bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of changes in health-related quality of life in coronary heart disease with coronary procedures and sociodemographic characteristics
Authors: Veenstra Marijke , Pettersen Kjell I , Rollag Arnfinn , Stavem Knut
Published: October 2004

Background

Few studies have focused on the association between the sociodemographic characteristics of a patient with the change in health-related quality of life (HRQOL) following invasive coronary procedures, and the results remain inconclusive. The objective of the present study was to measure the temporal changes in HRQOL of patients with coronary heart disease, and assess how these changes are associated with invasive coronary procedures and sociodemographic characteristics.

Methods

This was a prospective study of 254 patients with angina pectoris and 90 patients with acute coronary syndrome. HRQOL was assessed with the multi-item scales and summary components of the SF-36, both 6 weeks and 2 years after baseline hospitalization in 1998. Paired t-tests and multiple regression analyses were used to assess temporal changes in HRQOL and to identify the associated factors.

Results

Physical components of HRQOL had improved most during the 2 years following invasive coronary procedures. Our findings indicated that patients with angina pectoris who were younger, male, and more educated were most likely to increase their HRQOL following invasive coronary procedures. When adjusting for baseline HRQOL scores, invasive coronary procedures and sociodemographic characteristics did not explain temporal changes in patients with acute coronary syndrome, possibly due to higher comorbidity.

Conclusion

Sociodemographic characteristics should be taken into account when comparing and interpreting changes in HRQOL scores in patients with and without invasive coronary procedures.
Role of primary surgery in advanced ovarian cancer
Authors: Münstedt Karsten , Franke Folker E
Published: October 2004

Background

Major issues in surgery for advanced ovarian cancer remain unresolved. Existing treatment guidelines are supported by a few published reports and fewer prospective randomized clinical trials.

Methods

We reviewed published reports on primary surgical treatment, surgical expertise, inadequate primary surgery/quality assurance, neoadjuvant chemotherapy, interval debulking, and surgical prognostic factors in advanced ovarian cancer to help resolve outstanding issues.

Results

The aim of primary surgery is a well-planned and complete intervention with optimal staging and surgery. Surgical debulking is worthwhile as there are further effective treatments available to control unresectable residual disease. Patients of gynecologic oncology specialist surgeons have better survival rates. This may reflect a working 'culture' rather than better technical skills. One major problem though, is that despite pleas to restrict surgery to experienced surgeons, specialist centers are often left to cope with the results of inadequate primary surgical resections. Patients with primary chemotherapy or those who have had suboptimal debulking may benefit from interval debulking. A proposal for a better classification of residual tumor is given.

Conclusions

Optimal surgical interventions have definite role to play in advanced ovarian cancers. Improvements in surgical treatment in the general population will probably improve patients' survival when coupled with improvements in current chemotherapeutic approaches.
Reduced proviral loads during primo-infection of sheep by Bovine Leukemia virus attenuated mutants
Authors: Debacq Christophe , Sanchez Alcaraz Maria Teresa , Mortreux Franck , Kerkhofs Pierre , Kettmann Richard , Willems Luc
Published: October 2004

Background

The early stages consecutive to infection of sheep (e.g. primo-infection) by Bovine leukemia virus mutants are largely unknown. In order to better understand the mechanisms associated with this period, we aimed at analyzing simultaneously three parameters: B-lymphocytosis, cell proliferation and viral replication.

Results

Sheep were experimentally infected either with a wild type BLV provirus or with selected mutants among which: a virus harboring an optimalized LTR promoter with consensus cyclic AMP-responsive elements, two deletants of the R3 or the G4 accessory genes and a fusion-deficient transmembrane recombinant. Seroconversion, as revealed by the onset of an anti-viral antibody response, was detected at 3 to 11 weeks after inoculation. At seroconversion, all sheep exhibited a marked increase in the numbers of circulating B lymphocytes expressing the CD5 and CD11b cluster of differentiation markers and, interestingly, this phenomenon occurred independently of the type of virus. The net increase of the absolute number of B cells was at least partially due to accelerated proliferation as revealed, after intravenous injection of bromodeoxyuridine, by the higher proportion of circulating BrdU+ B lymphocytes. BLV proviral DNA was detected by polymerase chain reaction in the leucocytes of all sheep, as expected. However, at seroconversion, the proviral loads were lower in sheep infected by the attenuated proviruses despite similar levels of B cell lymphocytosis.

Conclusions

We conclude that the proviral loads are not directly linked to the extent of B cell proliferation observed during primo-infection of BLV-infected sheep. We propose a model of opportunistic replication of the virus supported by a general activation process of B lymphocytes.
Idiopathic isolated clitoromegaly: A report of two cases
Authors: Copcu Eray , Aktas Alper , Sivrioglu Nazan , Copcu Ozgen , Oztan Yucel
Published: October 2004

Background

Clitoromegaly is a frequent congenital malformation, but acquired clitoral enlargement is relatively rare.

Methods

Two acquired clitoromegaly cases treated in Atatürk Training Hospital, Izmir, Turkey are presented.

Results

History from both patients revealed clitoromegaly over the last three years. Neither gynecological nor systemic abnormalities were detected in either patient. Karyotype analyses and hormonal tests were normal. Abdominal and gynaecological ultrasound did not show any cystic lesion or other abnormal finding. Computerized tomography scan of the adrenal glands was normal. Clitoroplasty with preservation of neurovascular pedicles was performed for the treatment of clitoromegaly.

