bluuebunny/crossref_metadata_2025 huggingface dataset:
Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation
Authors: Stennard Fiona A. , Costa Mauro W. , Lai Donna , Biben Christine , Furtado Milena B. , Solloway Mark J. , McCulley David J. , Leimena Christiana , Preis Jost I. , Dunwoodie Sally L. , Elliott David E. , Prall Owen W. J. , Black Brian L. , Fatkin Diane , Harvey Richard P.
Published: April 2005

The genetic hierarchies guiding lineage specification and morphogenesis of the mammalian embryonic heart are poorly understood. We now show by gene targeting that murine T-box transcription factor Tbx20 plays a central role in these pathways, and has important activities in both cardiac development and adult function. Loss of Tbx20 results in death of embryos at mid-gestation with grossly abnormal heart morphogenesis. Underlying these disturbances was a severely compromised cardiac transcriptional program,defects in the molecular pre-pattern, reduced expansion of cardiac progenitors and a block to chamber differentiation. Notably, Tbx20-null embryos showed ectopic activation of Tbx2 across the whole heart myogenic field. Tbx2 encodes a transcriptional repressor normally expressed in non-chamber myocardium, and in the atrioventricular canal it has been proposed to inhibit chamber-specific gene expression through competition with positive factor Tbx5. Our data demonstrate a repressive activity for Tbx20 and place it upstream of Tbx2 in the cardiac genetic program. Thus, hierarchical,repressive interactions between Tbx20 and other T-box genes and factors underlie the primary lineage split into chamber and non-chamber myocardium in the forming heart, an early event upon which all subsequent morphogenesis depends. Additional roles for Tbx20 in adult heart integrity and contractile function were revealed by in-vivo cardiac functional analysis of Tbx20 heterozygous mutant mice. These data suggest that mutations in human cardiac transcription factor genes, possibly including TBX20,underlie both congenital heart disease and adult cardiomyopathies.
PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids
Authors: Goberdhan Deborah C. I. , Meredith David , Boyd C. A. Richard , Wilson Clive
Published: April 2005

Growth in normal and tumour cells is regulated by evolutionarily conserved extracellular inputs from the endocrine insulin receptor (InR) signalling pathway and by local nutrients. Both signals modulate activity of the intracellular TOR kinase, with nutrients at least partly acting through changes in intracellular amino acid levels mediated by amino acid transporters. We show that in Drosophila, two molecules related to mammalian proton-assisted SLC36 amino acid transporters (PATs), CG3424 and CG1139, are potent mediators of growth. These transporters genetically interact with TOR and other InR signalling components, indicating that they control growth by directly or indirectly modulating the effects of TOR signalling. A mutation in the CG3424 gene, which we have named pathetic (path), reduces growth in the fly. In a heterologous Xenopus oocyte system, PATH also activates the TOR target S6 kinase in an amino acid-dependent way. However, functional analysis reveals that PATH has an extremely low capacity and an exceptionally high affinity compared with characterised human PATs and the CG1139 transporter. PATH and potentially other PAT-related transporters must therefore control growth via a mechanism that does not require bulk transport of amino acids into the cell. As PATH is likely to be saturated in vivo, we propose that one specialised function of high-affinity PAT-related molecules is to maintain growth as local nutrient levels fluctuate during development.
Neural crest determination by co-activation ofPax3andZic1genes inXenopusectoderm
Authors: Sato Takahiko , Sasai Noriaki , Sasai Yoshiki
Published: April 2005

A number of regulatory genes have been implicated in neural crest development. However, the molecular mechanism of how neural crest determination is initiated in the exact ectodermal location still remains elusive. Here, we show that the cooperative function of Pax3 and Zic1 determines the neural crest fate in the amphibian ectoderm. Pax3 and Zic1 are expressed in an overlapping manner in the presumptive neural crest area of the Xenopus gastrula, even prior to the onset of the expression of the early bona fide neural crest marker genes Foxd3 and Slug. Misexpression of both Pax3 and Zic1 together efficiently induces ectopic neural crest differentiation in the ventral ectoderm, whereas overexpression of either one of them only expands the expression of neural crest markers within the dorsolateral ectoderm. The induction of neural crest differentiation by Pax3 and Zic1 requires Wnt signaling. Loss-of-function studies in vivo and in the animal cap show that co-presence of Pax3 and Zic1 is essential for the initiation of neural crest differentiation. Thus,co-activation of Pax3 and Zic1, in concert with Wnt, plays a decisive role for early neural crest determination in the correct place of the Xenopus ectoderm.
Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development
Authors: Takeuchi Jun K. , Mileikovskaia Maria , Koshiba-Takeuchi Kazuko , Heidt Analeah B. , Mori Alessandro D. , Arruda Eric P. , Gertsenstein Marina , Georges Romain , Davidson Lorinda , Mo Rong , Hui Chi-chung , Henkelman R. Mark , Nemer Mona , Black Brian L. , Nagy Andras , Bruneau Benoit G.
Published: April 2005

