bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing global leaders through international assignments
Authors: Kohonen Eeva
Published: January 2005

Purpose

International assignments, which are used as an integral part of global management development, are challenging in terms of one's managerial competencies and self‐concept. However, not much is known about how managers develop during international assignments, or about the process of their identity construction. The purpose of this paper is to show the need for studying international assignments from an identity construction perspective and to build up an interdisciplinary framework for this kind of study.

Design/methodology/approach

The paper offers a new and an eclectic approach on expatriation by reviewing and combining current literature on expatriation, identity and career.

Findings

As a result of the theoretical discussion the paper notes that more empirical research is needed about the consequences of foreign assignments on individual managers’ identity and subjective career and suggests narratives as a promising strategy to capture the fluid process of identity construction during expatriation.

Originality/value

The value of the paper for academics is that it opens up new avenues for research on international management development and international assignments in particular.
Job satisfaction among expatriates, repatriates and domestic employees
Authors: Bonache Jaime
Published: January 2005

Purpose

The present study aims to provide an empirical evaluation of job satisfaction among expatriates, repatriates, and domestic employees with no international experience.

Design/methodology/approach

The study was conducted on a large sample of employees from a Spanish multinational construction company. One‐way analysis of variance (ANOVA) and the Scheffe test were employed to analyse the data.

Findings

After controlling for hierarchical status, the results indicated that, among these three groups of employees, there are some significant differences in the satisfaction ratings on job characteristics, career prospects, and internal communication. The authors did not, however, find differences in the mean satisfaction rating on general job satisfaction. Findings are discussed, as are limitations and suggestions for future research.

Originality/value

The study contributes to the literature on job satisfaction.
Key success factors when implementing strategic manufacturing initiatives
Authors: Minarro‐Viseras Enrique , Baines Tim , Sweeney Mike
Published: January 2005

Purpose

This paper reports the study of key success factors (KSFs) in the project management of the implementation of strategic manufacturing initiatives (SMIs).

Design/methodology/approach

In order to gather the experience and knowledge of many industries, from different geographic locations, in a broad range of types and sizes of SMIs, a questionnaire‐based survey of practitioners worldwide was selected as the most appropriate research method among those available.

Findings

The identification of those tasks and activities that must be done well in order to succeed in the implementation of a SMI in practice.

Practical implications

Practitioners focusing their attention on the KSFs identified are more likely to succeed. Once these factors have been identified, the value of benchmarking project management methodologies then comes from drawing attention to those tasks that are key to the success of the implementation of SMIs.

Originality/value

The paper presents new thinking by bringing project management into the operations strategy implementation literature as an important mediating factor for success. In this context the factors that are required for successful implementation are identified.
Non‐planar interconnect
Authors: Williams Gavin , Seed Luke , Purvis Alan , Maiden Andrew , McWilliam Richard , Ivey Peter
Published: January 2005

Purpose

This paper describes a method for patterning fine line interconnections over non‐planar surfaces and introduces the idea of using holographic masks for more challenging geometries.

Design/methodology/approach

A photolithographic method for achieving grossly non‐planar interconnects is described. The patterning of electrical interconnections onto the piezo‐electric actuators of an ink‐jet print head is used as an example. Uniform coverage of the substrate is achieved using an electro‐depositable photoresist. The required pattern is transferred via a custom‐designed chrome‐on‐glass mask using a standard mask aligner.

Findings

Large arrays of 100 μm‐pitch electrical interconnections were successfully deposited onto 500 μm‐high high piezo‐electric actuators. It was necessary to modify the shapes of the line segments on the mask in order to compensate for diffractive line broadening. For more extreme 3D geometries it becomes necessary to consider the use of holographic masks.

Originality/value

Printed circuit boards and semiconductor wafers are nominally flat and traditional lithographic processes have been developed accordingly. However, future microelectronic packaging schemes and microsystems may require patterning to be achieved on grossly non‐planar surfaces. We have demonstrated that this can be achieved on ink‐jet print heads using photolithography and point to the research necessary to enable it to be realised on more extreme non‐planar substrates.
Neglected dimensions of development: inequality, conflict and aid
Authors: Gounder Rukmani
Published: January 2005

Purpose

As ethnic diversity is regarded as a determinant of growth, this study engages in an analysis of diversity as the forte behind better economic performance and where social stability of a nation is necessary to achieve growth. While these factors alone may not be sufficient to achieve growth and maintain social harmony, domestic institutions and good governance are regarded as vital factors.

Design/methodology/approach

Differential performances of diverse ethnic groups are most influential contributions of social capital and its growth impact. In this framework there is a larger role of aid to provide security to a nation to achieve its development objectives. An evaluation of ethnic diversity and land issues in Fiji is undertaken with concerns of a market economy, policies and governance.

Findings

An examination of the opposing nature of ethnic diversity and land issues in Fiji provides an insight not only of ethnic conflict, but also of the role of aid to solve conflict. A discussion on ethnicity and being equal in the market relates to the reason for equality before identity. The analysis indicates the role foreign aid can play to achieve stability and avoid ethnic conflict for growth in Fiji.