Conclusion

The patients were diagnosed as "idiopathic isolated" clitoromegaly. To the best of our knowledge, there has been no detailed report about idiopathic clitoromegaly in the literature.
The missed lessons of Sir Austin Bradford Hill
Authors: Phillips Carl V , Goodman Karen J
Published: October 2004

Austin Bradford Hill's landmark 1965 paper contains several important lessons for the current conduct of epidemiology. Unfortunately, it is almost exclusively cited as the source of the "Bradford-Hill criteria" for inferring causation when association is observed, despite Hill's explicit statement that cause-effect decisions cannot be based on a set of rules. Overlooked are Hill's important lessons about how to make decisions based on epidemiologic evidence. He advised epidemiologists to avoid over-emphasizing statistical significance testing, given the observation that systematic error is often greater than random error. His compelling and intuitive examples point out the need to consider costs and benefits when making decisions about health-promoting interventions. These lessons, which offer ways to dramatically increase the contribution of health science to decision making, are as needed today as they were when Hill presented them.
Menopausal status dependence of the timing of breast cancer recurrence after surgical removal of the primary tumour
Authors: Demicheli Romano , Bonadonna Gianni , Hrushesky William JM , Retsky Michael W , Valagussa Pinuccia
Published: October 2004

Introduction

Information on the metastasis process in breast cancer patients undergoing primary tumour removal may be extracted from an analysis of the timing of clinical recurrence.

Methods

The hazard rate for local-regional and/or distant recurrence as the first event during the first 4 years after surgery was studied in 1173 patients undergoing mastectomy alone as primary treatment for operable breast cancer. Subset analyses were performed according to tumour size, axillary nodal status and menopausal status.

Results

A sharp two-peaked hazard function was observed for node-positive pre-menopausal patients, whereas results from node-positive post-menopausal women always displayed a single broad peak. The first narrow peak among pre-menopausal women showed a very steep rise to a maximum about 8–10 months after mastectomy. The second peak was considerably broader, reaching its maximum at 28–30 months. Post-menopausal patients displayed a wide, nearly symmetrical peak with maximum risk at about 18–20 months. Peaks displayed increasing height with increasing axillary lymph node involvement. No multi-peaked pattern was evident for either pre-menopausal or post-menopausal node-negative patients; however, this finding should be considered cautiously because of the limited number of events. Tumour size influenced recurrence risk but not its timing. Findings resulting from the different subsets of patients were remarkably coherent and each observed peak maintained the same position on the time axis in all analysed subsets.

Conclusions

The risk of early recurrence for node positive patients is dependent on menopausal status. The amount of axillary nodal involvement and the tumour size modulate the risk value at any given time. For pre-menopausal node-positive patients, the abrupt increase of the first narrow peak of the recurrence risk suggests a triggering event that synchronises early risk. We suggest that this event is the surgical removal of the primary tumour. The later, broader, more symmetrical risk peaks indicate that some features of the corresponding metastatic development may present stochastic traits. A metastasis development model incorporating tumour dormancy in specific micro-metastatic phases, stochastic transitions between them and sudden acceleration of the metastatic process by surgery can explain these risk dynamics.
Expression of the Ghrelin Axis in the Mouse: An Exon 4-Deleted Mouse Proghrelin Variant Encodes a Novel C Terminal Peptide
Authors: Jeffery P. L. , Duncan R. P. , Yeh A. H. , Jaskolski R. A. , Hammond D. S. , Herington A. C. , Chopin L. K.
Published: October 2004

Ghrelin, an n-octanoylated 28-amino-acid peptide capable of inducing GH secretion and food intake in humans and rats, is the endogenous ligand for the GH secretagogue receptor (GHS-R). Here we describe the expression and tissue distribution of the ghrelin/GHS-R axis in the mouse. We also report for the first time the identification of a novel mouse ghrelin mRNA variant in which there is a complete deletion of exon 4. Translation of this variant mRNA yields a protein containing ghrelin and an alternative C-terminal domain with a unique C-terminal peptide sequence. RT-PCR with primers specific for mouse ghrelin was used to demonstrate the mRNA expression of the full preproghrelin transcript and the exon 4-deleted variant in multiple mouse tissues. Real-time PCR was also employed to quantitate mRNA expression of ghrelin, the novel isoform and a previously reported ghrelin gene variant, ghrelin gene-derived transcript. We also demonstrated the tissue expression of the functional GHS-R in the mouse. Immunohistochemistry, employing antibodies raised against the mature human n-octanoylated ghrelin peptide and the putative C-terminal peptide encoded by the exon 4-deleted proghrelin variant, was used to demonstrate protein expression of ghrelin and the variant in multiple mouse tissues including stomach, kidney, and reproductive tissues. The coexpression of ghrelin and its receptor in a wide range of murine tissues suggests varied autocrine/paracrine roles for these peptides. Exon 4-deleted proghrelin, a novel mouse proghrelin isoform with a unique C-terminal peptide sequence, is also widely expressed in the mouse and thus may possess biological activity in these tissues.
Transgenic Mice Overexpressing Des-Acyl Ghrelin Show Small Phenotype
Authors: Ariyasu Hiroyuki , Takaya Kazuhiko , Iwakura Hiroshi , Hosoda Hiroshi , Akamizu Takashi , Arai Yuji , Kangawa Kenji , Nakao Kazuwa
Published: October 2004

