bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual differences in post‐traumatic stress following post‐intimate stalking: Stalking severity and psychosocial variables
Authors: Kamphuis Jan H. , Emmelkamp Paul M. G. , Bartak Anna
Published: June 2003

Objective: Stalking can have a major psychosocial impact on its victims. Accumulating evidence suggests frequent post‐traumatic stress (PTS) reactions. The present study aimed to detail the affective and cognitive responses following post‐intimate stalking, and to assess the associations between stalking severity, person‐related psychosocial variables and symptoms of PTS.

Design: Female members (N = 131) of a Dutch nation‐wide support group were contacted by mail and completed questionnaires pertaining to their stalking history, Big Five personality traits, coping, social support, as well as PTS reactions and symptoms.

Method: The Traumatic Constellation Identification Scale was used to elucidate emotional and cognitive responses to post‐intimate stalking. To assess the associations between stalking severity indices, person‐related psychosocial variables and PTS, a regression analysis was conducted using the Impact of Events Scale as a dependent variable.

Results: Affective reactions included affective liability, fear, shame and loss. Associated maladaptive beliefs included decreased trust, increased alienation and isolation, and attributions of self‐blame. Indices of stalking severity accounted for 22% of the PTS variance, with stalking violence being the most potent predictor. Another 8% of PTS variance was associated with a passive coping reaction and (lower) openness to experience.

Conclusion: PTS following stalking was associated with both stressor‐related and person‐related variables. Risk factors for PTS included severe stalking including violence and passive coping. Prolonged post‐intimate stalking may lead to personality adaptation (i.e. becoming more closed, cautious and reserved).
CBT for psychosis: A qualitative analysis of clients' experiences
Authors: Messari Sophia , Hallam Richard
Published: June 2003

Objectives: The study explored clients' understanding and experience of cognitive behavioural therapy (CBT) for psychosis.

Design: Four inpatients and one outpatient who received CBT for psychosis were interviewed following a semi‐structured format, designed for the purpose of the study.

Method: The transcribed interviews were analysed using discourse analytic methods and focused in particular on the way clients positioned themselves in relation to their therapists. The consistencies and contradictions within clients' accounts were also examined.

Results: The following discourses are described: ‘This is truly lsquo’, ‘I am ill’, ‘CBT as an educational process’, ‘CBT as a respectful relationship between equals’, ‘CBT as a healing process’ and ‘CBT participation as compliance with the powerful medical establishment’. Three of the participants switched throughout the interview between insisting that their experiences were true and accepting that they were ill and in need of treatment. With one exception, all highlighted the value of the educational component of therapy. Two participants showed an awareness that their therapist was trying to convince them that their experiences were not true but presented this as educational rather than coercive. Most participants emphasized the value of a trusting and respectful therapeutic relationship. One client presented therapy as unhelpful and described it only in terms of his passive compliance with the powerful medical establishment.

Conclusions: The study throws light on the experience of receiving CBT for psychosis and points to some of the therapeutic process variables worthy of consideration in clinical practice and future research.
Staff reactions to self‐injurious behaviours in learning disability services: Attributions, emotional responses and helping
Authors: Jones Cheryl , Hastings Richard P.
Published: June 2003

Objectives: The aim of the study was to explore an amended version of Weiner's (e.g. Weiner, 1980) helping behaviour model potentially more specific to the context of care staff working with people with learning disabilities and challenging behaviours.

Design: Key elements of the helping model (causal attributions, affective responses, and helping behaviour) were assessed using self‐report questionnaires. In contrast to previous research, helping behaviour was conceptualized as behaviour more or less likely to reinforce challenging behaviours rather than as willingness to expend extra effort in helping. Furthermore, dimensions of positive and negative affect associated with challenging behaviour were used.

Method: A total of 123 care staff in adult services viewed one of two videos depicting a person with learning disabilities engaging in self‐injurious behaviour. Information about the behaviour's function was manipulated in order to assess reinforcing staff helping responses. Staff completed self‐report scales immediately after viewing the video material.

Results: There was very little evidence for the predicted associations between causal attributions and both positive and negative affect, and only one significant association between affect and reinforcing helping responses. Given this lack of association, we did not fully test Weiner's prediction that affect would mediate the impact of causal attributions on helping.

