bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti‐remodelling effect of canrenone in patients with mild chronic heart failure (AREA IN‐CHF study): final results
Authors: Boccanelli Alessandro , Mureddu Gian Francesco , Cacciatore Giuseppe , Clemenza Francesco , Di Lenarda Andrea , Gavazzi Antonello , Porcu Maurizio , Latini Roberto , Lucci Donata , Maggioni Aldo Pietro , Masson Serge , Vanasia Massimo , de Simone Giovanni ,   on behalf of AREA IN‐CHF Investigators
Published: January 2009

Aims

To test whether canrenone, an aldosterone receptor antagonist, improves left ventricular (LV) remodelling in NYHA class II heart failure (HF). Aldosterone receptor antagonists improve outcome in severe HF, but no information is available in NYHA class II.

Methods and results

AREA IN‐CHF is a randomized, double‐blind, placebo‐controlled study testing canrenone on top of optimal treatment in NYHA class II HF with low ejection fraction (EF) to assess 12‐month changes in LV end‐diastolic volume (LVEDV). Brain natriuretic peptide (BNP) was also measured. Information was available for 188 subjects on canrenone and 194 on placebo. Left ventricular end‐diastolic volume was similarly reduced (−18%) in both arms, but EF increased more (P = 0.04) in the canrenone (from 40% to 45%) than in the placebo arm (from 40–43%). Brain natriuretic peptide (n = 331) decreased more in the canrenone (−37%) than in the placebo arm (−8%; P < 0.0001), paralleling a significant reduction in left atrial dimensions (−4% vs. 0.2%; P = 0.02). The composite endpoint of cardiac death and hospitalization was significantly lower in the canrenone arm (8% vs. 15%; P = 0.02).

Conclusion

Canrenone on top of optimal treatment for HF did not have additional effects on LVEDV, but it increased EF, and reduced left atrial size and circulating BNP, with potential beneficial effects on outcome. A large‐scale randomized study should be implemented to confirm benefits on cardiovascular outcomes in patients with HF in NYHA class II.
Heart rate per se impacts cardiac function in patients with systolic heart failure and pacing: a pilot study
Authors: Logeart Damien , Gueffet Jean‐Pierre , Rouzet François , Pousset Françoise , Chavelas Christophe , Solal Alain Cohen , Jondeau Guillaume
Published: January 2009

Aims

This study was designed to compare the specific effects of two heart rates (HR), 55 and 75 b.p.m., in patients with heart failure (HF).

Methods and results

Patients with chronic HF, left ventricular ejection fraction (LVEF) ≤ 35%, and a pacemaker with >90% of paced QRS, were included in a randomized cross‐over trial of two 3‐month periods where pacing rate was set at either 55 or 75 b.p.m. At the end of each period, patients were examined and radionuclide ventriculography, echocardiography, and blood sampling were performed for centralized and blinded analysis. Two patients did not complete the study because of early worsening while paced at 75 b.p.m. Twelve patients completed the study. Compared with 75 b.p.m., pacing at 55 b.p.m. was associated with a higher LVEF [+4.7% (2.6–6.7), P < 0.001], lower B‐type natriuretic peptide levels [−91 pg/mL (−148 to −33), P < 0.01], lower systolic pulmonary artery pressure (41 ± 10 vs. 47 ± 10 mmHg, P = 0.02) and lower NYHA (New York Heart Association) class (2.2 ± 0.6 vs. 2.6 ± 0.5, P = 0.03). The baseline pacing rate prior to inclusion had no effect on results.

Conclusion

HR per se may impact cardiac function and low HR might be beneficial in patients with systolic HF compared with intermediate HR.
Liver function abnormalities and outcome in patients with chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program
Authors: Allen Larry A. , Felker G. Michael , Pocock Stuart , McMurray John J.V. , Pfeffer Marc A. , Swedberg Karl , Wang Duolao , Yusuf Salim , Michelson Eric L. , Granger Christopher B. ,   for the CHARM Investigators
Published: January 2009

Aims

The prevalence and importance of liver function test (LFT) abnormalities in a large contemporary cohort of heart failure patients have not been systematically evaluated.

Methods and results

We characterized the LFTs of 2679 patients with symptomatic chronic heart failure from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity program (CHARM). We used multivariable modelling to assess the relationships between baseline LFT values and long‐term outcomes. Liver function test abnormalities were common in patients with chronic heart failure, ranging from alanine aminotransferase elevation in 3.1% of patients to low albumin in 18.3% of patients; total bilirubin was elevated in 13.0% of patients. In multivariable analysis, elevated total bilirubin was the strongest LFT predictor of adverse outcome for both the composite outcome of cardiovascular death or heart failure hospitalization (HR 1.21 per 1 SD increase, P < 0.0001) and all‐cause mortality (HR 1.19 per 1 SD increase, P < 0.0001). Even after adjustment for other variables, elevated total bilirubin was one of the strongest independent predictors of poor prognosis (by global chi‐square).