Ghrelin, a 28-amino acid acylated peptide, displays strong GH-releasing activity in concert with GHRH. The fatty acid modification of ghrelin is essential for the actions, and des-acyl ghrelin, which lacks the modification, has been assumed to be devoid of biological effects. Some recent reports, however, indicate that des-acyl ghrelin has effects on cell proliferation and survival. In the present study, we generated two lines of transgenic mice bearing the preproghrelin gene under the control of chicken β-actin promoter. Transgenic mice overexpressed des-acyl ghrelin in a wide variety of tissues, and plasma des-acyl ghrelin levels reached 10- and 44-fold of those in control mice. They exhibited lower body weights and shorter nose-to-anus lengths, compared with control mice. The serum GH levels tended to be lower, and the serum IGF-I levels were significantly lower in both male and female transgenic mice than control mice. The responses of GH to administered GHRH were normal, whereas those to administered ghrelin were reduced, especially in female transgenic mice, compared with control mice. These data suggest that overexpressed des-acyl ghrelin may modulate the GH-IGF-I axis and result in small phenotype in transgenic mice.
The Androgen Metabolite, 5α-Androstane-3β, 17β-Diol, Is a Potent Modulator of Estrogen Receptor-β1-Mediated Gene Transcription in Neuronal Cells
Authors: Pak Toni R. , Chung Wilson C. J. , Lund Trent D. , Hinds Laura R. , Clay Colin M. , Handa Robert J.
Published: October 2004

5α-Androstane-3β, 17β-diol (3βAdiol) is a metabolite of the potent androgen, 5α-dihydrotestosterone. Recent studies showed that 3βAdiol binds to estrogen receptor (ER)-β and regulates growth of the prostate gland through an estrogen, and not androgen, receptor-mediated pathway. These data raise the possibility that 3βAdiol could regulate important physiological processes in other tissues that produce 3βAdiol, such as the brain. Although it is widely accepted that the brain is a target for 5α-dihydrotestosterone action, there is no evidence that 3βAdiol has a direct action in neurons. To explore the molecular mechanisms by which 3βAdiol might act to modulate gene transcription in neuronal cells, we examined whether 3βAdiol activates ER-mediated promoter activity and whether ER transactivation is facilitated by a classical estrogen response element (ERE) or an AP-1 complex. The HT-22 neuronal cell line was cotransfected with an expression vector containing ERα, ER-β1, or the ERβ splice variant, ER-β2 and one of two luciferase-reporter constructs containing either a consensus ERE or an AP-1 enhancer site. Cells were treated with 100 nm 17β-estradiol, 100 nm 3βAdiol, or vehicle for 15 h. We show that 3βAdiol activated ER-β1-induced transcription mediated by an ERE equivalent to that of 17β-estradiol. By contrast, 3βAdiol had no effect on ERα- or ER-β2-mediated promoter activity. Moreover, ER-β1 stimulated transcription mediated by an ERE and inhibited transcription by an AP-1 site in the absence of ligand binding. These data provide evidence for activation of ER signaling pathways by an androgen metabolite in neuronal cells.
Adenovirus-Mediated High Expression of Resistin Causes Dyslipidemia in Mice
Authors: Sato Naoichi , Kobayashi Kunihisa , Inoguchi Toyoshi , Sonoda Noriyuki , Imamura Minako , Sekiguchi Naotaka , Nakashima Naoki , Nawata Hajime
Published: October 2004

The adipocyte-derived hormone resistin has been proposed as a possible link between obesity and insulin resistance in murine models. Many recent studies have reported physiological roles for resistin in glucose homeostasis, one of which is enhancement of glucose production from the liver by up-regulating gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. However, its in vivo roles in lipid metabolism still remain to be clarified. In this study, we investigated the effects of resistin overexpression on insulin action and lipid metabolism in C57BL/6 mice using an adenoviral gene transfer technique. Elevated plasma resistin levels in mice treated with the resistin adenovirus (AdmRes) were confirmed by Western blotting analysis and RIAs. Fasting plasma glucose levels did not differ between AdmRes-treated mice and controls, but the basal insulin concentration was significantly elevated in AdmRes-treated mice. In AdmRes-treated mice, the glucose-lowering effect of insulin was impaired, as evaluated by insulin tolerance tests. Furthermore, total cholesterol and triglyceride concentrations were significantly higher, whereas the high-density lipoprotein cholesterol level was significantly lower. Lipoprotein analysis revealed that low-density lipoprotein was markedly increased in AdmRes-treated mice, compared with controls. In addition, in vivo Triton WR-1339 studies showed evidence of enhanced very low-density lipoprotein production in AdmRes-treated mice. The expressions of genes involved in lipoprotein metabolism, such as low-density lipoprotein receptor and apolipoprotein AI in the liver, were decreased. These results suggest that resistin overexpression induces dyslipidemia in mice, which is commonly seen in the insulin-resistant state, partially through enhanced secretion of lipoproteins.
Heparin and Activin-Binding Determinants in Follistatin and FSTL3
Authors: Sidis Yisrael , Schneyer Alan L. , Keutmann Henry T.
Published: October 2004