Conclusions: We found no evidence that Weiner's helping model can be amended to account for staff working with challenging behaviour. Close examination of previous studies also reveals very few supportive data of Weiner's original formulation. Therefore, we discuss the potential utility of alternative models in addition to methodological and conceptual issues.
Which pathological gamblers will complete treatment?
Authors: Leblond Jean , Ladouceur Robert , Blaszczynski Alex
Published: June 2003

Objective: The study examined the characteristics of pathological gamblers who complete treatment, compared with those who terminate treatment prematurely.

Design: Two comparison groups comprising treatment completers and drop‐outs.

Methods: In all, 112 pathological gamblers who undertook a cognitive treatment programme for gambling were compared on different variables.

Results: A high score on impulsivity at intake significantly differentiated those participants who dropped out from treatment completers. There were no differences on socio‐demographic and gambling‐related characteristics, depression, anxiety, problem‐solving skills and alcohol use.

Conclusions: These data implicate impulsivity as a significant factor in treatment drop‐outs.
Thought‐action fusion and schizotypy in undergraduate students
Authors: Muris Peter , Merckelbach Harald
Published: June 2003

Objective: To examine the relationship between thought‐action fusion (TAF) and schizotypy.

Method: In two separate samples of undergraduate students (Ns = 77 and 64), correlations were computed between a measure of TAF and indices of schizotypy and fantasy proneness.

Results: Positive correlations were found between TAF and various aspects of schizotypy (i.e. perceptual aberration, magical ideation, schizotypal personality characteristics, disposition to hallucinate). However, correlations between TAF and schizotypy no longer attained significance when controlling for fantasy proneness.

Conclusion: At least in the non‐clinical population, the connection between TAF and schizotypy seems to be a by‐product of fantasy‐prone individuals' tendency to report unusual experiences.
Paroxetine Controlled Release in the Treatment of Menopausal Hot Flashes
Authors: Stearns Vered , Beebe Katherine L. , Iyengar Malini , Dube Eric
Published: June 2003

Context

Standard therapy for hot flashes has been hormone replacement with estradiol or progestational agents, but recent data suggest that antidepressants inhibiting serotonin reuptake may also be effective.

Objective

To evaluate a selective serotonin reuptake inhibitor (paroxetine controlled release [CR]) in treating the vasomotor symptoms displayed by a general cross-section of menopausal women.

Design and Setting

Randomized, double-blind, placebo-controlled, parallel group study conducted across 17 US sites, including urban, suburban, and rural clinics.

Patients

A total of 165 menopausal women aged 18 years or older experiencing at least 2 to 3 daily hot flashes and must have discontinued any hormone replacement therapy for at least 6 weeks. Women were excluded if they had any signs of active cancer or were undergoing chemotherapy or radiation therapy.

Intervention

After a 1-week placebo run-in phase, study participants were randomized to receive placebo or receive 12.5 mg/d or 25.0 mg/d of paroxetine CR (in a 1:1:1 ratio) for 6 weeks.

Main Outcome Measures

Mean change from baseline to week 6 in the daily hot flash composite score (frequency × severity).

Results

Fifty-six participants were randomly assigned to receive placebo and 51 to receive 12.5 mg/d and 58 to receive 25.0 mg/d of paroxetine CR. The mean reductions in the hot flash frequency composite score from baseline to week 6 were statistically significantly greater for those receiving paroxetine CR than for those receiving placebo. By week 6, the mean daily hot flash frequency went from 7.1 to 3.8 (mean reduction, 3.3) for those in the 12.5-mg/d and from 6.4 to 3.2 (mean reduction, 3.2) for those in the 25-mg/d paroxetine CR groups and from 6.6 to 4.8 (mean reduction, 1.8) for those in the placebo group. Mean placebo-adjusted reduction in hot flash composite scores were −4.7 (95% confidence interval, − 8.1 to −1.3; P = .007) comparing 12.5-mg/d paroxetine CR with placebo; and −3.6 (95% confidence interval, −6.8 to −0.4; P = .03) comparing 25.0-mg/d paroxetine CR with placebo. This corresponded to median reductions of 62.2% for those in the 12.5-mg/d and 64.6% for those in the 25.0-mg/d paroxetine CR groups compared with 37.8% for those in the placebo group.