To elucidate the function of the T-box transcription factor Tbx20 in mammalian development, we generated a graded loss-of-function series by transgenic RNA interference in entirely embryonic stem cell-derived mouse embryos. Complete Tbx20 knockdown resulted in defects in heart formation, including hypoplasia of the outflow tract and right ventricle,which derive from the anterior heart field (AHF), and decreased expression of Nkx2-5 and Mef2c, transcription factors required for AHF formation. A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle, entities similar to human congenital heart defects, and demonstrated a critical requirement for Tbx20 in valve formation. Finally, an intermediate knockdown revealed a role for Tbx20 in motoneuron development, specifically in the regulation of the transcription factors Isl2 and Hb9, which are important for terminal differentiation of motoneurons. Tbx20 could activate promoters/enhancers of several genes in cultured cells, including the Mef2c AHF enhancer and the Nkx2-5 cardiac enhancer. The Mef2c AHF enhancer relies on Isl1- and Gata-binding sites. We identified a similar Isl1 binding site in the Nkx2-5 AHF enhancer,which in transgenic mouse embryos was essential for activity in a large part of the heart, including the outflow tract. Tbx20 synergized with Isl1 and Gata4 to activate both the Mef2c and Nkx2-5 enhancers, thus providing a unifying mechanism for gene activation by Tbx20 in the AHF. We conclude that Tbx20 is positioned at a critical node in transcription factor networks required for heart and motoneuron development where it dose-dependently regulates gene expression.
T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis
Authors: Cai Chen-Leng , Zhou Wenlai , Yang Lei , Bu Lei , Qyang Yibing , Zhang Xiaoxue , Li Xiaodong , Rosenfeld Michael G. , Chen Ju , Evans Sylvia
Published: April 2005

Mutations in T-box genes are the cause of several congenital diseases and are implicated in cancer. Tbx20-null mice exhibit severely hypoplastic hearts and express Tbx2, which is normally restricted to outflow tract and atrioventricular canal, throughout the heart. Tbx20 mutant hearts closely resemble those seen in mice overexpressing Tbx2 in myocardium,suggesting that upregulation of Tbx2 can largely account for the cardiac phenotype in Tbx20-null mice. We provide evidence that Tbx2 is a direct target for repression by Tbx20 in developing heart. We have also found that Tbx2 directly binds to the Nmyc1 promoter in developing heart, and can repress expression of the Nmyc1 promoter in transient transfection studies. Repression of Nmyc1 (N-myc) by aberrantly regulated Tbx2 can account in part for the observed cardiac hypoplasia in Tbx20 mutants. Nmyc1 is required for growth and development of multiple organs, including the heart, and overexpression of Nmyc1 is associated with childhood tumors. Despite its clinical relevance, the factors that regulate Nmyc1 expression during development are unknown. Our data present a paradigm by which T-box proteins regulate regional differences in Nmyc1 expression and proliferation to effect organ morphogenesis. We present a model whereby Tbx2 directly represses Nmyc1 in outflow tract and atrioventricular canal of the developing heart, resulting in relatively low proliferation. In chamber myocardium, Tbx20 represses Tbx2,preventing repression of Nmyc1 and resulting in relatively high proliferation. In addition to its role in regulating regional proliferation, we have found that Tbx20 regulates expression of a number of genes that specify regional identity within the heart, thereby coordinating these two important aspects of organ development.
Treatment and partner notification outcomes for gonorrhoea: effect of ethnicity and gender
Authors: Apoola Ade , Mantella Isabelle , Wotton Mari , Radcliffe Keith
Published: April 2005

We assessed if gender and ethnicity were associated with differences in the number of patients satisfactorily treated and number of partners successfully treated for genital gonococcal infection by reviewing 400 cases.

There were no differences in the rates of satisfactory treatment of gonorrhoea between men and women and the different ethnic groups. There was no difference in satisfactory partner treatment rates by ethnic origin; however, men were less likely to have their contacts satisfactorily treated within 28 days of diagnosis (odds ratio=0.05, 95% confidence interval 0.3–0.7).

This inequality may lead to difficulties in reducing the number of new gonorrhoea cases. More research is needed to find out why men behave differently from women regarding partner notification for genital gonorrhoea infection.
Willingness to participate in HIV vaccine trials among HIV-negative gay men in Sydney, Australia
Authors: Van de Ven Paul , Mao Limin , Crawford June , Prestage Garrett , Grulich Andrew , Kaldor John , Kippax Susan
Published: April 2005

This study aimed to determine and describe HIV-negative gay men's willingness to participate in HIV vaccine trials. Data were from participants who completed face-to-face interviews during the first 18 months (to the end of 2002) of recruitment into the Health in Men cohort of HIV-negative gay men in Sydney. A key outcome measure was a scale of Willingness to Participate in HIV Vaccine Trials, with scores ranging from 1 (unwilling) to 4 (willing). The 903 participants ranged in age from 18 to 75years (median=36). Mean of Willingness to Participate in HIV Vaccine Trials was 2.53 (standard deviation=0.54), with approximately 51% of the men having a score greater than the midpoint of 2.50. A reduced linear regression model yielded four significant independent associations with Willingness to Participate in HIV Vaccine Trials: lack of tertiary education ( P <0.001),having engaged 'in the previous six months' in any unprotected anal intercourse with casual or non-concordant regular partners ( P <0.001), higher self-rated likelihood of HIV infection ( P <0.01), and higher mean scores on a scale of Comfort with Participation in HIV VaccineTrials ( P <0.001). The willingness of HIV-negative gay men at potentially higher risk for HIV to participate in HIV vaccine trials augurs well for enrolment in HIV vaccine efficacy trials. Recruitment into trials is likely to be enhanced by addressing salient concerns such as confidentiality and vaccine-induced antibody positivity. Also, it will be important to ensure that gay men are educated and fully informed about HIV vaccines and trial processes.
Prevalence of Toxoplasma gondii infection and incidence of toxoplasma encephalitis in non-haemophiliac HIV-1-infected adults in Taiwan
Authors: Hung C C , Chen M Y , Hsieh S M , Hsiao C F , Sheng W H , Chang S C
Published: April 2005