Local regulation of pituitary FSH secretion and many other cellular processes by follistatin (FS) can be ascribed to its potent ability to bind and bioneutralize activin, in conjunction with binding to cell surface heparan-sulfate proteoglycans through a basic heparin-binding sequence (HBS; residues 75–86) in the first of the three FS domains. The FS homolog, FSTL3, also binds activin, but lacks any HBS and cannot associate with cell surfaces. We have used mutational analyses to define the determinants for heparin binding and activin interaction in FS and to determine the effects of conferring heparin binding to FSTL3. Mutants expressed from 283F cells were tested for cell surface and heparin affinity binding, for competititive activin binding and for bioactivity by suppression of pituitary cell FSH secretion. Replacement of the HBS or the full-length FS-domain 1 abolished cell surface binding but enhanced activin binding 4- to 8-fold. Surface binding was partially reduced after mutation of either lysine pair 75/76 or 81/82 and eliminated after mutation of both pairs. The 75/76 mutation reduced activin binding and, therefore, pituitary cell bioactivity by 5-fold. However, insertion of the HBS into FSTL3 did not restore heparin binding or pituitary-cell bioactivity. These results show that 1) the residues within the HBS are necessary but not sufficient for heparin binding, and 2) the HBS also harbors determinants for activin binding. Introduction of the full domain from FS conferred heparin binding to FSTL3, but activin binding was abolished. This implies an evolutionary safeguard against surface binding by FSTL3, supporting other evidence for physiological differences between FS and FSTL3.
Evidence that an Isoform of Calpain-10 Is a Regulator of Exocytosis in Pancreatic β-Cells
Authors: Marshall Catriona , Hitman Graham A. , Partridge Christopher J. , Clark Anne , Ma Hong , Shearer Thomas R. , Turner Mark D.
Published: October 2004

Calpain-10 (CAPN10) is the first type 2 diabetes susceptibility gene to be identified through a genome scan, with polymorphisms being associated with altered CAPN10 expression. Functional data have been hitherto elusive, but we report here a corresponding increase between CAPN10 expression level and regulated insulin secretion. Pancreatic β-cell secretory granule exocytosis is mediated by the soluble N-ethylmaleimide-sensitive fusion protein attachment receptor protein complex of synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin 1, and vesicle-associated membrane protein 2. We report, for the first time, direct binding of a calpain-10 isoform with members of this complex. Furthermore, SNAP-25 undergoes a Ca2+-dependent partial proteolysis during exocytosis, with calpain protease inhibitor similarly suppressing both insulin secretion and SNAP-25 proteolysis. Based upon these findings, we postulate that an isoform of calpain-10 is a Ca2+-sensor that functions to trigger exocytosis in pancreatic β-cells.
LBP Proteins Modulate SF1-Independent Expression of P450scc in Human Placental JEG-3 Cells
Authors: Huang Ningwu , Miller Walter L.
Published: October 2004

The cholesterol side-chain cleavage enzyme, P450scc, initiates biosynthesis of all steroid hormones. Adrenal and gonadal P450scc expression requires steroidogenic factor-1 (SF1), but P450scc expression in human placental JEG-3 cells utilizes an SF1-independent element at −155/−131 that is inactive in adrenals and gonads. We previously cloned two transcription factors, long terminal repeat binding protein (LBP)-1b and LBP-9, from JEG-3 cells. In transient transfection assays, LBP-1b activated the −155/−131 element whereas LBP-9 suppressed its LBP-1b-stimulated expression. To assess the roles of these factors on the intact P450scc gene, we stably expressed LBP-1b or LBP-9 in JEG-3 cells. All cell lines stably expressing a fusion protein of LBP-1b and enhanced green fluorescent protein increased P450scc expression, but cell lines stably expressing LBP-9 fused to enhanced green fluorescent protein either increased or decreased P450scc expression. 8-Br-cAMP induced endogenous LBP-9, but not LBP-1b expression. Glutathione-S-transferase pull-down assays showed that LBP-1b and LBP-9 can dimerize with themselves and with each other; LBP-1b residues 300–540 and LBP-9 residues 300–479 were required for dimer formation. Glutathione-S-transferase pull-down assays, bandshifts, and transient transfection assays showed that TReP-132 (another factor that can bind to −155/−131) does not interact with either LBP-1b or LBP-9, or influence their ability to induce or suppress transcription from the −155/−131 element. Gal4 transactivation assays showed that transcriptional repression activity by LBP-9 requires residues 100–200. RNAi interference of either LBP-1b or LBP-9 mRNAs decreased P450scc expression. LBP-1b is an important SF1-independent transcriptional activator stimulating P450scc expression in human placental JEG-3 cells, whereas LBP-9 modulates the action of LBP-1b, exerting both positive and negative effects.
The HeLa Cell Glucagon-Like Peptide-2 Receptor Is Coupled to Regulation of Apoptosis and ERK1/2 Activation through Divergent Signaling Pathways
Authors: Koehler J. A. , Yusta B. , Drucker D. J.
Published: October 2004