Conclusion

Paroxetine CR may be an effective and acceptable alternative to hormone replacement and other therapies in treating menopausal hot flash symptoms.
Novel Chromogenic Esters of ortho‐Phenylazonaphthols
Authors: Kocher C. , Weder C. , Smith P.
Published: June 2003

We have prepared the photo‐labile benzoic acid esters and the acid‐labile tert‐butoxycarbonyl esters of Sudan I and Sudan Red B, two representatives of the ortho‐phenylazonaphthol dye family, exhibiting hydroxyazo–hydrazone tautomerism with the hydrazone as the strongly favored form. The chromophores obtained are “locked” in an exclusive azo configuration and exhibit absorbance spectra which are dramatically blue‐shifted (more than 100 nm) and have strongly reduced extinction coefficients when compared to their parent chromophores. Thus, the esters of the orange dye Sudan I exhibit an absorption maximum in the ultraviolet (UV) regime, and the esters of the red dye Sudan Red B appear yellow. Depending on the nature of the ester moiety, by irradiation with UV light or by exposure to preferentially photochemically released acidic species at elevated temperatures, these esters can be reverted to the parent, highly tinctured Sudan I and Sudan Red B, respectively. Unlike conventional chromogenic systems, these dyes are compatible with melt‐processible polymers and do not require any wet‐chemical development. In polymer films comprised of these chromogenic dyes, color patterns can be produced directly by masked irradiation. We here report on the synthesis, spectral properties, and conversion kinetics of these novel chromogenic dyes, which may be potentially suitable for marking and labeling goods in a lithographic process and for optical data storage and sensing applications.
The Transient Phase of Amorphous Calcium Carbonate in Sea Urchin Larval Spicules: The Involvement of Proteins and Magnesium Ions in Its Formation and Stabilization
Authors: Raz S. , Hamilton P.C. , Wilt F.H. , Weiner S. , Addadi L.
Published: June 2003

Amorphous calcium carbonate (ACC) is a precursor phase of calcite in the formation of the sea urchin larval spicule. The goal of this research is to study the formation and stabilization mode of this transient phase. We first characterized the mineralogy of the spicules from the sea urchin Strongylocentrotus purpuratus. We then examined the role of the macromolecules extracted from the spicules at different growth stages in the formation of transient ACC in vitro.The biogenic amorphous transient phase is shown to be both structurally and compositionally different from the known stable ACC phases. It does not contain bound water, and is thus the first dehydrated ACC phase to be detected. The macromolecules that were extracted at early stages of spicule growth, when the amorphous content of the biogenic mineral is high, induced the formation of transient ACC in vitro in the presence of magnesium ions. In contrast, the macromolecules extracted at a later stage, when the spicules are completely crystalline, induced the formation of single crystals of low magnesian calcite. We therefore deduce that the macromolecules from the sea urchin larval spicules together with magnesium ions, mediate the transient formation of ACC as a precursor to calcite. These observations may well provide novel ideas for improved materials synthesis.
Medial temporal lobe dysgenesis in Muenke syndrome and hypochondroplasia
Authors: Grosso Salvatore , Farnetani Maria Angela , Berardi Rosario , Bartalini Gabriella , Carpentieri Marilisa , Galluzzi Paolo , Mostardini Rosa , Morgese Guido , Balestri Paolo
Published: June 2003

Hypochondroplasia (HCH) and Muenke syndrome (MS) are caused by mutations on FGFR3 gene. FGFR3 is known to play a role in controlling nervous system development. We describe the clinical and neuroradiological findings of the first two patients, to our knowledge, affected by HCH and MS, respectively, in whom bilateral dysgenesis of the medial temporal lobe structures has been observed. In both patients diagnosis was confirmed by molecular analysis. They were mentally normal and showed similarities in early‐onset temporal lobe‐related seizures. In both patients EEG recorded bilateral temporal region discharges. MRI detected temporal lobe anomalies with inadequate differentiation between white and gray matter, defective gyri, and abnormally shaped hippocampus. © 2003 Wiley‐Liss, Inc.
Haplotype analysis of the growth hormone releasing hormone receptor locus in three apparently unrelated kindreds from the indian subcontinent with the identical mutation in the GHRH receptor
Authors: Wajnrajch Michael P. , Gertner Joseph M. , Sokoloff Alisa S. , Ten Irina , Harbison Madeleine D. , Netchine Irène , Maheshwari Hiralal G. , Goldstein David B. , Amselem Serge , Baumann Gerhard , Leibel Rudolph L.
Published: June 2003