Originality/value

The paper indicates the global issues of inequality and conflict and policy implications for Fiji and the nations facing such problems and aid donors’ role for growth and development.
Toward a template for systematic reference and instruction programme analysis
Authors: Guise Janneka L.
Published: January 2005

Purpose

To develop a method of systematically analyzing reference and instruction programmes at academic libraries so managers of such services can identify potential areas of change and make more confident recommendations.

Design/methodology/approach

The paper reviews the library literature and then introduces a template for programme analysis. A case study is used to help illustrate the need for programme analysis, and also to clarify the template.

Findings

The reference and instruction literature on assessment and new service models indicates that academic librarians are struggling to update programming in order to meet the needs of current library patrons. There is no how‐to manual for managers of reference and instruction departments to analyze their services comprehensively and to decide what changes to make. This paper introduces a template that academic librarians could use to systematically analyze their reference and instruction programming with regard to the history of the programmes, internal and external environmental factors that affect the provision of service, and how the current service model compares with others.

Practical implications

The use of this template will allow academic librarians at any size library to investigate the historical and environmental factors that affect their services, so they can more confidently identify potential areas of change and make documented and supported recommendations to library administration.

Originality/value

This paper fulfils a gap in the literature and offers a guide to programme analysis for managers of reference and instruction departments.
The knowledge‐productive corporate university
Authors: Jansink Femke , Kwakman Kitty , Streumer Jan
Published: January 2005

Purpose

In this paper the concept of knowledge production is used as a framework to study Dutch corporate universities. Knowledge production serves not simply as a desirable aim of corporate universities, as the concept also offers guidelines for the design of corporate universities. The purpose is to clarify the extent to which corporate universities fulfil this aim of knowledge production and the way they produce new knowledge.

Design/methodology/approach

From different theoretical perspectives 11 design characteristics have been extracted that help corporate universities to be knowledge‐productive. Two empirical studies were carried out to find out to what extent corporate universities meet those features required for knowledge production. The first study implies an exploration of opinions of key actors within 12 Dutch corporate universities, in which data were gathered through interviews and analysis of documents. The second study can be characterised as a case study of a concrete training practice within one corporate university. Data were gathered by interviews, evaluative questionnaires, and observation.

Findings

Results reveal that knowledge production is viewed as important, but that concrete measures to stimulate it are often absent. Moreover, corporate universities need to pay more attention to the working environment of their employees in order to achieve their own goals.

Originality/value

Analysing the corporate university from the perspective of knowledge production may stimulate corporate universities to rethink their own goals as well as their position within the organisation.
The rise and rise of the corporate university
Authors: Blass Eddie
Published: January 2005

Purpose

As the boundaries between training and education have converged, the demand for the services of universities and the response of the traditional public have drifted apart, leaving a gap which has been filled by the development of the corporate university. Now the UK Government is proposing relaxing the regulations on university status which will allow corporate universities to gain degree‐awarding powers.

Design/methodology/approach

This paper charts the rise of the corporate university through turbulent times, looking at the external factors that have contributed to its development, and the internal benefits that have fuelled its success, drawing on a number of case studies. It also raises questions as to where it is going next.

Findings

The discussion focuses on the extrapolation of the current situation into the future, highlighting that corporate universities could pose an even greater threat to traditional public universities in the future as they may be better placed to provide a meaningful undergraduate experience to school‐leavers than is currently provided in the education sector.

Originality/value

The paper suggests a future for undergraduate education that has not yet been widely contemplated or even considered by parties in the education sector, and therefore it opens the arena for debate by raising awareness of the issues that are driving such a future outcome forward.
E‐learning in the corporate university
Authors: Homan Gill , Macpherson Allan
Published: January 2005

Purpose

To explore the development of e‐learning within the context of corporate universities with the aim of informing the debate on e‐learning and establishing key areas of concern for emerging corporate universities.

Design/methodology/approach

Three case reviews of large leading edge organizations in different sectors.

Findings

Whilst e‐learning has potential, its success is significantly limited by context which influences the degree of sophistication and integration of e‐learning and its ability to contribute to the corporate university learning processes and outcomes.

Research limitations/implications

Further research is required on both the learner experience and in the wider evaluation of learning outcomes beyond simple statistical evaluation of participation.

Practical implications

Key areas of difficulty are identified as: the focus on generic e‐learning solutions; the barrier imposed by the base technology level of the organization; the overriding concern for ROI at the expense of learner experiences; and the extent to which pedagogical possibilities are not fully exploited.

Originality/value

Raises the often overlooked issues of pedagogy and learner response to e‐learning as inhibitors to the contribution that e‐learning can make to the corporate university.
Rapid manufacturing of silicon carbide composites
Authors: Evans R.S. , Bourell D.L. , Beaman J.J. , Campbell M.I.
Published: January 2005

Purpose

To review the initial phase of research for realizing an SLS‐based rapid manufacturing method for silicon carbide composites. The research was oriented toward actual commercial fabrication of fully functional parts.