Glucagon-like peptide-2 (GLP-2) regulates proliferative and cytoprotective pathways in the intestine; however GLP-2 receptor (GLP-2R) signal transduction remains poorly understood, and cell lines that express the endogenous GLP-2R have not yet been isolated. We have now identified several expressed sequence tags from human cervical carcinoma cDNA libraries that correspond to GLP-2R nucleotide sequences. GLP-2R mRNA transcripts were detected by RT-PCR in two human cervical carcinoma cell lines, including HeLa cells. GLP-2 increased cAMP accumulation and activated ERK1/2 in HeLa cells transiently expressing the cloned human HeLa cell GLP-2R cDNA. However, the GLP-2R-induced activation of ERK1/2 was not mediated through Gαs, adenylyl cyclase, or transactivation of the epidermal growth factor receptor, but was pertussis toxin sensitive, inhibited by dominant negative Ras, and dependent on βγ-subunits. GLP-2 also induced a significant increase in bromodeoxyuridine incorporation that was blocked by dominant negative Ras. Furthermore, GLP-2 inhibited HeLa cell apoptosis induced by LY294002 in a protein kinase A-dependent, but ERK-independent, manner. These findings demonstrate that the HeLa cell GLP-2R differentially signals through both Gαs/cAMP- and Gi/Go-dependent pathways, illustrating for the first time that the GLP-2R is capable of coupling to multiple heterotrimeric G proteins defining distinct GLP-2R-dependent biological actions.
Assessment of Urinary Bone Markers for Monitoring Treatment of Osteoporosis
Authors: Worsfold Michael , Powell Diane E , Jones Teresa J W , Davie Michael W J
Published: October 2004

Background: The usefulness of urinary markers of bone turnover in monitoring therapy depends on their within-person variability compared with their responses to therapy. The aim of this study was to assess the performance of two such markers on this basis.

Methods: We measured variation, during a whole year, of cross-linked N-terminal telopeptide of collagen I (NTx) and urinary deoxypyridinoline (DPD) as ratios to creatinine concentration and after log-transformation of the ratios in untreated women stratified into three bone density classes, of which the lowest was osteoporotic. We also measured changes in bone mineral density at the lumbar spine (LSBMD) and hip (FNBMD) in untreated women with normal bones and in those with moderate osteopenia and calculated the reference change value (RCV; or least significant change) at P <0.05 for all of these measures. We made the same measurements on women treated with bisphosphonates, estrogen replacement (HRT), or calcium and examined their individual responses to treatment compared with RCV.

Results: After 12 months on bisphosphonates, LSBMD changed more than RCV (2.55%) in 47% of women compared with 44% of those on HRT and 13% of those on calcium. Response of FNBMD was less. Log NTx (RCV= −28%) responded to bisphosphonates in 78%, regardless of BMD, but less often to HRT (67%). Log DPD (RCV= −30%) responded to bisphosphonates less frequently (31% at 12 months).

Conclusions: NTx has advantages over DPD in monitoring therapy for osteoporosis when mailed urine samples are used.
Simultaneous and Sensitive Measurement of Anabasine, Nicotine, and Nicotine Metabolites in Human Urine by Liquid Chromatography–Tandem Mass Spectrometry
Authors: Xu Xu , Iba Michael M , Weisel Clifford P
Published: October 2004

Background: Determination of nicotine metabolism/pharmacokinetics provides a useful tool for estimating uptake of nicotine and tobacco-related toxicants, for understanding the pharmacologic effects of nicotine and nicotine addiction, and for optimizing nicotine dependency treatment.

Methods: We developed a sensitive method for analysis of nicotine and five major nicotine metabolites, including cotinine, trans-3′-hydroxycotinine, nicotine-N′-oxide, cotinine-N-oxide, and nornicotine, in human urine by liquid chromatography coupled with a TSQ Quantum triple quadrupole tandem mass spectrometer (LC/MS/MS). Urine samples to which deuterium-labeled internal standards had been added were extracted with a simple solid-phase extraction procedure. Anabasine, a minor tobacco alkaloid, was also included.

Results: The quantification limits of the method were 0.1–0.2 μg/L, except for nicotine (1 μg/L). Cotinine-N-oxide, trans-3′-hydroxycotinine, nicotine, and anabasine in urine were almost completely recovered by the solid-phase extraction, whereas the mean extraction recoveries of nicotine-N′-oxide, cotinine, and nornicotine were 51.4%, 78.6%, and 78.8%, respectively. This procedure provided a linearity of three to four orders of magnitude for the target analytes: 0.2–400 μg/L for nicotine-N′-oxide, cotinine-N-oxide, and anabasine; 0.2–4000 μg/L for cotinine, nornicotine, and trans-3′-hydroxycotinine; and 1.0–4000 μg/L for nicotine. The overall interday method imprecision and recovery were 2.5–18% and 92–109%, respectively.

Conclusions: This sensitive LC/MS/MS procedure can be used to determine nicotine metabolism profiles of smokers, people during nicotine replacement therapy, and passively exposed nonsmokers. This method avoids the need for a time-consuming and labor-intensive sample enrichment step and thus allows for high-throughput sample preparation and automation.
The concept of skill and the Spanish labour market
Authors: Rigby Mike , Sanchis Enric
Published: October 2004

The article first examines the different dimensions of the concept of skill and emphasizes the role of social definition in arriving at agreed versions of skill. It then goes on to examine how a consideration of these dimensions of skill can increase our understanding the Spanish labour market with particular reference to unemployment, the role of education and training agencies, the position of women in employment and the status of service-sector workers. Finally it seeks to draw out the implications of this analysis for employment policies in Spain.
Introduction: a letter from the Editor
Authors: Threlfall Monica
Published: October 2004