The growth hormone releasing hormone receptor (GHRHR) plays a critical role in growth. We identified three nominally unrelated kindreds harboring the identical mutation (E72X) in GHRHR, the gene that encodes GHRHR; all three families originated in the Indian subcontinent. Because of the relative geographic proximity of these populations, we employed haplotype analysis in the region of GHRHR to determine the likelihood that this mutation occurred in a common ancestor rather than having occurred on separate occasions in different individuals. Members of all three kindreds segregating the E72X mutation were genotyped for highly polymorphic dinucleotide repeat microsatellites in a 15.5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation. © 2003 Wiley‐Liss, Inc.
Sialic acid storage disease of the Salla phenotype in American monozygous twin female sibs
Authors: Martin Rick A. , Slaugh Rachel , Natowicz Marvin , Pearlman Kayla , Orvisky Eduard , Krasnewich Donna , Kleta Robert , Huizing Marjan , Gahl William A.
Published: June 2003

Salla disease, one of three disease phenotypes that manifest increased urinary excretion of unconjugated sialic acid, is an autosomal recessive condition caused by a mutation in SLC17A5. This gene encodes sialin, a lysosomal membrane transporter for sialic acid. Salla disease is rare outside of individuals of Finnish ancestry. In this report we describe the disorder in non‐Finnish monozygous twin siblings, the first reported American cases of Salla disease. © 2003 Wiley‐Liss, Inc.
Mutational analysis of the β‐ and δ‐sarcoglycan genes in a large number of patients with familial and sporadic dilated cardiomyopathy
Authors: Sylvius Nicolas , Duboscq‐Bidot Laetitia , Bouchier Christiane , Charron Philippe , Benaiche Abdelaziz , Sébillon Pascale , Komajda Michel , Villard Eric
Published: June 2003

Dilated cardiomyopathy (DCM) is defined by ventricular dilatation associated with impaired contractile function. Approximately one‐third of idiopathic dilated cardiomyopathy cases are due to inherited gene mutations. Mutations in the β‐ and δ‐sarcoglycan genes have been described in limb girdle muscular dystrophy and/or isolated DCM. In this study, the aim was to investigate the prevalence of these genes in isolated DCM. We screened these two genes for mutations in 99 unrelated patients with sporadic or familial DCM. The coding exon and intron‐exon boundaries of each gene were amplified by polymerase chain reaction. Mutation analyses were performed by single‐strand conformation polymorphism for the β‐sarcoglycan gene and by direct sequencing for the δ‐sarcoglycan gene. New polymorphisms, as well as already described ones, were found in these two genes, but none appeared to be responsible for dilated cardiomyopathy. We, therefore, conclude that these genes are not responsible for idiopathic isolated dilated cardiomyopathy in our population. Furthermore, based on previously published and present data, we could estimate the prevalence of δ‐sarcoglycan gene mutations to be less than 1% in idiopathic dilated cardiomyopathy, demonstrating that this gene is only marginally implicated in the disease.
Glutathione S‐transferase mu null genotype affords protection against alcohol induced chronic pancreatitis
Authors: Verlaan Mariette , te Morsche René H.M. , Roelofs Hennie M.J. , Laheij Robert J.F. , Jansen Jan B.M.J. , Peters Wilbert H.M. , Drenth Joost P.H.
Published: June 2003