Conclusion

Bilirubin is independently associated with morbidity and mortality. Changes in total bilirubin may offer insight into the underlying pathophysiology of chronic heart failure.
Finasteride-Induced Myalgia and HyperCKemia
Authors: Al-Harbi Talal M , Kagan Jennifer , Tarnopolsky Mark A
Published: January 2009

Background:

Finasteride is an antiandrogen, inhibits type II 5-α reductase (enzyme that converts testosterone to more potent form dihydrotestosterone), and is commonly used in the treatment of benign prostatic hyperplasia and male frontal baldness; however, it is not free from side effects, which include sexual dysfunction and, rarely, myopathy. We report a case of finasteride-associated myalgia and hyperCKemia and review similar cases reported in the literature.

Case report:

A 30-year-old man who had been taking finasteride 5 mg/d for 10 years to treat frontal baldness developed diffuse muscle aches associated with elevated creatine kinase level to 10,117 IU/L with neither weakness nor pigmenturia. His symptoms resolved and his creatine kinase level dropped down to 256 IU/L 3 weeks after finasteride discontinuation.

Conclusion:

Reversible myalgia associated with significant hyperCKemia is a possible adverse reaction of finasteride therapy.
Nitric Oxide Contributes to Cadmium Toxicity in Arabidopsis by Promoting Cadmium Accumulation in Roots and by Up-Regulating Genes Related to Iron Uptake
Authors: Besson-Bard Angélique , Gravot Antoine , Richaud Pierre , Auroy Pascaline , Duc Céline , Gaymard Frédéric , Taconnat Ludivine , Renou Jean-Pierre , Pugin Alain , Wendehenne David
Published: January 2009

Nitric oxide (NO) functions as a cell-signaling molecule in plants. In particular, a role for NO in the regulation of iron homeostasis and in the plant response to toxic metals has been proposed. Here, we investigated the synthesis and the role of NO in plants exposed to cadmium (Cd2+), a nonessential and toxic metal. We demonstrate that Cd2+ induces NO synthesis in roots and leaves of Arabidopsis (Arabidopsis thaliana) seedlings. This production, which is sensitive to NO synthase inhibitors, does not involve nitrate reductase and AtNOA1 but requires IRT1, encoding a major plasma membrane transporter for iron but also Cd2+. By analyzing the incidence of NO scavenging or inhibition of its synthesis during Cd2+ treatment, we demonstrated that NO contributes to Cd2+-triggered inhibition of root growth. To understand the mechanisms underlying this process, a microarray analysis was performed in order to identify NO-modulated root genes up- and down-regulated during Cd2+ treatment. Forty-three genes were identified encoding proteins related to iron homeostasis, proteolysis, nitrogen assimilation/metabolism, and root growth. These genes include IRT1. Investigation of the metal and ion contents in Cd2+-treated roots in which NO synthesis was impaired indicates that IRT1 up-regulation by NO was consistently correlated to NO's ability to promote Cd2+ accumulation in roots. This analysis also highlights that NO is responsible for Cd2+-induced inhibition of root Ca2+ accumulation. Taken together, our results suggest that NO contributes to Cd2+ toxicity by favoring Cd2+ versus Ca2+ uptake and by initiating a cellular pathway resembling those activated upon iron deprivation.
A rapid method for quantifying heavy atom derivatives for multiple isomorphous replacement in protein crystallography
Authors: Colip Leslie A. , Koppisch Andrew T. , Broene Richard D. , Berger Jennifer A. , Baldwin Sharon M. , Harris Michael N. , Peterson Lori J. , Warner Benjamin P. , Birnbaum Eva R.
Published: January 2009

A rapid and simple X-ray fluorescence-based method is reported for characterizing heavy atom derivatives of proteins for protein crystallography using multiple isomorphous replacement (MIR). MIR is a widely used technique for solving protein crystallographic structures which requires that a `heavy atom' be incorporated into the protein to provide a strong signal in the diffraction pattern. Current methods for determining the effectiveness of these protein–heavy atom reactions are not always successful. In contrast, X-ray fluorescence quickly determines the presence of heavy atom modifications of proteins and the stoichiometry of these modifications.
Board characteristics and involvement in strategic decision making
Authors: Ogbechie Chris , Koufopoulos Dimitrios N. , Argyropoulou Maria
Published: January 2009

Purpose

This paper aims to review how corporate governance is institutionalised in Nigeria and examine the relationship between board size, CEOs’ duality, board composition and the board's involvement in strategy.

Design/methodology/approach

A structured questionnaire was sent by post to the chairmen of 138 publicly quoted companies in Nigeria in November 2004.

Findings

Using primary and secondary data, our results suggest that the Nigerian public companies have embraced some principles of the Code of Best Practices for Public Companies. There is a high level of board involvement in strategy decision‐making process, but no correlation was found between board involvement and a number of governance variables (board size, board independence and CEO duality).

Research limitations/implications

The sample of 39 responding companies is small although it represents a 28 per cent of response rate and is representative of the Nigerian stock market. However, we are unable to look at other factors such as industry sectors and we cannot generalise our findings regarding corporate governance practices in Nigeria.

Practical implications

The investment climate in Nigeria can become more reassuring than in the past although there is room for further improvements as the effectiveness of the corporate government practices is still in doubt.

Originality/value

This paper adds to the scanty literature available on corporate governance practices in developing, countries. Findings extend our understanding about the strategic functions of the board in Nigeria, which is Africa's most populous nation, and the world's sixth larger producer of oil.
The relationship between knowledge management enablers and performance
Authors: Ho Chin‐Tsang
Published: January 2009

Purpose

This paper aims to study the correlation between knowledge management (KM) enablers and performance indices of KM.