It is a privilege and a pleasure to have taken over as the new editor of IJIS, and I thank the Annual General Meeting of the Association of Contemporary Iberian Studies for appointing me last year. IJIS has served a key role in the dissemination of scholarly knowledge about Spain and
Portugal to universities in the United Kingdom and elsewhere in the English-speaking world since the mid-1980s. The task benefited exceedingly from the skilful editorship of my predecessor Hugh O’Donnell and from the quality of the contributions submitted. Due in part to its multidisciplinary
approach, IJIS stands out as the only academic journal devoted exclusively to the study of modern Spanish and Portuguese history, society, politics and culture. This is its great strength.
Open Forum on Spanish politics after 11 March: a Chatham House debate
Authors: Threlfall Monica , Oppenheimer Walter , Heywood Paul
Published: October 2004

This is the edited text of the first meeting that Chatham House has held exclusively on Spain, held at the Royal Institute of International Affairs on April 19th 2004. The meeting was chaired by Professor Richard Whitman, head of the European programme. The speakers analysed the 2004
parliamentary election results, gave their views on the future of Spain’s foreign relations after the Madrid bombings and the priorities of the new PSOE Government.
Book Reviews
Authors: Morgan-Tamosunas Rikki , Clarke Margaret Anne , Rebelo Luís de Sousa , Magone José M. , Longhurst Alex
Published: October 2004

Las Brigadas Internacionales en la Pantalla, Magí Crusells (2001), Universidad de Castilla-La Mancha, 516 pp., ISBN 84-8427-149-8 (Paperback)

Contemporary Portugal. Dimensions of Economic and Political Change, Stephen Syrett (ed.) (2002), Hampshire:
Ashgate, xxiii + 235 pp., ISBN 0-7546-1265-1

Portugal Contemporáneo, António Costa Pinto (ed.) (2000), Madrid: Ediciones Sequitur, xiii + 303 pp, ISBN 84-95363-04-4

A República Ontem e Hoje, António Reis (ed.) (2002), Lisboa: Edições
Colibri, 182 pp., ISBN 972-772-322-5 (Paperback)

Contemporary Spain. A Handbook, Christopher J. Ross (2002), Second edition, London: Arnold. 334 pp., ISBN 0-340-76215-2 (Paperback)
Modeling Behavioral Regularities of Consumer Learning in Conjoint Analysis
Authors: Bradlow Eric T. , Hu Ye , Ho Teck-Hua
Published: October 2004

In this note, the authors propose several extensions of the model of consumer learning in conjoint analysis that Bradlow, Hu, and Ho (2004) develop. They present a clarification of the original model, propose an integration of several new imputation rules, add new measurement metrics for pattern matching, and draw a roadmap for further real-world tests. The authors also discuss general modeling challenges when researchers want to mathematically define and integrate behavioral regularities into traditional quantitative domains. They conclude by suggesting several critical success factors for modeling behavioral regularities in marketing.
Sticky Priors: The Perseverance of Identity Effects on Judgment
Authors: Bolton Lisa E. , Reed Americus
Published: October 2004

This research examines the perseverance of identity-based judgments by exploring the effectiveness of various corrective procedures that are intended to neutralize identity effects on judgment. The authors explore these effects in a series of studies that involve different kinds of identities (e.g., parent, teenager, businessperson, environmentalist) linked to different objects and issues (e.g., Internet censorship, pollution credits, electronic books). Moreover, they test the effectiveness of various corrective procedures, including feature-based analysis, counterfactual reasoning, counteridentification, and social influence. The authors find that identity-driven thinking leads to judgment that resists change, that is, a procedural bias or “sticky prior” in favor of an initial identity-based judgment. The findings attest to both the power of identity and the efficacy of analytic and nonanalytic corrective techniques.
To Buy or Not to Buy: Response Mode Effects on Consumer Choice
Authors: Dhar Ravi , Nowlis Stephen M.
Published: October 2004

This article extends research on evaluation differences in response modes to situations in which the no-choice option is available. Prior research on choice deferral has presented the no-choice option as just another response option (i.e., an unconditional brand-choice response mode), which has its primary focus on the selection decision. However, consumers in many marketplace situations may consider the buy/no-buy decision before the selection decision (i.e., a buy/no-buy response mode). This article examines the differences in evaluation processes and choice deferral for the two response modes. The authors' theoretical account suggests that an initial focus on the buy/no-buy decision activates greater use of alternative-based evaluations, thus making purchase deferral more sensitive to the valence of shared features and category reference information than in the unconditional brand-choice mode. The authors provide process evidence for their account and consider limiting conditions.
Linking Customer Management Effort to Customer Profitability in Business Markets
Authors: Bowman Douglas , Narayandas Das
Published: October 2004

Chain-link frameworks such as the service–profit chain (SPC) are much discussed as a means to link customer profits to operational resources under the influence of vendor managers, though empirical testing to date has been limited primarily to consumer services settings. In this article, the authors adapt the SPC framework to accommodate characteristics of business markets, specifically the complex decision-making unit, strategic supplier selection, and resource allocation at the individual customer level. They also extend the SPC framework to allow for a richer description of the complex linkages between vendor effort and account profitability, namely, nonlinear linkages and differential responsiveness occasioned by customer-specific factors such as competitive context. Controlling for such factors illuminates, to some degree, why similar levels of customer management effort and/or performance can yield quite different customer profitability outcomes. The authors present an application that demonstrates how adaptation and extension of the SPC to business markets can provide vendors with (1) insights into the process that culminates in individual customer profitability and (2) useful guidelines for adapting their customer management efforts at the individual account level with an aim to improve account profitability. The results show the importance of accounting for decreasing returns to customer management effort at a given account, and they reinforce the notion of customer delight.
Response Modeling with Nonrandom Marketing-Mix Variables
Authors: Manchanda Puneet , Rossi Peter E. , Chintagunta Pradeep K.
Published: October 2004