Glutathione S‐transferases (GSTs) play critical roles in providing protection against electrophiles and products of oxidative stress, by catalysing the formation of glutathione conjugates and by eliminating peroxides. Most extensively studied are four main families of human cytosolic GST: GSTAlpha(A), GSTMu(M), GSTPi(P) and GSTTheta(T). Absence of GSTM1 or GSTT1 can be attributed to absence of the GSTM1 or GSTT1 gene products (null genotype) in approximately 50% and 20% of the Caucasian population, respectively. We investigated whether polymorphisms in the GSTM1, GSTT1 and GSTP1 genes modified the risk for chronic pancreatitis (CP). DNA samples were obtained from 142 adult CP patients with alcoholic (n = 79), hereditary (n = 21) or idiopathic (n = 42) origin. DNA from 204 healthy controls and from 57 alcoholic controls was analysed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in GSTs were determined by PCR, eventually followed by restriction‐fragment‐length‐polymorphism analyses in all subjects. The rates of GSTT1 and GSTP1 genotypes did not differ between CP patients and healthy controls. However, GSTM1 null genotypes were significantly less common in alcoholic CP patients (OR = 0.56, 95% CI: 0.33–0.95) as compared to healthy controls and to alcoholic controls (OR = 0.52, 95% CI: 0.26–1.04). Age‐ and sex‐adjustment bolstered our finding (adjusted OR = 0.48, 95% CI: 0.26–0.89). The frequency of the GSTM1 null genotype is significantly lower in alcoholic CP patients, especially young female. This suggests that GSTM1 null alcohol users, particularly young female, are less susceptible to CP. © 2003 Wiley‐Liss, Inc.
Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: Evidence for a founder haplotype for the most common PEX10 gene mutation
Authors: Shimozawa Nobuyuki , Nagase Tomoko , Takemoto Yasuhiko , Ohura Toshihiro , Suzuki Yasuyuki , Kondo Naomi
Published: June 2003

We, as the only diagnostic center for peroxisome biogenesis disorders (PBD) in Japan, identified a total of 31 Japanese patients with PBD during the last 20 years. They were 27 patients with Zellweger syndrome (ZS), including two sib cases, three with neonatal adrenoleukodystrophy (NALD) and one with rhizomelic type chondrodysplasia punctata (RCDP). No patient with infantile Refsum disease has been detected. These patients were genetically subdivided into complementation group A (five ZS and one NALD), B (11 ZS), C (four ZS), E (five ZS and two NALD), F (two ZS), and R (one RCDP). They were subjected to mutation analysis of PEX1, PEX2, PEX6, PEX7, and PEX10. All the 11 ZS patients with group‐B PBD had a common mutation, i.e., a homozygous 2‐base‐pair deletion in PEX10. To determine whether this highly frequent mutation is due to a founder effect, we analyzed single nucleotide polymorphisms within PEX10 among patients and Japanese controls. The mutation apparently arose once on an ancestral chromosome in the Japanese population. Based on the value of 24 PBD patients identified during the last 10 years, we estimated the prevalence of PBD in Japan to be approximately one in 500,000 births. © 2003 Wiley‐Liss, Inc.
Mechanisms of monozygotic (MZ) twinning: A possible role for the cell adhesion molecule, E‐cadherin
Authors: Bamforth Fiona , Brown Lindsay , Senz Janine , Huntsman David
Published: June 2003

Monozygotic (MZ) twins account for about one‐third of all twins. Most MZ twins arise sporadically but there are familial occurrences. The causes of MZ twinning are largely speculative but involve both genetic and environmental factors. Genetic factors could include cell adhesion molecules and factors involved in growth and differentiation of the placenta and fetus. In this study, we examine the possible role of E‐cadherin, a cell adhesion molecule, in the causation of twinning. A common polymorphism in the E‐cadherin gene reduces expression of E‐cadherin by up to 68%. We examined the E‐cadherin polymorphism in DNA extracted from placental tissue from 121 MZ twins, 99 DZ twins, and 93 singletons. There was no significant difference in the distribution of the E‐cadherin polymorphism in MZ twins although there was a slight over‐representation of homozygotes for the polymorphism in MZ twins. We conclude that there is insufficient evidence to suggest that decreased E‐cadherin expression alone is a causative factor in MZ twinning but it could be a contributory factor along with other genetic and environmental influences. © 2003 Wiley‐Liss, Inc.
Prenatal diagnosis of mosaic tetrasomy 8p
Authors: Le Bris Marie‐Josée , Marcorelles Pascale , Audrézet Marie‐Pierre , Parent Philippe , Heren Patrick , Le Guern Hélène , Herry Angèle , Morel Fréderic , Collet Michel , Férec Claude , De Braekeleer Marc
Published: June 2003