Design/methodology/approach

A screening method for materials in SLS was established using the operating parameters of the SLS machine, polymer analysis, heat transfer analysis and powder mechanics. The quality and potential application of the parts made during the research were assessed by rapid prototyping industry experts.

Findings

Thermosetting materials can be used as binders in SLS. Free‐standing metal infiltration is possible and yields near‐net shape parts. Polymer matrix composites can also be produced readily. The part quality in terms of dimensional stability, detail and surface finish were commensurate with current commercially available rapid prototyping materials.

Research limitations/implications

Although several binders were initially screened, only phenolic was explored as a binder material. The curing aspects were examined, but not the melt rheology. Glass and silicon carbide base materials were examined. Future work will include addition base, binder and infiltrant materials. Pursuing thermosets as neat resin systems on SLS is another future research element.

Practical implications

The search for new SLS materials should not be limited to thermoplastic materials. Indirect SLS processing offers a low cost means of achieving fully functional parts in support of rapid manufacturing.

Originality/value

This paper reports on what may be considered a platform technology for producing fully functional parts from SLS, a prominent rapid prototyping technique. It will be valuable to researchers and industrial practitioners of rapid prototyping technologies, particularly those interested in realizing commercially viable manufacturing.
Laser densification of extruded dental porcelain bodies in multi‐material laser densification process
Authors: Li Xiaoxuan , Wang Jiwen , Shaw Leon L. , Cameron Thomas B.
Published: January 2005

Purpose

Commercial dental porcelain powder was deposited via slurry extrusion and laser densified to fabricate dental restorations in a multi‐material laser densification (MMLD) process.

Design/methodology/approach

A dental porcelain slurry was made from ball milled dental porcelain powders and extruded using the MMLD system. Extruded lines and rings were laser densified under different conditions in order to study how to build fully dense porcelain layers without warping and cracking during the MMLD process.

Findings

The geometric cross section of laser densified porcelain lines were dependent on laser processing parameters. Laser densified single ring showed no warping, and multiple layer body after laser densification showed cracks in the rings. The interface microstructure suggested good bonding between multiple layers. The mechanism to achieve single porcelain ring without warping and cracking is discussed. Alternate ways to build physical tooth layer by layer are proposed.

Originality/value

In the MMLD process, dental porcelain slurry was extruded from a human tooth computer file and laser densified to manufacture dental restorations based on solid freeform fabrication (SFF) principles. The understanding developed will pave the way for fabricating a physical dental restoration unit in the near future.
Recreating the university from within
Authors: Moore Janet , Pagani Freda , Quayle Moura , Robinson John , Sawada Brenda , Spiegelman George , Van Wynsberghe Rob
Published: January 2005

Purpose

In 1997, the University of British Columbia (UBC) adopted a sustainable development policy stating that the campus should adhere to sustainable practices in all of its actions and mandates and that all students who attend UBC will be educated about sustainability. The purpose of the paper is to consider how far UBC has moved in the last six years in the direction of sustainability education, what has been accomplished, what lessons have been learned and what challenges lie ahead.

Design/methodology/approach

This paper is a collaborative inquiry created by a number of faculty, staff and one doctoral student working on sustainability education issues at UBC.

Findings

The shift to sustainability involves: a fundamental thinking‐through of basic issues about the role of the university in society, creating a strong relationship between sustainability principles and the core goals of the university. It also will require a reworking of the design and operation of institutional reward systems, creating an appropriate linkage between the operational and academic functions of the university, and finding an appropriate mix of disciplinarity and interdisciplinarity. The collaborative writing process helped to bring people together to reflect on the projects of the past and consider the plans for the future.

Originality/value

The intention of the paper is to summarize the sustainability education initiatives at UBC, and address barriers and pathways to creating sustainability education programs at the university level. The collaborative stories aim to help other individuals and groups implement sustainability in higher education and contribute to a process of institutional learning for sustainability.
Dealing with the knowledge economy: intellectual capital versus balanced scorecard
Authors: Mouritsen J. , Thorsgaard Larsen H. , Bukh P.N.
Published: January 2005

Purpose

This paper compares balanced scorecard and intellectual capital and finds important differences between their theoretical underpinnings, which suggest that the breath of indicators will work differently in organisations.

Design/methodology/approach

Analysing texts about balanced scorecard and intellectual capital, the paper discusses not the obvious similarities – that they are both integrated performance management systems – but four more aspects: strategy, organisation, management, and indicators. Comparing these four dimensions the paper discusses the differences arising from the very different theories of strategy that they presuppose: competitive advantage versus competency strategy.

Findings

The paper suggests that the very different notions of strategy that underpin the balanced scorecard and the intellectual capital approach make such comprehensive performance management systems behave in very different ways – the difference between a tightly coupled and a loosely coupled system accounts for this.

Research limitations/implications

The main limitation is that the paper is primarily a literature study and therefore it is not certain that in practical situations companies will necessarily adopt the theoretical perspectives mobilised behind balance scorecard and intellectual capital.

Practical implications

The usefulness of that paper is that practitioners may understand the breath of implications of a shift in strategic focus and realise the various organisational conditions that can help mobilise the use of indicators in different ways.