We assessed the seroprevalence of Toxoplasma gondii infection and incidence of toxoplasma encephalitis (TE) in 844 non-haemophiliac HIV-infected patients in Taiwan between June 1994 and April 2003. Approximately 70% (69.3%) of them had a baseline CD4+ lymphocyte count of 200 × 106/L or less, and more than 70% (73.9%) having initiated highly active antiretroviral therapy. The seroprevalence of T. gondii infection was 10.2%, which did not differ with sex, age, route of transmission, birth inside or outside of Taiwan, or CD4+ lymphocyte stratifications. After a median observation duration of 603 days (range, 1–3264 days), 10 (1.2%) patients developed 11 episodes of TE after a median interval of 30 days (range, 1–941 days) between enrolment and diagnosis of TE, with an incidence of 0.59 per 100 person-years (PY) (95% confidence interval, 0.56–0.63 per 100 PY). We concluded that the incidence of TE of HIV-infected patients in Taiwan was lower than that reported in western countries because of a lower seroprevalence of T. gondii infection and use of antimicrobial prophylaxis and antiretroviral therapy, although most of the patients were at the late stage of HIV infection.
Treatment failure of vaginal trichomoniasis in clinical practice
Authors: Das Satyajit , Huengsberg Mia , Shahmanesh Mohsen
Published: April 2005

We have conducted a retrospective study of treatment failure of Trichomonas vaginalis (TV) infection in a busy, urban genitourinary medicine clinic in Birmingham, UK, between 1998 and 2002. The prevalence of non-response to standard doses of metronidazole without any history of reinfection or nonadherence was 1.7% (28/1603) overall, and has significantly increased from 0.38% in 1999 to 3.5% in 2002 ( P=0.001, χ2 test). There were no associated demographic factors. The majority of patients (53% or 15/28) responded to either a repeat of standard (10/26) or higher oral dose (5/7) of metronidazole. A standardized treatment algorithm using a high dose of metronidazole may be useful in the absence of any new, efficacious non-imidazole-based TV therapy in the clinical management of persistent TV infection.
An oral fluid test for syphilis
Authors: Baguley S D K , Horner P J , Maple P A C , Stephenson L
Published: April 2005

We have developed a time-resolved fluorescence immunoassay to detect antibodies to Treponema pallidum recombinant antigens in oral fluid specimens. Using an 'Oracol' swab, oral fluid was collected from 34 subjects with a serological diagnosis of syphilis and 97 seronegative controls. Using a cut-off of three standard deviations over control mean, the sensitivity and specificity of the assay in all subjects with positive syphilis serology was 76.5% and 97.9%, respectively. In those with early syphilis, the sensitivity and specificity of the assay was 100% and 97.9%. In a non-outbreak situation, screening clinic attendees for syphilis using oral fluid specimens is potentially useful when collection of blood is not practicable. In addition, it may have much to offer in outreach projects and epidemiological investigations.
Sociodemography of genital co-infection with Neisseria gonorrhoeae and Chlamydia trachomatis in Coventry, UK
Authors: Das Satyajit , Sabin Caroline , Wade Abdel , Allan Sriskandab
Published: April 2005

While genital co-infection with Neisseria gonorrhoeae and Chlamydia trachomatis in the same individual is relatively common, little is known about the characteristics of individuals co-infected with both pathogens. We describe the sociodemographic and geographic characteristics of those with genital co-infection with N. gonorrhoeae and C. trachomatis.

We reviewed the case-notes of all patients presenting with co-infection between March 1989 and February 2000. Incidence rates were calculated for those aged 15–64 living in the 18 different electoral wards of the city and subjects were assigned a Townsend deprivation score based on residence. A total of 332 cases of co-infection were included over the study period (overall mean annual incidence rate 16.1 [95% confidence interval [CI] 9.9–22.3]/100,000). The infection rate was significantly higher in those of black ethnicity (rate: 82.6/105, relative rate 5.81, 95% CI [4.03–8.38], P=0.0001) than in those of other ethnicities. The highest incidence was noted in men aged 20–24 ( n=81, 45.6%) and in women aged 15–19 ( n=66, 45.2%) years, living in the most deprived area of the city. After controlling for year of diagnosis, those aged 25–64 years had significantly lower incidence rates (0.13 [0.10–0.17], P=0.0001, Poisson regression) than those aged <20 years. Increased incidence rates were also associated with high deprivation scores.