Tetrasomy 8p is a rare chromosomal disorder that has only been detected in a mosaic form. At the present time, 11 cases have been reported; their phenotype included agenesis of the corpus callosum, enlarged ventricles, minor facial dysmorphism, rib and vertebral anomalies, and mild to moderate developmental delay. To the best of our knowledge, tetrasomy 8p has never been prenatally diagnosed. This 43‐year‐old woman was referred for amniocentesis at 20 weeks' gestation because of advanced maternal age. Amniotic fluid cells were cultured according to standard techniques by the in situ method. A supernumerary chromosomal marker was detected in a single clone of cultured amniotic cells and interpreted by RHG banding as an isochromosome of the short arm of chromosome 8 (i(8p)). The ultrasound investigation at 27 weeks gestation revealed enlarged ventricles and agenesis of the corpus callosum, which were confirmed at fetal autopsy after medical termination of the pregnancy. Chromosomal analyses, including RHG banding and FISH, of several tissues showed different levels of i(8p) mosaicism. Whereas no i(8p) was detected on cytotrophoblast nor additional amniotic fluid cells, 97% and 30% of cells from long‐term cultures of placenta and lymphocytes, respectively, had the i(8p). Using DNA markers, the isochromosome 8p was interpreted as the result of a prezygotic event during maternal meiosis. Our findings suggest that the i(8p) is the subject of tissue selection. Tetrasomy 8p might be underdiagnosed during pregnancy; therefore, karyotyping on a fetal blood sample following detection of agenesis of the corpus callosum when no chromosomal abnormality has been found on the amniotic fluid cell cultures should be discussed with the parents. © 2003 Wiley‐Liss, Inc.
Reduktiver Elektronentransfer und Transport von Überschusselektronen in DNA
Authors: Wagenknecht Hans‐Achim
Published: June 2003

DNA‐vermittelte Ladungstransferprozesse lassen sich prinzipiell in oxidative Lochtransferprozesse und reduktive Elektronentransferprozesse einteilen. Im Hinblick auf die Entstehung von DNA‐Schäden lag das Hauptaugenmerk bisheriger Forschung auf der Untersuchung des oxidativen Lochtransfers oder ‐transportes. Daraus wurden wichtige Informationen beispielsweise über den Mechanismus erhalten. Dagegen hat der Transport oder Transfer von Überschusselektronen ein großes Potenzial für biomedizinische Anwendungen, hauptsächlich in der DNA‐Chiptechnologie. Zur Untersuchung der mechanistischen Details wurden in γ‐Puls‐Radiolyse‐Studien Elektronenacceptoren eingesetzt , die nicht kovalent an DNA gebunden sind. Der entscheidende Nachteil dieses experimentellen Aufbaus liegt darin, dass sowohl die Injektion als auch das Abfangen der Elektronen nicht regiospezifisch erfolgen kann. Kürzlich wurden neue photochemische DNA‐Systeme publiziert, die eine chemische und spektroskopische Untersuchung des reduktiven Elektronentransfers sowie der Wanderung von Überschusselektronen in der DNA erlauben. Basierend auf diesen Resultaten wurde ein Elektronen‐Hopping‐Mechanismus vorgeschlagen, bei dem die Pyrimidin‐Radikalanionen als intermediäre Elektronenträger auftreten.
Titelbild: The High‐Resolution Solution Structure of Epothilone A Bound to Tubulin: An Understanding of the Structure–Activity Relationships for a Powerful Class of Antitumor Agents (Angew. Chem. 22/2003)
Authors: Carlomagno Teresa , Blommers Marcel J. J. , Meiler Jens , Jahnke Wolfgang , Schupp Thomas , Petersen Frank , Schinzer Dieter , Altmann Karl‐Heinz , Griesinger Christian
Published: June 2003

Leistungsstarke Tumortherapeutika der Epothilon‐Familie wirken durch Bindung an Tubulin und Beeinflussung der Microtubuli‐Entwicklung. Bisher sind keine hochaufgelösten Strukturen von Tubulin‐Epothilon‐Komplexen verfügbar, doch ließen sich NMR‐spektroskopisch zwei größere Konformationsänderungen bei Tubulin‐gebundenem Epothilon A gegenüber freiem nachweisen. Die Strukturdaten stimmen gut mit den Resultaten chemischer Derivatisierungsexperimente überein. Diese Ergebnisse und neue NMR‐Techniken schildern Carlomagno et al. in den Zuschriften auf S. 2615–2621.
Cover Picture: The High‐Resolution Solution Structure of Epothilone A Bound to Tubulin: An Understanding of the Structure–Activity Relationships for a Powerful Class of Antitumor Agents (Angew. Chem. Int. Ed. 22/2003)
Authors: Carlomagno Teresa , Blommers Marcel J. J. , Meiler Jens , Jahnke Wolfgang , Schupp Thomas , Petersen Frank , Schinzer Dieter , Altmann Karl‐Heinz , Griesinger Christian
Published: June 2003