Originality/value

The paper's analysis shows how the two models assume how indicators work in an organisational systems and concludes that the differences are significant and that therefore there are considerable differences in how a system of indicators may work in the context of balanced scorecard compared with the context of intellectual capital.
Innovation in SMEs: the impact of strategic orientation and environmental perceptions
Authors: O'Regan Nicholas , Ghobadian Abby
Published: January 2005

Purpose

To investigate the role and impact of strategic orientation and environmental perceptions on innovation and supporting mechanisms such as process technologies and management practices, in SMEs.

Design/methodology/approach

A quantitative approach based on a random sampling methodology of 1,000 SMEs. Construct validity was tested in the qualitative phase of the research.

Findings

SMEs can be categorised as either prospectors or defenders. This polarisation was confirmed in this study. For example, prospectors are more likely to engage in new product development, whereas defenders are five times more likely to modify an existing product than introduce a newly patented product. Prospector‐type firms tend to deploy more new process technologies and leading management practices compared with defender type firms, particularly in a turbulent operating environment. Defenders recognise the need to “catch up” and indicate that they intend to introduce process technologies over the next two years. Firms tend to place a greater emphasis on innovation in turbulent operating environments.

Research limitations/implications

The study was restricted to two different sector types: engineering and electronics. Future studies should examine other sectors and their sub sectors, possibly augmented by qualitative in‐depth case studies or an ethnographic approach.

Practical implications

The practical implications of the study are outlined in the paper. Chief executives are encouraged to align their strategic orientation with their innovation strategy. In addition, defender type firms should consider the greater use of process technologies and management practices.

Originality/value

This paper contributes to the integration of strategic orientation and innovation.
Changing trends in incidence and mortality of thyroid cancer in Scotland
Authors: Reynolds Rebecca M. , Weir Jennifer , Stockton Diane L. , Brewster David H. , Sandeep Thekkepat C. , Strachan Mark W. J.
Published: January 2005

Objective  The incidence of thyroid cancer is increasing in several countries. The aim was to investigate trends in the incidence and mortality of thyroid cancer in Scotland, where thyroid cancer is relatively uncommon, between 1960 and 2002.

Design  Descriptive epidemiological study.

Methods  Thyroid cancer registrations between 1960 and 2000 were obtained from the Scottish Cancer Registry. Mortality data (1960–2002) and population estimates were supplied by the Registrar General for Scotland. Incidence and mortality data are expressed as age‐specific rates and European age‐standardized rates (EASRs).

Results  Thyroid cancer was three times more common in females than in males and was more common in older than younger age groups. Between 1960 and 2000, the annual EASR of thyroid cancer increased from 1·76 to 3·54 per 100 000 for females (P < 0·001) and from 0·83 to 1·25 per 100 000 in males (P < 0·001). The overall thyroid cancer increase between 1975 and 2000 was primarily caused by an increase in papillary thyroid cancer, particularly over the most recent decade. The incidence of follicular thyroid cancer also increased while the incidence of anaplastic and medullary thyroid cancer did not change significantly. Mortality from thyroid cancer fell progressively between 1960 and 2002. EASR for females decreased from 1·05 to 0·28 (P < 0·001) and in males from 0·73 to 0·34 (P < 0·001). For both sexes, in general, survival at 1‐, 5‐ and 10‐year follow‐up intervals from diagnosis improved steadily over the study period. In both females and males, survival from thyroid cancer was better if the diagnosis was made under the age of 50 years.

Conclusions  Thyroid cancer incidence has increased in Scotland over the past 40 years. This is accompanied by a change in the distribution of histological type with a particular increase in papillary carcinoma. The reasons for this may relate partly to changes in clinical practice and histological criteria. Falling mortality in the face of increasing incidence reflects improvements in survival, which should improve further with the introduction and implementation of standardized treatment protocols.
Different responses to chronic somatostatin analogues in patients with central hyperthyroidism
Authors: Mannavola Deborah , Persani Luca , Vannucchi Guia , Zanardelli Maddalena , Fugazzola Laura , Verga Uberta , Facchetti Marco , Beck‐Peccoz Paolo
Published: January 2005

Objective  Central hyperthyroidism is mainly due to two different causes, TSH‐secreting pituitary adenoma (TSH‐oma) and resistance to thyroid hormone in its pituitary variant, i.e. patients presenting with signs and symptoms of hyperthyroidism (PRTH). Because therapeutic approach and the clinical follow‐up are extremely different in these two disorders, a correct differential diagnosis is mandatory. Unfortunately, no definite pathognomonic tool is presently available and an extensive biochemical and instrumental workup is frequently needed in order to reach the correct diagnosis. Aim of the present study was to investigate the use of somatostatin analogues in the differential diagnosis between TSH‐omas and PRTH, as well as the possible treatment of PRTH with these analogues.

Design and Patients  Eight patients with TSH‐oma and four with PRTH underwent the acute test with somatostatin analogue Octreotide (0·1 mg subcutaneously), as well as long‐acting Octreotide‐LAR (30 mg intramuscularly every 28 days) for two months.