There is a complex interaction between age, sex, ethnicity, geographic distribution, social deprivation and the risk of acquiring genital co-infection with N. gonorrhoeae and C. trachomatis. This study may help to identify the geographic areas of high incidence of sexually transmitted diseases in Coventry, and could be used as the baseline to measure the need for subsequent interventions.
Selecting Telecommunication Carriers to Obtain Volume Discounts
Authors: van de Klundert Joris , Kuipers Jeroen , Spieksma Frits C. R. , Winkels Maarten
Published: April 2005

During 2001 many European markets for mobile phones reached saturation. Hence, mobile phone operators have shifted their focus from growth and market share to cutting costs. One way of doing so is to reduce spending on international calls, which are routed via network operating companies (carriers). These carriers charge per call-minute for each destination and may use a discount on total business volume to price their services. We developed a software system that supports decisions on allocating destinations to carriers. The core of this system is a min-cost flow routine that is embedded in a branch-and-bound framework. Our system solves the operational problem to optimality and performs what-if analyses and sensitivity analyses. A major telecommunication services provider implemented the system, realizing two benefits: it has structured the business process of allocating carriers to destinations and cut the costs of routing international calls.
The Value of Intrusion Detection Systems in Information Technology Security Architecture
Authors: Cavusoglu Huseyin , Mishra Birendra , Raghunathan Srinivasan
Published: April 2005

The increasing significance of information technology (IT) security to firms is evident from their growing IT security budgets. Firms rely on security technologies such as firewalls and intrusion detection systems (IDSs) to manage IT security risks. Although the literature on the technical aspects of IT security is proliferating, a debate exists in the IT security community about the value of these technologies. In this paper, we seek to assess the value of IDSs in a firm’s IT security architecture. We find that the IDS configuration, represented by detection (true positive) and false alarm (false positive) rates, determines whether a firm realizes a positive or negative value from the IDS. Specifically, we show that a firm realizes a positive value from an IDS only when the detection rate is higher than a critical value, which is determined by the hacker’s benefit and cost parameters. When the firm realizes a positive (negative) value, the IDS deters (sustains) hackers. However, irrespective of whether the firm realizes a positive or negative value from the IDS, the IDS enables the firm to better target its investigation of users, while keeping the detection rate the same. Our results suggest that the positive value of an IDS results not from improved detection per se, but from an increased deterrence enabled by improved detection. Finally, we show that the firm realizes a strictly nonnegative value if the firm configures the IDS optimally based on the hacking environment.
A Theoretical Integration of User Satisfaction and Technology Acceptance
Authors: Wixom Barbara H. , Todd Peter A.
Published: April 2005

In general, perceptions of information systems (IS) success have been investigated within two primary research streams—the user satisfaction literature and the technology acceptance literature. These two approaches have been developed in parallel and have not been reconciled or integrated. This paper develops an integrated research model that distinguishes beliefs and attitudes about the system (i.e., object-based beliefs and attitudes) from beliefs and attitudes about using the system (i.e., behavioral beliefs and attitudes) to build the theoretical logic that links the user satisfaction and technology acceptance literature. The model is then tested using a sample of 465 users from seven different organizations who completed a survey regarding their use of data warehousing software. The proposed model was supported, providing preliminary evidence that the two perspectives can and should be integrated. The integrated model helps build the bridge from design and implementation decisions to system characteristics (a core strength of the user satisfaction literature) to the prediction of usage (a core strength of the technology acceptance literature).
Perceived Individual Collaboration Know-How Development Through Information Technology–Enabled Contextualization: Evidence from Distributed Teams
Authors: Majchrzak Ann , Malhotra Arvind , John Richard
Published: April 2005

In today’s global market environment, enterprises are increasingly turning to use of distributed teams to leverage their resources and address diverse markets. Individual members of structurally diverse distributed teams need to develop their collaboration know-how to work effectively with others on their team. The lack of face-to-face cues creates challenges in developing the collaboration know-how—challenges that can be overcome by communicating not just content, but also context. We derive a theoretical model from Te’eni’s (2001) cognitive-affective model of communication to elaborate how information technology (IT) can support an individual’s communication of context to develop collaboration know-how. Two hundred and sixty-three individuals working in structurally diverse distributed teams using a variety of virtual workspace technologies to support their communication needs were surveyed to test the model. Results indicate that when individuals perceive their task as nonroutine, there is a positive relationship between an individual’s perceived degree of IT support for communicating context information and his collaboration know-how development. However, when individuals perceive their task as routine, partial IT support for contextualization is associated with lower levels of collaboration know-how development. This finding is attributed to individuals’ misunderstanding of the conveyed context, or their struggling to utilize the context conveyed with partial IT support, making a routine task more prone to misunderstanding and leaving the user worse than if she had no IT support for contextualization. We end the paper by drawing theoretical and practical implications based on these findings.
Post-Adoption Variations in Usage and Value of E-Business by Organizations: Cross-Country Evidence from the Retail Industry
Authors: Zhu Kevin , Kraemer Kenneth L.
Published: April 2005