Design/methodology/approach

Referring to the literature reviews, it attempts to construct the KM process performance index, analyze its importance, and further analyze a company's characteristics, the relationship between KM enablers with the importance of the KM process performance index, and try to adopt four KM enablers as independent variables. Lastly, it intends to explore whether the relationship between the importance of the KM process performance and financial performance indices affects the importance of the financial performance index.

Findings

Among KM enablers, the factor strategy and leadership appears to be one of the most significant positive relationships among all of the KM process performance indices. The importance of performance indices in knowledge creation and knowledge internalization on the operational and customer sides show a positive, significant relationship in the importance of the financial performance index.

Research limitations/implications

With the constraint of the number of samples, this study does not construct the KM process performance indices of every industry category or strategy.

Originality/value

The main contribution of the paper is that it explores the causes that influence KM process performance indices, and this enriches empirical research literatures in the domain of the KM process performance indices.
An output approach to property portfolio performance measurement
Authors: Price Ilfryn , Clark Elizabeth
Published: January 2009

Purpose

The purpose of this paper is to demonstrate the analysis of portfolios of office properties using measures of business outputs, namely occupation efficiency and staff satisfaction.

Design/methodology/approach

Satisfaction is measured using a proprietary online survey instrument that has proved highly reliable and repeatable in three separate trials. The data on 192 buildings are analysed using data envelopment analysis.

Findings

Instant and significant differences are revealed between clusters of buildings and individual properties. The approach reveals inefficiencies that are concealed by more conventional cost‐based metrics.

Practical implications

The study has proven to be of use in gaining organisational commitment to strategic property improvements.

Originality/value

The authors are not aware of this approach having been applied elsewhere in either research or application.
Ultrasonic bonding of flexible PCB to rigid PCB using an Sn interlayer
Authors: Kim Kyoo‐Seok , Jung Jae‐Pil , Norman Zhou Y.
Published: January 2009

Purpose

The aim of the paper is to study the feasibility of direct ultrasonic bonding between contact pad arrays on flexible printed circuit boards (FPCB) and rigid printed circuit boards (RPCB) at ambient temperature.

Design/methodology/approach

Metallization layers on the RPCB comprised Sn on Cu while the pads on the FPCB consisted of Au/Ni/Cu. Prepared RPCB and FPCB were bonded by ultrasound at ambient temperature using an ultrasonic frequency of 20 kHz, a power of 1,400 W, and 0.62 MPa of bonding pressure. The bonded samples were cross‐sectioned and the joints and microstructures were observed by Field Emission Scanning Electron Microscopy (FE‐SEM) and Energy Dispersive Spectroscopy (EDS). The soundness of the joints was evaluated by pull testing.

Findings

Robust bonding between FPCB and RPCB was obtained by bonding for 1.0 and 1.5 s. This result has confirmed that direct room temperature ultrasonic bonding of Au and Sn is feasible. At a longer bonding time of 3.0 s, cracks and voids were found in the joints due to excessive ultrasonic energy. The IMC (intermetallic compound) between the Sn layer and pads of the RPCB was confirmed as Cu6Sn5. On the FPCB side, Cu6Sn5 and Ni3Sn4 were formed by contact with the facing Sn coating, and mechanically alloyed Cu0.81Ni0.19 was found within the pads. Meanwhile, the strength of bonded joints between FPCB and RPCB increased with bonding time up to 1.5 s and the maximum value reached 12.48 N. At 3.0 s bonding time, the strength decreased drastically, and showed 5.75 N. Footprints from the fracture surfaces showed that bonding started from the edges of the metal pads, and extended to the pad centers as ultrasonic bonding time was increased.

Originality/value

Direct ultrasonic bonding with transverse vibration at ambient temperature between the surface layers of the pads of FPCB and RPCB has been confirmed to be feasible.
Organizational commitment among high school teachers of India and Iran
Authors: Joolideh Faranak , Yeshodhara K.
Published: January 2009

Purpose

This paper aims to investigate the organizational commitment of teachers in India and Iran. It is an attempt to understand how these perceptions vary by demographic variables such as age and subject taught by teachers.

Design/methodology/approach

Data were collected from 721 high school teachers in Bangalore (India) and Sanandaj (Iran). They were asked to responsed to the Meyer and Allen questionnaire. Data were analyzed via SPSS version 11.0.

Findings

Results revealed that Indian teachers had better organizational commitment in the affective and normative components and Iranian teachers were found to have better organizational commitment in the continuance component. In both countries age groups and subject taught by teachers did not have any influence over their organizational commitment.

Research limitations/implications

This research was limited by the relatively restricted sample of high school teachers in both countries. Future research should test initially confirmed associations in different school contexts with substantially dissimilar teacher demographics, and include consideration of dispositional antecedents that may affect teacher perceptions.

Originality/value

This is the only study comparing Indian and Iranian organizational commitment in schools. The study provides an initial understanding of the possible effect of cultures on the organizational commitment of teachers in two different countries.
Wincanton reduces sickness absence by 10,000 days
Authors: Madden Carol
Published: January 2009

Purpose

This paper aims to demonstrate how supply‐chain company Wincanton has reduced sickness absence, improved productivity and heightened morale.