Measurements  Serum TSH, FT3 and FT4 were evaluated in basal condition, at time 0 and every hour for 6 h during acute test, and every 15 days for 2 months during chronic treatment.

Results  During acute test, in both patients with PRTH and TSH‐oma, a similar reduction in immunoreactive TSH and FT3 levels was observed, while no variations were found in FT4 concentrations. In contrast, during the administration of Octreotide‐LAR, no significant variations of all tested parameters were observed in PRTH group, whereas FT3 and FT4 concentrations normalized or presented a significant reduction (> 30% of pretreatment values) in seven of eight patients with TSH‐oma, despite minor variation of immunoreactive TSH levels.

Conclusions  Chronic administration of long‐acting somatostatin analogues in patients with central hyperthyroidism caused a marked decrease of FT3 and FT4 levels in all patients but one with TSH‐oma, while patients with PRTH did not respond at all. Thus, administration of long acting somatostatin analogues for at least 2 months can be useful in the differential diagnosis in problematic cases of central hyperthyroidism. Furthermore, the present findings exclude the possibility of a beneficial effect of chronic administration of somatostatin analogues in controlling thyrotoxic symptoms in PRTH patients.
Substitutions in the CYP21A2 promoter explain the simple‐virilizing form of 21‐hydroxylase deficiency in patients harbouring a P30L mutation
Authors: Araujo Rogério S. , Billerbeck Ana Elisa C. , Madureira Guiomar , Mendonca Berenice B. , Bachega Tânia A. S. S.
Published: January 2005

The classical and nonclassical phenotypes of 21‐hydroxylase deficiency represent a continuous spectrum of the impairment of 21‐hydroxylase activity due to mutations between the CYP21A2 gene. These mutations occur mainly by microconversion in the homologous nonfunctional CYP21A1P gene. The P30L mutation is associated with the nonclassical form, and it reduces the activity to 30–40% of the normal enzyme. We have described three female patients exhibiting a simple virilizing phenotype and bearing the P30L mutation in compound heterozygosis with a severe mutation. To identify additional mutations causing this phenotype, the promoter region was sequenced and four mutations were identified: −126C → T, −113G → A, −110T → C and −103 A → G. These substitutions are normally present in the promoter region of the pseudogene and in vitro studies demonstrated that they reduced the transcriptional activity fivefold. They might have been converted to the CYP21A2 promoter together with the P30L mutation in these patients. Therefore, these substitutions in synergism with the P30L mutation might decrease the enzyme activity resulting in a more severe phenotype, and a DNA sequence of −167 bases of the CYP21A2 gene should be performed in patients with 21‐hydroxylase deficiency in whom the phenotype is more severe than predicted by the genotype.
Increasing urine albumin excretion is associated with growth hormone hypersecretion and reduced clearance of insulin in adolescents and young adults with type 1 diabetes: The Oxford Regional Prospective Study
Authors: Amin Rakesh , Williams Rachel M. , Frystyk January , Umpleby Margot , Matthews David , Orskov Hans , Dalton R Neil , Dunger David B.
Published: January 2005

Hypothesis  We previously described lower insulin‐like growth factor I (IGF‐I) levels in association with increased microalbuminuria (MA) risk in type 1 diabetic subjects followed from diabetes diagnosis through puberty into adulthood. By inference lower IGF‐I levels may be associated with higher GH levels and changes in insulin sensitivity.

Methods  To test this hypothesis, microalbuminuric subjects (MA+, n = 14) from the same cohort had overnight GH levels measured during euglycaemia (5 mmol/l, 01:00–07:30 h) maintained by a variable rate insulin infusion followed by a 2‐step hyperinsulinaemic, euglycaemic clamp study using [6·6 2H2] glucose, and were compared to MA– controls (MA–, n = 14), matched for age (median 19·3 years, range 15·8–30·5), sex, duration of diabetes (11·1 years, range 5·1–16·4).

Results  In MA+ cases GH levels, measured by the Pulsar programme, were higher (baseline; 1·8 ± 1·4 vs. 0·7 ± 0·5 ng/ml, P = 0·02, mean; 3·8 ± 1·3 vs. 2·6 ± 1·6 ng/ml, P = 0·03, maximum; 16·7 ± 7·0 vs. 12·3 ± 5·4, P = 0·02), despite similar HbA1c levels (9·8%vs. 9·6%, P = 0·6) and body or truncal fat mass. Fourier transform revealed increased GH pulse amplitude at all periodicities and overnight insulin clearance was reduced (11·7 ± 6·9 vs. 20·1 ± 6·5 ml/kg/min, P < 0·02). In multiple regression analysis, urine albumin excretion was associated with higher GH levels and reduced insulin clearance, independent of HbA1c and body composition. In female cases (n = 9), dextrose requirements were reduced during the first step of the euglycaemic clamp (1·7 ± 0·8 vs. 2·7 ± 1·4, P < 0·05) but no such differences existed in males or in the rate of glucose production or disposal.