Sales response models are widely used as the basis for optimizing the marketing mix. Response models condition on the observed marketing-mix variables and focus on the specification of the distribution of observed sales given marketing-mix activities. The models usually fail to recognize that the levels of the marketing-mix variables are often chosen with at least partial knowledge of the response parameters in the conditional model. This means that contrary to standard assumptions, the marginal distribution of the marketing-mix variables is not independent of response parameters. The authors expand on the standard conditional model to include a model for the determination of the marketing-mix variables. They apply this modeling approach to the problem of gauging the effectiveness of sales calls (details) to induce greater prescribing of drugs by individual physicians. They do not assume a priori that details are set optimally, but instead they infer the extent to which sales force managers have knowledge of responsiveness, and they use this knowledge to set the level of sales force contact. The authors find that their modeling approach improves the precision of the physician-specific response parameters significantly. They also find that physicians are not detailed optimally; high-volume physicians are detailed to a greater extent than low-volume physicians without regard to responsiveness to detailing. It appears that unresponsive but high-volume physicians are detailed the most. Finally, the authors illustrate how their approach provides a general framework.
Folate Deficiencies and Cardiovascular Pathologies
Authors: Durand Philippe , Prost Michel , Blache Denis
Published: October 2004

Although folates are widely distributed in foods, folate deficiencies may be more frequent than expected because their true availability may be impaired due to their lability under various food cooking and processing conditions. Folate deficiency is frequently observed in elderly people, smokers, alcoholics and oral contraceptive users. It is also associated with the mutation leading to the thermolabile variant of N5, 10-methylenetetrahydrofolate reductase which is observed in about 10 % of the population. In addition to the essential role of the intracellular pool of polyglutamates in de novo biosynthesis of deoxyribonucleotides which allow cell growth and division, the reduced and methylated form of folate, N5-methyltetrahydrofolate, is required for the remethylation of homocysteine to methionine. By inhibiting this remethylation pathway, folate deficiency induces homocysteine efflux into the circulation. Many studies have shown a negative correlation between plasma folate, particularly N5-methyltetrahydrofolate, and circulating homocysteine levels. In addition, folate deficiency is a major cause of hyperhomocysteinemia which is fully recognised as an independent risk factor for atherothrombosis. Epidemiological and recent experimental studies have demonstrated that folate deficiency might increase the risk of cardiovascular disease by increasing circulating homocysteine levels. Thus, the clinical efficiency of folate supplementation, especially N5-methyltetrahydrofolate, in reducing homocysteine-dependent cardiovascular risk should be evaluated.
Molecular Diagnosis of Lecithin: Cholesterol Acyltransferase Deficiency in a Presymptomatic Proband
Authors: Cirera Susanna , Julve Josep , Ferrer Immaculada , Mainou Carles , Bonet Rosa , Martín-Campos Jesús M. , González-Sastre Francesc , Blanco-Vaca Francisco
Published: October 2004

We report the molecular diagnosis of a lecithin : cholesterol acyltransferase deficiency in a 12-year old proband with a high-density lipoprotein deficiency. The increased percentage of free cholesterol in plasma and high-density lipoprotein indicated an inherited lecithin : cholesterol acyltransferase deficiency as the underlying cause. This diagnosis was confirmed by a low plasma lecithin : cholesterol acyltransferase activity and a combination of genetic analyses which demonstrated compound heterozygosity for two mutations in the lecithin : cholesterol acyltransferase gene of the proband. One was a previously unreported 2 bp deletion leading to a stop signal in codon 77 and the other a point mutation causing Arg 135 → Gln transition. To our knowledge, this is the first diagnosis of lecithin : cholesterol acyltransferase deficiency in a pre-symptomatic patient. Whether the proband will develop signs of complete lecithin : cholesterol acyltransferase deficiency or the milder form (Fish Eye Disease) is uncertain, although the former possibility is more likely. The risk of premature atherosclerosis conferred by lecithin : cholesterol acyltransferase deficiency is not well established. The proband will need to be carefully monitored in the future.
Cathepsin D and Cathepsin L Activities in Aortic Aneurysm Wall and Parietal Thrombus
Authors: Gacko Marek , Glowiński Stanislav
Published: October 2004

Deterioration of the aortic wall resulting in formation of aneurysms may be caused by increased activity of metalloproteases and lysosomal proteases. The aim of this work was the evaluation of cathepsin D and cathepsin L activities, and activities of inhibitors of cysteine cathepsins in the wall of aortic aneurysms and in parietal thrombus. Aortic aneurysms were obtained during operation. Aortas taken from organ donors and blood clots were used as control material. Activities of cathepsin D and cathepsin L in the aortic aneurysm wall and parietal thrombus were higher than in the control groups. The aneurysm wall showed lower activity of inhibitors of cysteine proteases than the normal aorta. Parietal thrombus had a higher level of cysteine protease inhibitor activity than blood clot. Cathepsin D and cathepsin L present in the aneuerysm wall and in the parietal thrombus filling the aneurysm may act on proteins determining elasticity and mechanical resistance of arteries.
The Diagnostic Value of Serum Homocysteine Concentration as a Risk Factor for Coronary Artery Disease
Authors: Dierkes Jutta , Bissé Emmanuel , Nauck Matthias , Orth Matthias , Mayer Horst , Luley Claus , Wieland Heinrich
Published: October 2004