Design/methodology/approach

Draws upon the experience of Wincanton's sickness absence management program, driven by the partnership between the HR department, Wincanton employees and absence‐management specialist active health partners (AHP).

Findings

Describes the significant variation in staff‐absence levels across different sites and types of work contract and the detrimental effects of such absence on Wincanton's performance. The company selected an absence‐management service led by nurses in order to provide effective, timely medical advice, encouraging staff to take responsibility for their health while at the same time facilitating a prompt return to work.

Practical implications

Shows how taking an active approach to staff absence and aligning reporting systems to identify and share good practice have had a positive impact on staff morale, productivity and profitability.

Originality/value

Highlights a significant reduction in average absence figures per employee and cost savings for the business.
Application of Taguchi loss functions for supplier selection
Authors: Ordoobadi Sharon
Published: January 2009

Purpose

This paper seeks to provide a tool for decision makers to make more informed decisions regarding their outsourcing decisions and selection of the appropriate supplier.

Design/methodology/approach

The method uses the Taguchi loss function for the inclusion of intangibles in the evaluation and selection of suppliers. Intangibles are defined as factors that have an impact on the selection of an appropriate supplier but are not easily quantified to be included in the financial evaluation. These intangibles are classified as the benefits and risks of using a supplier to perform the outsourcing function. A decision maker has certain expectations regarding these intangibles and a loss occurs when a supplier's performance does not meet the decision maker's expectations. The Taguchi loss function has been selected as a means of measuring the loss. The decision maker defines the target value and the specification limits for each benefit and risk category. The weighted loss scores are calculated where the weights are the importance ratings assigned to benefit/risk categories by the decision maker. Based on this analysis each supplier will receive a weighted loss score for all the pertinent benefit categories and one weighted loss score for all the risk categories. To achieve a single measure, the aforementioned weighted loss scores are combined to determine a single aggregate loss score for each supplier, which is then used to rank them. The supplier who receives the highest ranking (minimum loss score) will be selected to perform the outsourcing function.

Findings

The procedure proposed here can help companies to identify the best supplier to perform an outsourcing function.

Originality/value

The paper presents a phased decision model that begins with economic evaluation and then uses Taguchi functions to measure the impact of intangibles.
Antecedents and consequences of teamwork quality in new product development projects
Authors: Dayan Mumin , Di Benedetto C. Anthony
Published: January 2009

Purpose

The purpose of this paper is to explore the quality of interactions among new product development team members, wherein functional diversity, team stability, and transactive memory system are antecedents of teamwork quality. Three measures of outcomes are used (team learning, speed to market, product success), and task complexity is a moderating variable.

Design/methodology/approach

A theoretical model was developed and tested on the survey data collected from 93 product managers of Turkish companies. The product managers who participated in this study represented various industries including those of telecommunications, food, material, software, machinery, chemicals, and service technologies.

Findings

An inverted‐U impact of both functional diversity and team stability on teamwork quality was found, and a positive impact of transactive memory system on teamwork quality. Teamwork quality was significantly related to improved performance, and task complexity moderates this relationship.

Originality/value

The paper is the first attempt to explore the role antecedents and its outcomes in NPD teams.
Orthopaedic physiotherapy practitioners
Authors: Rabey Martin , Morgans Sharon , Barrett Cathy
Published: January 2009

Purpose

The purpose of this paper is to discuss the scepticism that persists among medics regarding appropriateness of some aspects of services provided by extended scope physiotherapists (ESPs). This paper aims to highlight the extent and appropriateness of surgical and radiological referrals by ESPs working in an adult orthopaedic service.

Design/methodology/approach

The patient pathway following ESP assessment was audited over 31 months. Parameters explored included ESP referral rates to orthopaedic consultants; the percentage of patients where the entire episode of care was managed by the ESP; whether orthopaedic referrals were appropriate in terms of surgical interventions; and numbers of radiology referrals specifically for knee or lumbar complaints.

Findings

Of the patients, 79 per cent had their entire episode of care managed by ESPs. Of the patients, 9 per cent were referred on for a surgical opinion (of which 42 per cent knees, 20 per cent lumbar). 13 per cent were referred for x‐rays, 10 per cent for magnetic resonance imaging. Of the patients referred on for surgical opinion surgical intervention was appropriate in 89 per cent of cases.

Research limitations/implications

Data from an ESP service with broad guiding protocols in a specific hospital are not readily extrapolated to ESPs elsewhere. Appropriateness of onwards referrals was based on the opinions of consultants to whom patients were referred. The potential benefit of a second opinion even if surgery is not offered is not taken into account by this model.

Practical implications

These audits reinforce the impact ESPs have on efficiency within orthopaedics. They document referral rates for x‐rays and magnetic resonance imaging by ESPs for lumbar and knee complaints that may benefit units proposing new ESP services.

Originality/value

This paper reinforces published data on ESP management of the entire episode of care of the majority of referrals to orthopaedics, and on the highly appropriate nature of onwards referrals. Documented for possibly the first time, data regarding investigations for lumbar and knee disorders highlight low referral rates.
On becoming a manager and attaining managerial integrity
Authors: Bergin Elsmari
Published: January 2009

Purpose

The call for cuts and streamlining in health organizations has resulted in middle managers having more responsibilities. The main aim of this study is to explore and understand the way middle managers in Swedish health care organizations handle multiple obligations and continuous challenges.