Conclusion  The development of MA during puberty and young adulthood is associated with higher GH levels and abnormalities in insulin metabolism, particularly in females. These data extend support for our previous findings indicating a role for the GH/IGF‐I axis in the pathogenesis of MA.
Measuring disease activity to predict therapeutic outcome in Graves’ ophthalmopathy
Authors: Terwee C. B. , Prummel M. F. , Gerding M. N. , Kahaly G. J. , Dekker F. W. , Wiersinga W. M.
Published: January 2005

Objective  The concept of disease activity in Graves’ ophthalmopathy (GO) might explain why as many as one‐third of patients do not respond to immunosuppressive treatment, because only patients in the active stage of disease are expected to respond. The hypothesis was adopted that a parameter used to measure disease activity should be able to predict a response to immunosuppressive treatment. The aim of this study was to develop a multivariate prediction model in which all previous tested activity parameters are integrated.

Design and Patients  We included 66 consecutive patients with untreated moderately severe GO who had been euthyroid for at least 2 months. All patients were treated with radiotherapy.

Measurements  Treatment efficacy after 6 months follow‐up was used as the primary outcome measure. Disease severity and 15 different disease activity parameters were assessed before treatment. Univariate and multivariate logistic regression models were used to predict response (model 1) or no change (model 2).

Results  In multivariate analyses, we found that duration of GO, soft tissue involvement, elevation, soluble interleukin‐2 receptor (sIL‐2R), soluble CD30 (sCD30), eye muscle reflectivity and octreotide uptake ratio were significant predictors of a response to radiotherapy. Gender, duration of GO, soft tissue involvement, eye muscle reflectivity, IL‐6 and urinary glycosaminoglycan (GAG) excretion were significant predictors of no change upon radiotherapy. Prognostic score charts were developed for use in clinical practice to calculate the probability of response (model 1) and the probability of no change (model 2) for each new patient. Finally we used a combination of both models to define a recommended treatment modality for each individual patient, based on both the predicted probabilities of response and no change. We were able to identify the correct treatment (based on a comparison with the observed response) in 89% of the patients.

Conclusions  Although we strongly recommend that our results should be confirmed in other studies, our findings are the first evidence for the idea that disease (in)activity should determine which kind of treatment should be used.
Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing
Authors: Ellard S. , Hattersley A. T. , Brewer C. M. , Vaidya B.
Published: January 2005

Objective  Diagnostic molecular genetic testing for multiple endocrine neoplasia type 1 (MEN1) has been available since the identification of the MEN1 gene in 1997. Mutation screening of the MEN1 gene has been recommended for patients who meet clinical criteria for MEN1 (at least two of the following: parathyroid hyperplasia, pancreatic endocrine tumour or pituitary adenoma) and those in whom a diagnosis of MEN1 is suspected. We examined the appropriateness of these clinical criteria.

Patients and Methods  A total of 292 patients were referred for diagnostic testing. The coding region of the MEN1 gene was sequenced in 186 index cases and mutation testing was requested for 106 subjects, including 83 asymptomatic relatives.

Results  MEN1 gene mutations were identified in 68/186 index cases (37%). Twenty‐nine of the 60 MEN1 mutations reported are novel. The likelihood of finding a mutation was correlated with the number of MEN1‐related tumours (mutation detection rate of 79%, 37% and 15% in patients with three, two and one main MEN1‐related tumours; P ≤ 0·00001) and increased in the presence of a family history (mutation detection rate of 91%, 69% and 29%vs. 69%, 23% and 0% in sporadic cases with three, two or one main MEN1‐related tumours, respectively; P ≤ 0·00001). The pick‐up rate in the 83% of subjects who met proposed criteria for diagnostic testing was 42%, but in those who did not meet these criteria this fell to 0%.

Conclusions  The likelihood of finding an MEN1 mutation depends on the clinical features of the patient and their family. This large series supports present referral criteria for diagnostic mutation screening, but suggests that patients with sporadic isolated tumours rarely have MEN1 mutations.
Insulin sensitivity is impaired in adults with varying degrees of GH deficiency
Authors: Murray Robert D. , Shalet Stephen M.
Published: January 2005

Background  Severe GH deficiency (GHD) is arbitrarily defined by a peak GH (pGH) response to provocative tests of less than 3 µg/l. The impact of lesser degrees of GHD (pGH of 3–7 µg/l) in the adult is less well defined. Hypopituitary adults with severe GHD are insulin resistant as defined by the short insulin tolerance test (ITT), homeostatic model assessment (HOMA) or the hyperinsulinaemic euglycaemic clamp. Whether insulin action is impaired in the presence of lesser degrees of GHD (GH insufficiency, GHI) is not known.

Patients and Methods  We studied 30 patients with GHD (median pGH 0·5 µg/l; 0·3–1·3 µg/l), 24 with GHI (median pGH 4·0 µg/l; 3·6–4·9 µg/l), and 30 age‐, sex‐ and body mass index (BMI)‐matched controls. A short ITT was performed in a subset of 20 patients from each group and the rate constant for glucose disappearance (KITT) calculated.