The powerful antitumor agents, the epothilones, bind to tubulin and interfere with microtubule dynamics. Until now, no high‐resolution structure for the tubulin–epothilone complex was available. NMR spectroscopy studies provide a high‐resolution structure of epothilone bound to tubulin and show two major conformational changes of epothilone relative to the free conformation. These results correlate well with chemical‐modification data. These findings and NMR techniques are discussed in the Communications by Carlomagno and co‐workers on pp. 2511–2517.
Hadrian's Wall National Mapping Programme—a World Heritage Site from the air
Authors: Kershaw Antonia
Published: June 2003

A survey of Hadrian's Wall is to be undertaken by English Heritage Aerial Survey as part of the National Mapping Programme (NMP). All archaeological features visible on aerial photographs as earthworks or cropmarks will be recorded and mapped. The proposed project area is a broad band along the Roman frontier works and up to 10 km wide, within which sites of all periods will be recorded. This will allow the World Heritage Site to be better understood and managed in its landscape context. Copyright © 2002 John Wiley & Sons, Ltd.
The house of the Bailiff of Sövestad, Sweden—a multi‐method geophysical case study
Authors: Lück E. , Callmer J. , Skånberg T.
Published: June 2003

The village Sövestad, 5 km north of Ystad, in southern Sweden has been known historically since 1085. Over the past 12 years a large number of finds were collected in the furrows of the field south of Sövestad. Some extraordinary finds from medieval time indicate an aristocratic site. To prepare for excavation, geophysical explorations were carried out. The aim was to accurately locate of the main house and to obtain a survey of the archaeological structures in their surroundings. The results of the geophysical investigations are very valuable. The house of the bailiff was found and also many traces of human occupation were observed. The level of modern excavation costs makes this method a valuable alternative to direct excavation as a survey method. However, for the next stage of the study of this manor site a regular excavation will be necessary.

The good results obtained so far are an inspiration for further work in the highly interesting region, including a number of manor sites in historical villages close by (e.g. Gundralöv, Katslösa and Stora Herrestad). Only the comparative approach to these aristocratic milieus can contribute substantially to our understanding of this important aspect of rural social life in the Middle Ages. Copyright © 2003 John Wiley & Sons, Ltd.
Frequent infection with a viral pathogen, parvovirus B19, in rheumatic diseases of childhood
Authors: Lehmann Hartwig W. , Knöll Antje , Küster Rolf‐Michael , Modrow Susanne
Published: June 2003

Objective

To find further evidence of the association of parvovirus B19 infection with juvenile rheumatic diseases, and to get new insights into the immunopathogenesis of these diseases.

Methods

Paired serum and synovial fluid samples from 74 children with rheumatic disease were analyzed with respect to their content of viral DNA and antibodies directed against the B19 viral proteins VP1, VP2, and NS1. Control sera from 124 children with noninflammatory bone diseases or growth retardation were also analyzed. The sequence of the viral DNA, amplified by polymerase chain reaction (PCR), was determined. IgG‐complexed virus was isolated from sera and synovial fluid by adsorption to protein A beads. The amount of free virus versus immunocomplexed virus particles was determined by quantification of the viral genomes by quantitative PCR.

Results

Twenty‐six of the 74 patients (35%) had detectable amounts of parvovirus B19 DNA in the serum (n = 22 [30%]) and/or the synovial fluid (n = 16 [22%]), whereas only 9 of the 124 control sera (7%) were positive for the viral DNA (P< 0.0001). Forty‐six patients (62%) had serum IgG against the structural proteins, indicating past infection with B19. NS1‐specific antibodies were detected in sera from 29 patients (39%) and 27 controls (22%) (P< 0.001). In addition, 3 patients (4%) showed VP2‐specific IgM. In 15 patients, viral DNA could be repeatedly detected in followup samples of serum and synovial fluid. Sequencing revealed low‐degree nucleotide variations that are in the range of genotype 1 of parvovirus B19. Immunocomplexed virus was present in varying amounts, both in the sera and in the synovial fluid samples.