Design/methodology/approach

Middle managers in health organizations were interviewed in an open‐ended, interactive mode. The transcribed interviews were analysed using grounded theory as the method of study.

Findings

The participating managers started their careers as nurses or physiotherapists and they describe their experiences of transition in role taking and transformation of earlier approaches to work assignments. An understanding of a process of managerial development is identified. During this process, the subjects are going from “being prepared” to “defining limits”, from “action” to “wait‐and‐see”, gradually regaining self‐respect and establishing authority, all to attain a non‐negotiable managerial integrity.

Practical implications

The findings can be used to support first line managers in health care, who often leave their positions in the early stages of their managerial career, as well as middle managers in their managerial development.

Originality/value

The development of managerial integrity, with support from findings in in‐depth interviews, has not been described until now.
Allergenicity and immunogenicity of the major mugwort pollen allergen Art v 1 chemically modified by acetylation
Authors: Perovic I. , Milovanovic M. , Stanic D. , Burazer L. , Petrovic D. , Milcic‐Matic N. , Gafvelin G. , Van Hage M. , Jankov R. , Velickovic T. Cirkovic
Published: January 2009

Background
Treating allergies with modified allergens is an approach to make the treatment safer and more efficient. Art v 1 is the most prominent allergen of mugwort pollen and a significant cause of hayfever around Europe. The aim of this study was to reduce the allergenicity of Art v 1 by acetylation, and to investigate the capacity of the modified protein to generate blocking antibodies.

Methods
The reduction of allergenicity of Art v 1 following acetylation was monitored by immunoblot, ELISA inhibition using a pool of sera from mugwort pollen allergic patients, basophil activation assay and by skin prick testing of mugwort‐allergic patients. Rabbits were immunized against Art v 1 and acetylated Art v 1 (acArt v 1) and the rabbit antisera were tested for their capacity to block human IgE binding in ELISA. Human T cell proliferation against Art v 1 and acArt v 1 was examined in peripheral blood mononuclear cells (PBMCs) of mugwort pollen allergic patients and cytokine release in PBMC cultures was monitored.

Results
Acetylation of Art v 1 gave a derivative of reduced allergenicity in the in vitro and ex vivo tests applied. The skin test reactivity to acArt v 1 was significantly reduced in 19 patients when compared with the reactivity to Art v 1. Rabbit antibodies to acArt v 1 and Art v 1 showed similar capacity to block human IgE binding to Art v 1 in inhibition ELISA. Both proteins were able to induce proliferation of PBMCs and CD3/CD4+ cells of mugwort‐allergic patients. Release of IL‐5 was significantly reduced in cultures stimulated with acArt v 1.

Conclusions
Art v 1 modified by acetylation had a significantly reduced allergenicity in vitro and in vivo, while its immunogenicity was retained. Modification of allergens by acetylation could be a new strategy for allergen‐specific immunotherapy.
High‐fat feeding redirects cytokine responses and decreases allergic airway eosinophilia
Authors: De Vries A. , Hazlewood L. , Fitch P. M. , Seckl J. R. , Foster P. , Howie S. E. M.
Published: January 2009

Background
Dietary fat intake has been associated with obesity and obesity in its turn with attenuated airway function and asthma, but it is unclear whether or how high‐fat intake per se alters immune function relevant to development of allergic asthma.

Objective
To use a non‐obese mouse model of mild to moderate allergic asthma to compare effects of high‐fat with isocaloric control‐diet on allergic immune responses.

Methods
C57BL/6 mice weaned and maintained on control (11% fat calories) or isocaloric high‐fat diet (58% fat calories) were systemically sensitized with ovalbumin and challenged in the lungs. Allergic airway inflammation was assessed by measuring lung inflammation; serum antibodies; and, cytokines in serum, bronchoalveolar lavage (BAL) fluid and in supernatants of in vitro stimulated lung draining lymph node and spleen lymphocytes.

Results
There was a significant reduction in lung eosinophilia and IL‐5 in high‐fat fed mice. Lung draining lymph node cells from these mice showed reduced pro‐inflammatory cytokine (MCP‐1 and TNF‐α) release after ovalbumin re‐stimulation and reduced release of IL‐13 after concanavalin‐A stimulation, indicating a general rather than just an antigen‐specific change. There was no difference in IFN‐γ release. In contrast, pro‐inflammatory cytokine release was increased from splenocytes. Decreased eosinophilia was not due to increased regulatory T cell or IL‐10 induction in draining lymph nodes or spleen, nor to changes in antibody response to ovalbumin. However, decreased levels of serum and BAL eotaxin were found in high‐fat fed animals.

Conclusions
The data indicate that high‐fat dietary content redirects local immune responses to allergen in the lungs and systemic responses in the spleen and serum. These effects are not due to changes in regulatory T cell populations but may reflect a failure to mobilize eosinophils in response to allergic challenge.
Conditioned polarized Caco‐2 cell monolayers allow to discriminate for the ability of gut‐derived microorganisms to modulate permeability and antigen‐induced basophil degranulation
Authors: Thierry A.‐C. , Bernasconi E. , Mercenier A. , Corthésy B.
Published: January 2009

Background
Food allergy is a common allergic disorder – especially in early childhood. The avoidance of the allergenic food is the only available method to prevent further reactions in sensitized patients. A better understanding of the immunologic mechanisms involved in this reaction would help to develop therapeutic approaches applicable to the prevention of food allergy.