Grounded in the innovation diffusion literature and the resource-based theory, this paper develops an integrative research model for assessing the diffusion and consequence of e-business at the firm level. Unlike the typical focus on adoption as found in the literature, we focus on postadoption stages, that is, actual usage and value creation. The model thus moves beyond dichotomous “adoption versus nonadoption” and accounts for the “missing link”—actual usage—as a critical stage of value creation. The model links technological, organizational, and environmental factors to e-business use and value, based on which a series of hypotheses are developed. The theoretical model is tested by using structural equation modeling on a dataset of 624 firms across 10 countries in the retail industry. To probe deeper into whether e-business use and value are influenced by economic environments, two subsamples from developed and developing countries are compared. The study finds that technology competence, firm size, financial commitment, competitive pressure, and regulatory support are important antecedents of e-business use. In addition, the study finds that, while both front-end and back-end capabilities contribute to e-business value, back-end integration has a much stronger impact. While front-end functionalities are becoming commodities, e-businesses are more differentiated by back-end integration. This is consistent with the resource-based theory because back-end integration possesses the value-creating characteristics of resources (e.g., firm specific, difficult to imitate), which are strengthened by the Internet-enabled connectivity. Our study also adds an international dimension to the innovation diffusion literature, showing that careful attention must be paid to the economic and regulatory factors that may affect technology diffusion across different countries.
New Results on the Mixed General Routing Problem
Authors: Corberán Angel , Mejía Gustavo , Sanchis José M.
Published: April 2005

In this paper, we deal with the polyhedral description and the resolution of the Mixed General Routing Problem. This problem, in which the service activity occurs both at some of the nodes and at some of the arcs and edges of a mixed graph, contains a large number of important arc and node routing problems as special cases. Here, a large family of facet-defining inequalities, the Honeycomb inequalities, is described. Furthermore, a cutting-plane algorithm for this problem that incorporates new separation procedures for the K-C, Regular Path-Bridge, and Honeycomb inequalities is presented. Branch and bound is invoked when the final solution of the cutting-plane procedure is fractional. Extensive computational experiments over different sets of instances are included.
Stochastic Comparisons in Production Yield Management
Authors: Gupta Diwakar , Cooper William L.
Published: April 2005

Manufacturing firms routinely commit resources to increase yield rates through product- and process-improvement initiatives. Champions of such yield-improvement projects may assume that stochastically larger yield rates are beneficial. In this note, we show that this need not hold, even when the contingent production lot sizes are chosen optimally. We employ stochastic comparison techniques to show that a yield rate that is smaller in the convex order ensures higher expected profit, and we provide a distribution-free bound on the size of increase in expected profit. We also identify properties of yield-rate distributions that do make stochastically larger yield rates beneficial.
A Series System with Returns: Stationary Analysis
Authors: DeCroix Gregory , Song Jing-Sheng , Zipkin Paul
Published: April 2005

This paper analyzes a series inventory system with stationary costs and stochastic demand over an infinite horizon. A distinctive feature is that demand can be negative, representing returns from customers, as well as zero or positive. We observe that, as in a system with nonnegative demand, a stationary echelon base-stock policy is optimal here. However, the steady-state behavior of the system under such a policy is different from that in systems with nonnegative demands. We present an exact procedure and several approximations for computing the operating characteristics and system costs for any stationary echelon base-stock policy, and also describe an algorithm for computing a good policy. As an alternative to the echelon base-stock policy, we discuss a policy that uses only local information. Finally, we describe how to extend the analysis to the case where returns occur at multiple stages instead of just at the stage closest to demand, and the case where returns require a recovery lead time.
Transmigration of a Maxillary Canine. A Case Report
Authors: Ryan Fiona S , Batra Puneet , Witherow Helen , Calvert Mary
Published: April 2005

In the oral cavity, transmigration is defined as a tooth that crosses the mid-line by more than half its length. Following extensive literature review, it was found that, although well documented with respect to mandibular canines, there were only two publications detailing maxillary cuspid transmigration. This report presents a case of transmigration where the left maxillary canine gradually crossed the mid-line and migrated to the right side in a patient with hemifacial microsomia and cleft palate. The Mupparapu classification of the migratory pattern of the mandibular canines is discussed. Various clinical considerations, as well as guidelines for general practitioners to diagnose and manage such a condition, are also discussed.
How Do We Move Forward?
Authors: Eaton Kenneth
Published: April 2005

In March 2004, a keynote national conference on the topic of ‘Reflection and Moving Forward’ was held in Manchester, as part of the national programme for primary dental care research and development (R&D). The conference was reported1 in the July 2004 edition of Primary Dental Care. It considered what had been achieved during the national research and development (R&D) programme, which had been targeted at primary dental care, and looked to the future. Abstracts of all the 47 completed projects, funded during the programme, were published at the time of the conference.2 The report in Primary Dental Care1 ended with the words, ‘it is hoped that the full proceedings of the day will be published later on this year’.

On 25 January 2005, Professor Raman Bedi, Chief Dental Officer (CDO) for England, convened a meeting, held at the British Medical Association's London headquarters, to announce that the proceedings of the ‘Reflection and Moving Forward’ conference3 were now available and to discuss how to develop the capacity for research in primary oral healthcare in the future. Nineteen people ( Appendix 1) were invited to and attended the meeting. They included the Dean of the FGDP(UK) and the Editor of this journal. This article reports the meeting.
Evaluation of the Potential Risk of Occupational Asthma in Dentists Exposed to Contaminated Dental Unit Waterlines
Authors: Pankhurst Caroline L , Coulter Wilson , Philpott-Howard John N , Surman-Lee Susanne , Warburton Fiona , Challacombe Stephen
Published: April 2005

Introduction

Most of the organisms isolated from dental unit waterlines (DUWL) are Gram-negative bacteria, which contain cell wall endotoxin. A consequence of endotoxin exposure is the exacerbation of asthma.