Results  Both GHD and GHI hypopituitary adults were found to be insulin resistant from the KITT values compared with the control group [analysis of variance (anova) on ranks, −0·0210 vs. −0·0223 vs. −0·0261, P < 0·05]. No difference in KITT values was detected between the GHD and GHI groups. Calculation of insulin resistance using the HOMA did not detect a significant difference between groups (anova on ranks, 2·04 vs. 1·54 vs. 1·34, P = 0·40). No significant difference in the fasting glucose, insulin or IGFBP‐I levels between groups was detected. Insulin resistance estimated from the KITT correlated with the serum IGF‐I (r = −0·30, P = 0·01), and pGH level to the ITT (r = −0·31, P = 0·03). KITT also correlated with total body percentage fat mass (r = −0·28, P = 0·03). Multivariate analysis found KITT to be dependent on percentage fat mass, gender and age (r = 0·53, P = 0·0002). Insulin resistance increased in concert with percentage fat mass, age and male gender.

Conclusions  Although not detected under basal conditions, hypopituitary adults with both severe GHD and GHI are insulin resistant under conditions of insulin stimulation. This finding may be explained by the concomitant adverse changes in body composition observed in both these states of varying degrees of GHD. Insulin resistance is associated with a number of adverse cardiovascular risk factors that may place patients with GHI at risk of premature cardiovascular disease.
Free and bound plasma leptin in normal weight and obese men and women: relationship with body composition, resting energy expenditure, insulin‐sensitivity, lipid profile and macronutrient preference
Authors: Magni Paolo , Liuzzi Antonio , Ruscica Massimiliano , Dozio Elena , Ferrario Silvia , Bussi Isabella , Minocci Alessandro , Castagna Alessandra , Motta Marcella , Savia Giulio
Published: January 2005

Objective  The adipose‐borne hormone leptin circulates in free and protein‐bound forms but little information is available about their biological significance. Free leptin (FL) levels are related to changes in fat mass, whereas bound leptin (BL) appears to be associated with resting energy expenditure (REE). Our aim was to assess FL and BL levels in normal weight and obese subjects and correlate them with metabolic and nutritional variables.

Design and Patients  The partitioning of plasma leptin between FL and BL was evaluated in a population (n = 44) including both genders and different degrees of adiposity [body mass index (BMI) range 18·6–79·6 kg/m2].

Measurements  Total leptin and FL and BL concentrations were measured by fast protein liquid chromatography (FPLC) followed by radioimmunoassay (RIA). Body composition, REE, insulin sensitivity, lipid parameters associated with cardiovascular risk and macronutrient preference were also assessed.

Results  The BL/FL ratio was significantly reduced in obese subjects due to a major increase in FL compared with BL. Consequently, the gender difference of the %BL/%FL ratio present in lean subjects (35/65 in women; 65/35 in men) was lost in obese subjects. REE was negatively correlated with total leptin (P < 0·0001) and %FL (P < 0·0001), and positively with %BL (P < 0·001). Total leptin and FL were correlated with the diet carbohydrate content in all subjects.

Conclusions  FL increases with the amount of fat mass; the prevalence of FL in normal weight women in comparison to men suggests that this fraction is particularly linked to the amount of subcutaneous fat. Moreover, the correlation of BL with REE and the relationship of FL with food intake favours the view of different biological activities for the two circulating forms of leptin.
Preserved inhibitory effect of recurrent hypoglycaemia on the male gonadotrophic axis
Authors: Oltmanns Kerstin M. , Peters Achim , Kern Werner , Fehm Horst L. , Born Jan , Schultes Bernd
Published: January 2005

Objective  Hypoglycaemia‐induced decreases in male LH and testosterone concentrations are possibly mediated by activation of the hypothalamus–pituitary–adrenal (HPA) axis or by an increase in PRL. As counterregulatory stress hormone release is attenuated during recurrent hypoglycaemia, we questioned whether the gonadotrophic axis and PRL adapt similarly.

Design  We performed two consecutive hypoglycaemic clamps on day 1 and one clamp on the following day in 15 healthy men. Blood concentrations of gonadotrophins, PRL, testosterone, ACTH and cortisol were measured during the first and the third clamp, taking place at the same time of day.

Results  During hypoglycaemia, serum concentrations of LH and testosterone decreased (P < 0·003 for both), PRL, ACTH and cortisol increased (P < 0·001), and FSH remained unchanged (P = 0·90). The hypoglycaemia‐induced decreases in LH and testosterone concentrations were similar during the first and the last clamp (P > 0·28 for both) whereas the increase in PRL, ACTH and cortisol was markedly attenuated during the third clamp (P < 0·001).