Objective
To establish a multi‐cell in vitro model of sensitized intestinal epithelium that mimics the intestinal epithelial barrier to study the capacity of probiotic microorganisms to modulate permeability, translocation and immunoreactivity of ovalbumin (OVA) used as a model antigen.

Methods
Polarized Caco‐2 cell monolayers were conditioned by basolateral basophils and used to examine apical to basolateral transport of OVA by ELISA. Activation of basophils with translocated OVA was measured by β‐hexosaminidase release assay. This experimental setting was used to assess how microorganisms added apically affected these parameters. Basolateral secretion of cytokine/chemokines by polarized Caco‐2 cell monolayers was analysed by ELISA.

Results
Basophils loaded with OVA‐specific IgE responded to OVA in a dose‐dependent manner. OVA transported across polarized Caco‐2 cell monolayers was found to trigger basolateral basophil activation. Microorganisms including lactobacilli and Escherichia coli increased transepithelial electrical resistance while promoting OVA passage capable to trigger basophil activation. Non‐inflammatory levels of IL‐8 and thymic stromal lymphopoietin were produced basolaterally by Caco‐2 cells exposed to microorganisms.

Conclusion
The complex model designed inhere is adequate to learn about the consequence of the interaction between microorganisms and epithelial cells vis‐a‐vis the barrier function and antigen translocation, two parameters essential to mucosal homeostasis. It can further serve as a direct tool to search for microorganisms with anti‐allergic and anti‐inflammatory properties.
L-carnitine, a diet component and organic cation transporter OCTN ligand, displays immunosuppressive properties and abrogates intestinal inflammation
Authors: Fortin G , Yurchenko K , Collette C , Rubio M , Villani A-C , Bitton A , Sarfati M , Franchimont D
Published: January 2009

Allele variants in the L-carnitine (LCAR) transporters OCTN1 (SLC22A4, 1672 C → T) and OCTN2 (SLC22A5, -207 G → C) have been implicated in susceptibility to Crohn's disease (CD). LCAR is consumed in the diet and transported actively from the intestinal lumen via the organic cation transporter OCTN2. While recognized mainly for its role in fatty acid metabolism, several lines of evidence suggest that LCAR may also display immunosuppressive properties. This study sought to investigate the immunomodulatory capacity of LCAR on antigen-presenting cell (APC) and CD4+ T cell function by examining cytokine production and the expression of activation markers in LCAR-supplemented and deficient cell culture systems. The therapeutic efficacy of its systemic administration was then evaluated during the establishment of colonic inflammation in vivo. LCAR treatment significantly inhibited both APC and CD4+ T cell function, as assessed by the expression of classical activation markers, proliferation and cytokine production. Carnitine deficiency resulted in the hyperactivation of CD4+ T cells and enhanced cytokine production. In vivo, protection from trinitrobenzene sulphonic acid colitis was observed in LCAR-treated mice and was attributed to the abrogation of both innate [interleukin (IL)-1β and IL-6 production] and adaptive (T cell proliferation in draining lymph nodes) immune responses. LCAR therapy may therefore represent a novel alternative therapeutic strategy and highlights the role of diet in CD.
Enhanced expression of interferon-inducible protein-10 correlates with disease activity and clinical manifestations in systemic lupus erythematosus
Authors: Kong K O , Tan A W , Thong B Y H , Lian T Y , Cheng Y K , Teh C L , Koh E T , Chng H H , Law W G , Lau T C , Leong K P , Leung B P , Howe H S
Published: January 2009

Our objective was to investigate the serum levels of interferon-inducible protein-10 (IP-10) in systemic lupus erythematosus (SLE) and their correlation with disease activity and organ manifestations. Serum IP-10 levels were assessed in 464 SLE patients and 50 healthy donors. Disease activity was assessed by the revised SLE Activity Measure, and the concomitant active organ manifestations, anti-ds DNA antibody titres, complement levels and erythrocyte sedimentation rates recorded. Peripheral blood mononuclear cell (PBMC) synthesis of IP-10 in SLE patients and controls was determined by in vitro cultures stimulated with mitogen or lipopolysaccharide. Elevated serum IP-10 levels were observed in SLE patients, which were significantly higher in the presence of active haematological and mucocutaneous manifestations. SLE PBMCs exhibited enhanced spontaneous IP-10 production in vitro. Serial IP-10 levels correlated with longitudinal change in SLE activity, even at low levels where anti-dsDNA antibody and complement levels remain unchanged. These data demonstrate that IP-10 levels are increased in SLE and serum IP-10 may represent a more sensitive marker for monitoring disease activity than standard serological tests.
Expression of chemokine receptors CXCR4, CXCR5 and CCR7 on B and T lymphocytes from patients with primary antibody deficiency
Authors: Payne D , Drinkwater S , Baretto R , Duddridge M , Browning M J
Published: January 2009