Objectives

This study examined the prevalence and onset of asthma among dentists and determined whether or not these were associated with the microbiological quality of DUWL in their practices.

Methods

266 randomly selected dentists (100 from rural Northern Ireland, 166 from London) completed a health questionnaire, which included questions on prevalence and time of onset of asthma. Water samples taken from the dental hand-pieces and surgery washbasin cold taps in all the practices were analysed using standard techniques. The questionnaire data were evaluated using both single and multivariable logistic regression. The variables considered were: smoking; surgery location; time treating patients per week; DUWL counts of Pseudomonas aeruginosa, total Pseudomonas spp., fungi, Mycobacterium spp., total aerobic colony counts (ACC) at 22°C and 37°C.

Results

There was no significant association between any of the variables tested in dentists and a history of asthma. A subgroup analysis was performed on dentists (n=33) who reported developing asthma since they started dental training. The final multivariable model indicated that passive smoking (OR 0.08, 95% CI 0.01 0.87, P=0.038) and total aerobic counts of >200 cfu/ml at 37°C (OR 6.72, 95% CI 1.15–39.24, P=0.034) were significant variables for developing asthma since starting training as a dentist. ACC were significantly higher in London (P<0.0001) and London dentists were more likely to have developed asthma since they started training than their Northern Ireland counterparts (OR 4.4, 95% CI 1.09–17.72, P=0.033).

Conclusions

This study suggests that the temporal onset of asthma may be associated with occupational exposure to contaminated DUWL among dentists in London and Northern Ireland.
Postmenopausal hormone therapy: from monkey glands to transdermal patches
Authors: Davis S R , Dinatale I , Rivera-Woll L , Davison S
Published: April 2005

The climacteric is not a condition of the modern age, although with increased life expectancy over the centuries, more women will experience this physiological transition. As women are living longer there is a greater expectation that good health will be maintained through to the late decade. Thus the potential long-term adverse health consequences of using hormonal therapies (HTs) to alleviate menopausal symptoms are of considerable concern for women and medical practitioners. This concern is often the basis for a decision whether or not to use HT.

We have reviewed the history of knowledge of the menopause and the development of HT for the treatment of climacteric complaints. We have also summarised the current evidence for specific benefits and risks of HT. Data indicate that postmenopausal HT is appropriate for the management of vasomotor symptoms, but that HT should not be prescribed for the prevention of cardiovascular disease or dementia. HT does prevent bone loss and osteoporotic fracture; however, use for this purpose remains controversial. The risk of breast cancer with HT varies according to the preparation used, such that oestrogen without concurrent progestin appears to convey little, or possibly even no significant breast cancer risk. There is insufficient information regarding the long-term use of non-oral HT, low-dose HT or novel compounds such as tibolone or the selective oestrogen receptor modulators with respect to breast cancer and cardiovascular risk for specific recommendations to be made.
Chronic treatment with exendin(9–39)amide indicates a minor role for endogenous glucagon-like peptide-1 in metabolic abnormalities of obesity-related diabetes in ob/ob mice
Authors: Green B D , Irwin N , Gault V A , Bailey C J , O’Harte F P M , Flatt P R
Published: April 2005

Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic hormone proposed to play a role in both the pathophysiology and treatment of type 2 diabetes. This study has employed the GLP-1 receptor antagonist, exendin-4(9–39)amide (Ex(9–39)) to evaluate the role of endogenous GLP-1 in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob and normal mice. Acute in vivo antagonistic potency of Ex(9–39) was confirmed in ob/ob mice by blockade of the insulin-releasing and anti-hyperglycaemic actions of intraperitoneal GLP-1. In longer term studies, ob/ob mice were given once daily injections of Ex(9–39) or vehicle for 11 days. Feeding activity, body weight, and both basal and glucose-stimulated insulin secretion were not significantly affected by chronic Ex(9–39) treatment. However, significantly elevated basal glucose concentrations and impaired glucose tolerance were evident at 11 days. These disturbances in glucose homeostasis were independent of changes of insulin sensitivity and reversed by discontinuation of the Ex(9–39) for 9 days. Similar treatment of normal mice did not affect any of the parameters measured. These findings illustrate the physiological extrapancreatic glucose-lowering actions of GLP-1 in ob/ob mice and suggest that the endogenous hormone plays a minor role in the metabolic abnormalities associated with obesity-related diabetes.
Sexual dysfunction in males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression?
Authors: Kraus M R , Schäfer A , Bentink T , Scheurlen M , Weissbrich B , Al-Taie O , Seufert J
Published: April 2005