Conclusions  LH and testosterone responses do not adapt to recurrent hypoglycaemia, whereas the increase in PRL is attenuated, indicating adaptation. Considering the marked decrease in the responses of PRL and the HPA axis after antecedent hypoglycaemia, the data suggest that the hypoglycaemia‐induced decreases in LH and testosterone concentrations, not adapting to recurrent hypoglycaemia, are mediated independently, probably by blood glucose itself.
Tetraplegic subjects have hyperleptinaemia with marked circadian variation
Authors: Hjeltnes Nils , De Groot Patricia , Birkeland Kåre I. , Falch Jan A. , Iversen Per O.
Published: January 2005

Objective  The disruption between the brain and the spinal cord leads to a decentralized sympathetic nervous system in people with chronic, cervical spinal cord lesions. These tetraplegic subjects are prone to disorders of energy metabolism and osteoporosis, and they experience alterations in their body composition with a relative accumulation of fat. The adipocyte‐derived cytokine leptin is a key signal in caloric intake and energy expenditure, and it might modify bone remodelling, possibly regulated by sympathetic neuronal signalling. In able‐bodied subjects leptin exhibits circadian variations, possibly mediated via sympathetic neurones. We have examined the plasma concentration of leptin among tetraplegics, to determine whether plasma leptin in these subjects exhibits circadian variations.

Measurements and Results  Blood samples were collected during a 24‐h study period from tetraplegic subjects (n = 6) and from able‐bodied controls (n = 8). Fasting, tetraplegic subjects had mean plasma concentrations of leptin about four times those of able‐bodied controls (P < 0·05). In tetraplegia, plasma leptin was negatively correlated with total lean mass (r =−0·88, P < 0·05) but correlated positively with total fat mass (r = 0·89, P < 0·05). A marked circadian variation in plasma leptin concentrations was more evident in tetraplegia than in able‐bodied controls.

Conclusion  Plasma leptin is markedly elevated and it shows more prominent circadian variations in tetraplegia compared with able‐bodied subjects. Possibly the regulation of leptin metabolism is impaired among these patients. This might distort thermogenesis and energy expenditure, thus explaining the enhanced risk of the metabolic syndrome and of osteoporosis among tetraplegic subjects.
Effect of aromatase inhibition on lipids and inflammatory markers of cardiovascular disease in elderly men with low testosterone levels
Authors: Dougherty Ryan H. , Rohrer Jacqueline L. , Hayden Douglas , Rubin Stephen D. , Leder Benjamin Z.
Published: January 2005

Objective  Although androgen replacement has been shown to have beneficial effects in hypogonadal men, there is concern that androgens may deleteriously affect cardiovascular risk in elderly men.

Design  Anastrozole is an oral aromatase inhibitor that normalizes serum testosterone levels and decreases oestradiol levels modestly in elderly men with mild hypogonadism. Thirty‐seven elderly hypogonadal men were randomized to receive either anastrozole 1 mg daily (n = 12), anastrozole 1 mg twice weekly (n = 11), or daily placebo (n = 14) for 12 weeks in a double‐blind fashion.

Patients  Men aged 62–74 years with mild hypogonadism defined by testosterone levels less than 350 ng/dl.

Measurements  Serum levels of fasting lipids, C‐reactive protein (CRP), interleukin‐6 (IL‐6), intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1) and homeostatic model assessment (HOMA) scores were measured at 4‐week intervals.

Results  Treatment with anastrozole did not significantly affect fasting lipids, inflammatory markers (IL‐6, CRP), adhesion molecules (ICAM‐1, VCAM‐1) or insulin sensitivity (HOMA). There was, however, a positive correlation between changes in serum triglycerides and changes in serum oestradiol levels (P = 0·04).

Conclusions  While short‐term administration of anastrozole is an effective method of normalizing serum testosterone levels in elderly men with mild hypogonadism, it does not appear to adversely affect lipid profiles, inflammatory markers of cardiovascular risk or insulin resistance.
Lysosome is a primary organelle in B cell receptor‐mediated apoptosis: an indispensable role of Syk in lysosomal function
Authors: He Jinsong , Tohyama Yumi , Yamamoto Ken‐ichi , Kobayashi Masahiko , Shi Yuhong , Takano Tomoko , Noda Chiseko , Tohyama Kaoru , Yamamura Hirohei
Published: January 2005

To investigate the mechanism of B cell receptor (BCR)‐mediated apoptosis, we utilized immature B cell lines, DT40 and WEHI‐231. In both cell lines, BCR‐crosslinking caused the increase in lysosomal pH with early apoptotic changes characterized by chromatin condensation and phosphatidylserine exposure. This increase was detected in c‐Abl‐deficient DT40 cells but not in Syk‐deficient cells, which corresponded to the fact that the former cells but not the latter revealed BCR‐induced apoptosis. In contrast, BCR‐crosslinking caused no apparent change in mitochondrial transmembrane potential. Therefore, the lysosomal change might be a primary event in BCR‐induced apoptosis in DT40 cells. The increased activity of cathepsin B and apoptosis‐preventing effect of a cathepsin inhibitor suggested a significant role of lysosomal enzymes in this apoptosis. By microscopic studies, lysosomes of wild‐type DT40 cells fused to BCR‐carrying endosomes became enlarged and accumulated one another. In contrast, these changes of lysosomal dynamics did not occur in Syk‐deficient cells but transfer of wild‐type Syk restored the lysosomal changes and apoptosis. These results demonstrated that the lysosomal change accompanied with the activation of lysosomal enzymes is a primary step in BCR‐crosslinking‐mediated apoptosis and Syk is responsible for this step through the fusion of BCR‐carrying endosomes to lysosomes.