The interaction of chemokines and their receptors directs lymphocyte migration, and is involved in the distribution and organization of lymphocytes within lymphoid tissues. We reasoned that abnormal chemokine receptor expression might give rise to defects of lymphocyte migration into and within lymphoid tissues, and consequently be associated with defective antibody production in primary antibody deficiencies. In this study, we have investigated the expression of chemokine receptors CXCR4, CXCR5 and CCR7 on lymphocyte subpopulations (naive and memory B cells; CD4+ and CD8+ T cells) in a cohort of patients with primary antibody deficiency (n = 23), and compared these with a group of healthy controls (n = 19). We show that there were significant differences in both the proportions of lymphocytes expressing, and the levels of expression of, specific chemokine receptors on individual lymphocyte subpopulations between patients and controls. Furthermore, these changes appeared more pronounced in patients with more severe antibody deficiency. These data support the hypothesis that abnormal lymphocyte trafficking may be involved in the pathogenesis of primary antibody deficiencies.
Intrinsic defect of the immune system in children with Down syndrome: a review
Authors: Kusters M A A , Verstegen R H J , Gemen E F A , De Vries E
Published: January 2009

Down syndrome (DS) is the most frequent cause of mental retardation in man. Immunological changes in DS have been observed since the 1970s. The neurological system appears to be ageing precociously, with early occurrence of Alzheimer disease; until now, the observed immunological differences have been interpreted in the same context. Looking back at past and present results of immunological studies in DS children in relation to the clinical consequences they suffer, we conclude that it is more likely that the DS immune system is intrinsically deficient from the very beginning.
Putative tumor suppressor EDD interacts with and up‐regulates APC
Authors: Ohshima Ryuichi , Ohta Tomohiko , Wu Wenwen , Koike Ayaka , Iwatani Tsuguo , Henderson Michelle , Watts Colin K. W. , Otsubo Takehito
Published: January 2009

Adenomatous polyposis coli (APC), whose mutation causes colorectal cancers, is a key player in the Wnt signaling pathway. While the role of APC in inhibition of β‐catenin/LEF1‐dependent activation of transformation‐inducing genes has been intensively studied and well established, regulation of APC expression at the protein level is only partially understood. Here we report that APC is up‐regulated by EDD, the mammalian orthologue of Drosophila melanogaster“hyperplastic discs” gene (hyd) that is considered to be a putative tumor suppressor. Screening of APC immunocomplexes by mass spectrometry identified EDD as a putative APC‐interacting protein. Exogenously expressed and endogenous APC interacted with EDD in vivo. Indirect immunofluorescent analyses demonstrated that APC and EDD co‐localized in the cytoplasm of the cell. Over‐expression of EDD enhanced the protein expression level of APC and its binding partner Axin, resulting in inhibition of Wnt signaling downstream of β‐catenin. Conversely, siRNA knock‐down of EDD down‐regulated APC at the protein level without altering its mRNA level, causing enhanced protein expression of β‐catenin. Thus, through protein–protein interaction, EDD stabilizes APC and up‐regulates APC's function to inhibit β‐catenin, suggesting that EDD could act as a colorectal tumor suppressor.
Rapamycin sensitivity of the Schizosaccharomyces pombe tor2 mutant and organization of two highly phosphorylated TOR complexes by specific and common subunits
Authors: Hayashi Takeshi , Hatanaka Mitsuko , Nagao Koji , Nakaseko Yukinobu , Kanoh Junko , Kokubu Aya , Ebe Masahiro , Yanagida Mitsuhiro
Published: January 2009

Nutrients are essential for cell growth and division. Screening of Schizosaccharomyces pombe temperature‐sensitive strains led to the isolation of a nutrient‐insensitive mutant, tor2‐287. This mutant produces a nitrogen starvation‐induced arrest phenotype in rich media, fails to recover from the arrest, and is hypersensitive to rapamycin. The L2048S substitution mutation in the catalytic domain in close proximity to the adenine base of ATP is unique as it is the sole known genetic cause of rapamycin hypersensitivity. Localization of Tor2 was speckled in the vegetative cytoplasm, and both speckled and membranous in the arrested cell cytoplasm. Using mass spectroscopic analysis, we identified six subunits (Tco89, Bit61, Toc1, Tel2, Tti1 and Cka1) that, in addition to the six previously identified subunits (Tor1, Tor2, Mip1/Raptor, Ste20/Rictor, Sin1/Avo1 and Wat1/Lst8), comprise the TOR complexes (TORCs). All of the subunits so far examined are multiply phosphorylated. Tel2 bound to Tti1 interacts with various phosphatidyl inositol kinase (PIK)‐related kinases including Tra1, Tra2 and Rad3, as well as Tor1 and Tor2. Schizosaccharomyces pombe TORCs should thus be functionally redundant and might be broadly regulated through different subunits that are either common or specific to the two TORCs, or even common to various PIK‐related kinases. Functional redundancy of the TORCs may explain the rapamycin hypersensitivity of tor2‐287.
Functional dissection of transformation by c‐Src and v‐Src
Authors: Oneyama Chitose , Hikita Tomoya , Nada Shigeyuki , Okada Masato
Published: January 2009