Decrease of libido and erectile dysfunction are reported by male patients during antiviral therapy of chronic hepatitis C, but therapy-associated underlying factors for sexual dysfunction are not well defined. To assess putative contributions of interferon-induced sex hormone changes to sexual dysfunction, we prospectively investigated changes in free testosterone, total testosterone, dehydroepiandrosterone sulfate, prolactin, sex hormone-binding globulin, FSH and LH levels and psychometric self-assessment scores in 34 male patients treated with interferon alfa-2b (5 MIU three times weekly) (n=19)+ ribavirin (n=15) for 6–12 months. Depression was measured by the Hospital Anxiety and Depression Scale. Sexual dysfunction was evaluated by the Symptom Checklist 90 Item Revised and a five-point rating scale assessing sexual arousal disorder. Free and total testosterone decreased significantly during antiviral therapy in close correlation with libido/sexual function. Depression scores increased during therapy and were also significantly associated with sexual dysfunction. However, androgen levels displayed no significant correlation with depression. These results suggest that interferon-induced decrease in sexual function is associated – but not causally related –with both androgen reduction and increased depressive symptoms. These findings may affect care for male hepatitis C patients during interferon therapy.
Dexamethasone-induced intrauterine growth restriction impacts the placental prolactin family, insulin-like growth factor-II and the Akt signaling pathway
Authors: Ain Rupasri , Canham Lindsey N , Soares Michael J
Published: April 2005

Intrauterine growth restriction (IUGR) is a major cause of perinatal death and neonatal morbidity and mortality. There are numerous causes of IUGR. Glucocorticoid-induced IUGR is highly relevant because administration of synthetic glucocorticoids, principally dexamethasone, to women threatened by premature labor is widely used in clinical practice. Fetal growth is directly related to placental growth and development. In this report, we analyzed the effect of dexamethasone on placental development in the rat. Dexamethasone administered between days 13 and 20 of pregnancy not only induced IUGR but also decreased placental mass by approximately 50%. Impaired placental development was associated with dysregulated placental prolactin (PRL) family and insulin-like growth factor-II (IGF-II) gene expression. Furthermore, there was a significant decrease in the activation of Akt/protein kinase B in the junctional zone of the placenta, as assessed by the phosphorylation status of Akt and the pro-apoptotic protein BAD, a downstream target of the Akt signaling pathway. Such changes are consistent with increases in indices of apoptosis, including increased cleavage of poly(ADP-ribose) polymerase (PARP) in the junctional zone of the placenta of dexamethasone-treated rats. In summary, dexamethasone-induced IUGR is associated with placental insufficiency, including dysregulated placental hormone/cytokine gene expression and down-regulation of the IGF-II/Akt signaling pathway resulting in increases in indices of placental apoptosis.
Insulin and IGF-I stimulate the formation of the eukaryotic initiation factor 4F complex and protein synthesis in C2C12 myotubes independent of availability of external amino acids
Authors: Shen Wei-Hua , Boyle David W , Wisniowski Paul , Bade Aashia , Liechty Edward A
Published: April 2005

The objective of this study was to investigate the effect of insulin and IGF-I on protein synthesis and translation initiation in C2C12 myotubes in nutrient-deprived Dulbecco’s phosphate buffered saline (DPBS). The results showed that insulin and IGF-I increased protein synthesis by 62% and 35% respectively in DPBS, and the effect was not affected by rapamycin, but was blocked by LY294002. Insulin and IGF-I stimulated eukaryotic initiation factor 4E (eIF4E) binding protein (4EBP1) phosphorylation in a dose-dependent manner, and the stimulation was independent of availability of external amino acids. Both LY294002 and rapamycin blocked the insulin and IGF-I-induced increases in 4EBP1 phosphorylation. The results also showed that insulin and IGF-I were able to stimulate PKB/Akt phosphorylation, glycogen synthase kinase (GSK) 3β phosphorylation and mTOR phosphorylation in DPBS. Insulin and IGF-I increased the amount of eIF4G associated with eIF4E in nutrient-deprived C2C12 myotubes. The amount of 4EBP1 associated with eIF4E was decreased after insulin or IGF-I stimulation. We conclude that in C2C12 myotubes, insulin and IGF-I may regulate protein synthesis and translation initiation independent of external amino acid supply via the phosphatidylinositol-3 kinase-PKB/Akt-mTOR pathway.
Cited1 Is a Bifunctional Transcriptional Cofactor That Regulates Early Nephronic Patterning
Authors: Plisov Sergey , Tsang Michael , Shi Genbin , Boyle Scott , Yoshino Kiyoshi , Dunwoodie Sally L. , Dawid Igor B. , Shioda Toshi , Perantoni Alan O. , de Caestecker Mark P.
Published: April 2005

In a screen to identify factors that regulate the conversion of mesenchyme to epithelium during the early stages of nephrogenesis, it was found that the Smad4-interacting transcriptional cofactor, Cited1, is expressed in the condensed cap mesenchyme surrounding the tip of the ureteric bud (UB), is downregulated after differentiation into epithelia, and has the capacity to block UB branching and epithelial morphogenesis in cultured metanephroi. Cited1 represses Wnt/β-catenin but activates Smad4-dependent transcription involved in TGF-β and Bmp signaling. By modifying these pathways, Cited1 may coordinate cellular differentiation and survival signals that regulate nephronic patterning in the metanephros.
Protein Kinase Cβ Inhibition Attenuates Osteopontin Expression, Macrophage Recruitment, and Tubulointerstitial Injury in Advanced Experimental Diabetic Nephropathy
Authors: Kelly Darren J. , Chanty Anna , Gow Renae M. , Zhang Yuan , Gilbert Richard E.
Published: April 2005