Hyperhomocysteinemia is now regarded as an established risk factor for coronary artery disease and is present frequently in the general population. However, the diagnostic value of this risk factor relative to others has only occasionally been investigated. We compared the diagnostic value of classic risk factors and of homocysteine in a retrospective case-control study in 191 cases with angiographically established coronary artery disease and 231 healthy controls. Life style habits were assessed by a detailed questionnaire. Laboratory parameters including lipoproteins and blood lipids, homocysteine, folate, and vitamin B12 were measured and their diagnostic value compared with each other by use of receiver-operator characteristic analysis. Comparison of the receiver-operator characteristic curves revealed that homocysteine significantly discriminated between cases and control subjects. High-density-lipoprotein cholesterol, triglycerides and non-esterified fatty acids also had an area under the curve significantly different from 0.5 (the area under the curve representing no discrimination). Homocysteine was weakly related to folate, vitamin B12, age and serum creatinine concentration. We conclude that hyperhomocysteinemia is at least as important as conventional risk factors for coronary artery disease and that receiver operator characteristic analysis of homocysteine is suitable to determine patients at the highest risk for coronary artery disease. Clinical trials testing the effect of homocysteine lowering by vitamin supplementation in the prevention of coronary artery disease are needed.
The Uncertainty Associated with the Predictive Value of Test Results
Authors: Malvano Renzo , Chiecchio Andrea , Borsa Margherita , Messeri Gianni
Published: October 2004

The uncertainty associated with predictive value of test results was taken into consideration, as concerns both sampling error (related to the size of the statistical reference samples) and analytical imprecision (unavoidably involved by the measurement itself). A software package, developed for the statistical calculations, was used for the treatment of the results obtained for serum free thyroxin in euthyroid and dysthyroid subjects, assumed as an experimental model. Examples are shown for the obtainable functions predictive value vs. estimate and the related uncertainy regions. These data could help in comparing test results and, in particular, in preparing fully informative laboratory reports. The difficulties involved by an extensive application of the procedure are discussed.
Clinical Evaluation of the CARDIAC STATus™, a Rapid Immunochromatographic Assay for Simultaneous Detection of Elevated Concentrations of CK-MB and Myoglobin in Whole Blood
Authors: Schouten Yvonne , de Winter Robbert J. , Gorgels Jozef P. M. C. , Koster Rudolph W. , Adams Rob , Sanders Gerard T.
Published: October 2004

We studied the performance of the CARDIAC STATusTM, a new rapid, easy to perform qualitative whole blood bedside test for detection of elevated CK-MB and myoglobin in the emergency room. Blood samples from 182 consecutive patients with chest pain were drawn on admission and at five and seven hours after the onset of symptoms. The CARDIAC STATusTM tests were performed by coronary care unit nurses and, independently, by a trained laboratory technician. The results were compared with quantitative assays for CK-MB mass and myoglobin. At the end of the study, a second test series using a new lot number of cartridges was performed on the same blood samples because of possible elution buffer contamination. Nurses produced more false negative results than the technician (CK-MB 43 vs. 27 %, p=0.01, myoglobin 31 vs. 13 %, p<0.0001), but the technician produced more false positive myoglobin results (9.3 vs. 5.5 %, p=0.0001). In the second test series, the nurses produced significantly fewer false negative tests both for CK-MB (19 %, p<0.0001) and myoglobin (13 %, p=0.0002). The false negative rate for the technician was not different between the first and the second test series. The CARDIAC STATusTM yields a substantial number of false negative results both for CK-MB and myoglobin when compared to a quantitative assay, and therefore at present has limited value for ruling out an acute myocardial infarction.
Multicentre Evaluation of KONE Optima Analysis System
Authors: Ferrero Carlo , Modenese Annalisa , Bonini Pier Angelo , Ceriotti Ferruccio , Carobene Anna , Franzin Michela , Guder Walter G. , Hofmann Walter , Puukka Matti , Laitinen Harri , Makarovsky Vladimir , Gaidukova Natalia , Lampinen Hannu
Published: October 2004

Optima from KONE Instruments Corporation is a new selective laboratory analyzer for turbidimetric, colorimetric and ion selective electrode measurements. Overall analytical performance of Optima and reagents provided by KONE was evaluated according to ECCLS guidelines, in a multicentre study involving four different laboratories, including substrates (cholesterol, high-density lipoprotein-cholesterol, creatinine), specific proteins (transferrin, IgG), enzyme activities (γ-glutamyltransferase, alanine aminotransferase) and electrolytes (sodium, potassium, chloride).

The results obtained attest good precision of the system for all the analytes tested: the range of withinrun CV is 0.5%–4.3%, and range of between-day CV% is 0.8%–7.9% (median of four laboratories). Except for total cholesterol (5 % overestimation compared to the reference method) accuracy of measurement is adequate. Creatinine and uric acid assays were subjects of interference (defined as deviation > 10% from target value) by bilirubin and haemoglobin respectively.