The c‐src proto‐oncogene product, c‐Src, is frequently over‐expressed and activated in various human malignant cancers, implicating a role for c‐Src in cancer progression. To verify the role of c‐Src, we analyzed the transforming ability of c‐Src in mouse embryonic fibroblasts that lack Csk, a negative regulator of Src family kinases. Although Csk deficiency is not sufficient for cell transformation, c‐Src over‐expression induced characteristic transformed phenotypes including anchorage‐independent growth and tumorigenecity. These phenotypes were dose‐dependently inhibited by the re‐expression of Csk, indicating that there is a certain threshold for c‐Src transformation, which is determined by the c‐Src : Csk ratio. In contrast to v‐Src, c‐Src induced the phosphorylation of a limited number of cellular proteins and elicited a restricted change in gene expression profiles. The activation of some critical targets for v‐Src transformation, such as STAT3, was not significantly induced by c‐Src transformation. Several genes that are involved in cancer progression, that is, cyclin D1 and HIF‐1α, were induced by v‐Src, but not by c‐Src. Furthermore, v‐Src tumors exhibited aggressive growth and extensive angiogenesis, while c‐Src tumors grew more slowly accompanied by the induction of hematomas. These findings demonstrate that c‐Src has the potential to induce cell transformation, but it requires coordination with an additional pathway(s) to promote tumor progression in vivo.
Mash1 is required for neuroendocrine cell development in the glandular stomach
Authors: Kokubu Hiroshi , Ohtsuka Toshiyuki , Kageyama Ryoichiro
Published: January 2009

In the epithelium of the developing glandular stomach, neuroendocrine cells differentiate from common progenitors, but the mechanism of how these cells are specified remains to be determined. Here, we show that the basic helix–loop–helix (bHLH) gene, mammalian achaete‐scute homologue 1 (Mash1), is highly expressed in the glandular stomach epithelium. In Mash1‐null mice, almost all gastric neuroendocrine cells are missing, whereas development of non‐neuroendocrine cells is not significantly affected. The bHLH gene Neurogenin3 (Ngn3), which is known to regulate formation of subsets of gastric neuroendocrine cells (gastrin‐, glucagon‐ and somatostatin‐producing cells), is expressed normally in the Mash1‐null stomach. Thus, Ngn3 alone is not sufficient but Mash1 is additionally required for the differentiation of these neuroendocrine cells. Taken together, these results indicate that formation of gastrin‐, glucagon‐ and somatostatin‐producing cells depends on both Mash1 and Ngn3, while that of other neuroendocrine cells depends on Mash1 alone, suggesting that combinations of bHLH genes may contribute to cell type diversity.
Geology and the London Underground
Authors: Paul Jonathan D.
Published: January 2009

Geology as a whole is the main influence on determining the feasibility of tunnelling for underground railways, and at what cost. Favourable conditions encouraged the early development of a network, significantly alter the methods used for construction, and are what form the tunnels, in terms of horizontal and vertical alignment. Local geology is shown, by means of two cross‐sections following the tunnels, to be more important than the overall regional geology, where the underlying strata exhibit pronounced variations in permeability, and so mechanical properties. Geological complexities specific to the area of tunnelling generate problems during construction, but lead to technological innovation in the long term and a better understanding of local stratigraphy. As the result of this, and the increase in the quality of preliminary surveys, we are increasingly able to tunnel in areas previously considered treacherous.
The Araguainha impact: a South American Permo–Triassic catastrophic event
Authors: Lana Cristiano , Marangoni Yara
Published: January 2009

The Araguainha meteorite impact was certainly one of the most catastrophic events in the history of the South American continent. The impact occurred around 250 Ma ago, when the region was covered by the estuarine waters of the Parana Basin in central parts of Brazil. The impacting body of approximately 2–3 km in diameter was sufficiently large to excavate a 2 km‐thick sedimentary sequence of the Parana Basin and to expose a 4 km‐wide core of basement crystalline rocks in the central part of the crater. The huge scar left by the meteorite collision is 40 km in diameter, the largest and best preserved impact crater on the continent. Combined field observations and remote sensing analysis demonstrates that the Araguainha impact structure preserves all morphological/structural features of large lunar craters, being thus an important analogue to study large extraterrestrial craters. The catastrophic energy released upon impact, close to 106 megatons of TNT, must have been disastrous for marine organisms living in the Parana Basin. Ongoing studies are currently evaluating the link between the Araguainha impact and the Permian–Triassic mass extinction, which is the greatest of the mass extinctions in Earth history.
Phreatic cave calcites – archives of two realms
Authors: Immenhauser Adrian
Published: January 2009

Two main types of karst formation are commonly known: the surficial meteoric one and the subsurface (hypogenic) karst, related to both carbonic (H2CO3) and sulphuric (H2S) acids. Nevertheless, a third, less well studied type exists that is referred to here as CO2‐regime related karst. This article describes Pleistocene phreatic cave spar from the diapiric Jabal Madar dome in Northern Oman. These caverns and their precipitates probably represent examples of CO2‐related karsting and subsequent calcite precipitation. Phreatic calcites form at the interface between two fundamentally different diagenetic and hydrogeological domains: the deep‐seated, hydrothermal and the near‐surficial, meteoric–vadose one. Changes in the ratio between hydrothermal upwelling and meteoric influx are recorded in the geochemistry and mineralogy of these calcites making them uncommon archives of two contrasting realms.