Tubulointerstitial macrophage accumulation is an important marker of prognosis that correlates closely with declining renal function in a range of human and experimental diseases, including diabetic nephropathy. These inflammatory cells are rich in the profibrotic growth factor TGF-β such that their presence in areas of injury is frequently associated with tissue fibrosis. The migration of macrophages occurs in response to the site-specific production of chemokines, with osteopontin closely associated with their trafficking into the tubulointerstitium of the kidney. Although cell culture studies indicate that protein kinase C (PKC) mediates the expression of osteopontin, its role in the

in vivo

setting is unknown. Accordingly, Ren-2 control and diabetic rats that were treated with or without the specific PKC-β isoform inhibitor ruboxistaurin (10 mg/kg per d) were examined. After 12 wk, diabetic rats showed increases in osteopontin expression in tubular epithelial cells of the cortex in association with macrophage infiltration, interstitial fibrosis, and activity of TGF-β as indicated by the expression of its receptor activated protein phospho-Smad2 (

P

< 0.05 for all parameters). Ruboxistaurin treatment significantly attenuated these parameters (

P

< 0.05) in diabetic rats without affecting either BP or glycemic control. These findings suggest that osteopontin and macrophage accumulation may play a role in the tubulointerstitial injury in diabetic nephropathy and that inhibition of osteopontin expression may be one of the mechanisms by which inhibition of the β-isoform of PKC confers a renoprotective effect.
Cultured Podocytes Establish a Size-Selective Barrier Regulated by Specific Signaling Pathways and Demonstrate Synchronized Barrier Assembly in a Calcium Switch Model of Junction Formation
Authors: Hunt Jennifer L. , Pollak Martin R. , Denker Bradley M.
Published: April 2005

Podocytes form unique cell-cell junctions (slit diaphragms) that are central to glomerular selectivity, although regulation and mechanisms of slit diaphragm assembly are poorly understood. With the use of cultured podocytes, a paracellular permeability flux assay was established to characterize properties of the size-selective barrier. Paracellular flux of differentiated podocytes was measured using anionic fluorescent dextrans of 3, 10, 40, and 70 kD. Podocytes form a highly selective barrier with a 160-fold difference in flux from the 3-kD dextran (11 pmol/min) to the 70-kD dextran (0.06 pmol/min). Barrier development was dependent on podocyte differentiation and not affected by dextran charge. Puromycin, a known podocyte toxin, increased flux 250% in a dose-dependent manner without affecting cell viability. Screening with modulators of specific signaling pathways identified reversible increases in flux with Src tyrosine and Rho kinase inhibition. The calcium switch model of epithelial junction assembly was modified to determine whether podocytes regulate barrier assembly. When cultured in low calcium for 90 min, flux increased by 300% and consistently returned to baseline 24 to 48 h after switching to normal calcium. Similar to classical epithelial junctions, barrier recovery occurred in the presence of cyclohexamide, an inhibitor of protein synthesis. During the calcium switch, there were reversible changes in localization and detergent solubility of the slit diaphragm protein ZO-1 and α-actinin-4, whereas nephrin and podocin solubility were unchanged. Taken together, these findings demonstrate that cultured podocytes develop a selective size barrier that is regulated by specific signaling pathways, and similar to classical epithelial junctions, podocytes demonstrate synchronized assembly of the barrier.
Dual Effects of Hypertonicity on Aquaporin-2 Expression in Cultured Renal Collecting Duct Principal Cells
Authors: Hasler Udo , Vinciguerra Manlio , Vandewalle Alain , Martin Pierre-Yves , Féraille Eric
Published: April 2005

The driving force for renal water reabsorption is provided by the osmolarity gradient between the interstitium and the tubular lumen, which is subject to rapid physiologic variations as a consequence of water intake fluctuations. The effect of increased extracellular tonicity/osmolarity on vasopressin-inducible aquaporin-2 (AQP2) expression in immortalized mouse collecting duct principal cells (mpkCCDcl4) is investigated in this report. Increasing the osmolarity of the medium either by the addition of NaCl, sucrose, or urea first decreased AQP2 expression after 3 h. AQP2 expression then increased in cells exposed to NaCl- or sucrose-supplemented hypertonic medium after longer periods of time (24 h), while urea-supplemented hyperosmotic medium had no effect. Altered AQP2 expression induced by both short-term (3 h) and long-term (24 h) exposure of cells to hypertonicity arose from changes in AQP2 gene transcription because hypertonicity did not modify AQP2 mRNA stability nor AQP2 protein turnover. On the long-term, vasopressin (AVP) and hypertonicity increased AQP2 expression in a synergistic manner. Hypertonicity altered neither the dose-responsiveness of AVP-induced AQP2 expression nor cAMP-protein kinase (PKA) activity, while PKA inhibition did not reduce the extent of the hypertonicity-induced increase of AQP2 expression. These results indicate that in collecting duct principal cells: (

1

) a short-term increase of extracellular osmolarity decreases AQP2 expression through inhibition of AQP2 gene transcription; (

2

) a long-term increase of extracellular tonicity, but not osmolarity, enhances AQP2 expression

via

stimulation of AQP2 gene transcription; and (

3

) long-term hypertonicity and PKA increases AQP2 expression through synergistic but independent mechanisms.