetables, vitamin supplements, selenium, or antioxidant vitamins, including carotenes and vitamins A, C, and E. However, the frequency of the Ala allele was low (14%) in the study population, and most of the ORs provided above were not statistically significant.

Conclusion

The present study provides some evidence that genetic polymorphism in the MnSOD gene may be associated with increased risk of breast cancer among Chinese women with high levels of oxidative stress or low intake of antioxidants. Studies with a larger sample size are needed to confirm the findings.
Birthweight, parental age, birth order and breast cancer risk in African-American and white women: a population-based case–control study
Authors: Hodgson M Elizabeth , Newman Beth , Millikan Robert C
Published: September 2004

Introduction

Much recent work has focused on hypotheses that very early life exposures influence adult cancer risk. For breast cancer it has been hypothesized that high in utero estrogen exposure may increase risk.

Methods

We used data from the Carolina Breast Cancer Study, a population-based case–control study of incident breast cancer in North Carolina, to examine associations for three possible surrogates of high prenatal estrogen exposure: weight at birth, maternal age, and birth order. We also examined paternal age. Birthweight analyses were conducted for white and African-American women born in North Carolina on or after 1949 (196 cases, 167 controls). Maternal age was analyzed for US born participants younger than 49 years of age (280 cases, 236 controls).

Results

There was a weak inverse association between birthweight in the highest tertile and breast cancer overall (odds ratio [OR] 0.7, 95% confidence interval [CI] 0.4–1.2), although associations differed by race (OR 0.5, 95% CI 0.2–1.0, and OR 1.0, 95% CI 0.5–2.1 for African-American and white women, respectively). For maternal age there was an approximately threefold increase in risk in women whose mothers were older than 22 years of age, relative to 19–22 years of age, when the women were born. After adjustment for maternal age, older paternal age increased risk in the oldest and youngest age categories (relative to 23–27 years of age at the woman's birth: OR 1.6, 95% CI 0.8–3.1 for age 15–22 years; OR 1.2, 95% CI 0.7–2.2 for age 28–34 years; and OR 1.5, 95% CI 0.7–3.2 for age 35–56 years). There was no association with older paternal age for white women alone. After adjustment for maternal age (265 cases, 224 controls), a birth order of fifth or higher relative to first had an inverse association with breast cancer for women younger than 49 years old (OR 0.6, 95% CI 0.3–1.3).

Conclusion

Although the CIs are wide, these results lend support to the possibility that the prenatal period is important for subsequent breast cancer risk, but they do not support the estrogen hypothesis as a unifying theory for the influence of this period.
Over-expression of lysophosphatidic acid receptor-2 in human invasive ductal carcinoma
Authors: Kitayama Joji , Shida Dai , Sako Akihiro , Ishikawa Makoto , Hama Kotaro , Aoki Junken , Arai Hiroyuki , Nagawa Hirokazu
Published: September 2004

Introduction

Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse effects on various cells. It interacts with at least three G-protein-coupled transmembrane receptors, namely LPA1, LPA2 and LPA3, whose expression in various tumours has not been fully characterized. In the present study we characterized the expression profile of LPA receptors in human breast cancer tissue and assessed the possible roles of each receptor.

Methods

The relative expression levels of each receptor's mRNA against β-actin mRNA was examined in surgically resected invasive ductal carcinomas and normal gland tissue using real-time RT-PCR. LPA2 expression was also examined immunohistochemically using a rat anti-LPA2 monoclonal antibody.

Results

In 25 cases normal and cancer tissue contained LPA1 mRNA at similar levels, whereas the expression level of LPA2 mRNA was significantly increased in cancer tissue as compared with its normal counterpart (3479.0 ± 426.6 versus 1287.3 ± 466.8; P < 0.05). LPA3 was weakly expressed in both cancer and normal gland tissue. In 48 (57%) out of 84 cases, enhanced expression of LPA2 protein was confirmed in carcinoma cells as compared with normal mammary epithelium by immunohistochemistry. Over-expression of LPA2 was detected in 17 (45%) out of 38 premenopausal women, as compared with 31 (67%) out of 46 postmenopausal women, and the difference was statistically significant (P < 0.05).

Conclusion

These findings suggest that upregulation of LPA2 may play a role in carcinogenesis, particularly in postmenopausal breast cancer.
Early management after self-poisoning with an organophosphorus or carbamate pesticide – a treatment protocol for junior doctors
Authors: Eddleston Michael , Dawson Andrew , Karalliedde Lakshman , Dissanayake Wasantha , Hittarage Ariyasena , Azher Shifa , Buckley Nick A
Published: September 2004

Severe organophosphorus or carbamate pesticide poisoning is an important clinical problem in many countries of the world. Unfortunately, little clinical research has been performed and little evidence exists with which to determine best therapy. A cohort study of acute pesticide poisoned patients was established in Sri Lanka during 2002; so far, more than 2000 pesticide poisoned patients have been treated. A protocol for the early management of severely ill, unconscious organophosphorus/carbamate-poisoned patients was developed for use by newly qualified doctors. It concentrates on the early stabilisation of patients and the individualised administration of atropine. We present it here as a guide for junior doctors in rural parts of the developing world who see the majority of such patients and as a working model around which to base research to improve patient outcome. Improved management of pesticide poisoning will result in a reduced number of suicides globally.