Conclusion

Parvovirus B19 is frequently found in serum or synovial fluid of children with rheumatism. The rate of persistent B19 infection in these patients is significantly higher than in age‐matched controls.
A thrombin–cross‐reactive anticardiolipin antibody binds to and inhibits the anticoagulant function of activated protein C
Authors: Hwang Kwan‐Ki , Yang Cheng‐De , Yan Weihong , Grossman Jennifer M. , Hahn Bevra H. , Chen Pojen P.
Published: June 2003

Objective

To test the hypotheses that some thrombin‐reactive anticardiolipin antibodies (aCL) may bind to protein C (PC) and/or activated PC (APC), and that some of the PC‐ and APC‐reactive aCL may inhibit PC activation and/or the function of APC.

Methods

We studied the reactivity of patient‐derived monoclonal aCL with PC and APC. We examined the effects of the reactive antibodies on PC activation and on the activity of APC in plasma coagulation.

Results

Five of 5 patient‐derived, thrombin‐reactive monoclonal aCL bound to PC and APC. In addition, 1 patient‐derived monoclonal antiprothrombin antibody (APT) that displayed aCL activity and reacted with thrombin also bound to PC and APC. Of these 6 PC‐ and APC‐reactive aCL/APT, all failed to inhibit PC activation, but 1 (CL15) shortened the plasma coagulation time in the presence of exogenous APC and thus inhibited the anticoagulant function of APC.

Conclusion

Most of the thrombin‐reactive aCL in patients with antiphospholipid syndrome may bind to PC and APC. Of the APC‐reactive aCL, some (like CL15) may inhibit the anticoagulant function of APC and are thus likely to be prothrombotic in the host.
Sex effect on clinical and immunologic quantitative trait loci in a murine model of rheumatoid arthritis
Authors: Adarichev Vyacheslav A. , Nesterovitch Andrew B. , Bárdos Tamás , Biesczat Darci , Chandrasekaran Raman , Vermes Csaba , Mikecz Katalin , Finnegan Alison , Glant Tibor T.
Published: June 2003

Objective

To explore the effect of sex on clinical and immunologic traits in major histocompatibility complex–matched (H‐2d) F2 hybrid mice with proteoglycan (PG)–induced arthritis and to identify how the quantitative trait locus (QTL) on the X chromosome influences the onset QTL of another chromosome.

Methods

(BALB/c × DBA/2)F2 hybrid mice were immunized with cartilage PG, and a genome‐wide linkage analysis was performed using >200 simple sequence‐length polymorphic markers. The major clinical traits (susceptibility, onset, and severity) were assessed, and PG‐specific T and B cell responses, and the production of proinflammatory and antiinflammatory cytokines (tumor necrosis factor α, interleukin‐1 [IL‐1], IL‐6, interferon‐γ, IL‐4, IL‐10, and IL‐12) were measured in 133 arthritic and 426 nonarthritic female and male F2 hybrid mice. The major clinical and immunologic traits were linked to genetic loci, and potential linkages among these QTLs and the effect of sex were analyzed.

Results

Thirteen QTLs reported in previous studies were confirmed. Binary traits (susceptibility to arthritis) and disease onset were female specific and were identified on chromosomes 3, 7, 10, 11, 13, and X. QTLs for disease severity were mostly male specific and were located on chromosomes 1, 4, 5, 8, 14, 15, and 19. In addition, we identified 4 new QTLs for the onset of arthritis on chromosomes 3, 4, and 11, and 1 new QTL for severity on chromosome 14; all showed a strong gender association. A locus on the X chromosome interacted with a QTL on chromosome 10, and these 2 loci together seemed to control disease incidence and onset. Most of the clinical traits (QTLs) shared common regions with the immunologic traits and frequently showed a locus–locus interaction.

Conclusion

Numerous immunologic QTLs overlap with clinical QTLs, thus providing information about possible mechanisms underlying QTL function. Disease susceptibility and onset showed predominant linkage with the female sex, under the control of a QTL on the X chromosome, while the severity QTLs were more strongly linked to the male sex.
Mediation of interleukin‐1β–induced transforming growth factor β1 expression by activator protein 4 transcription factor in primary cultures of bovine articular chondrocytes: Possible cooperation with activator protein 1
Authors: Andriamanalijaona R. , Felisaz N. , Kim S.‐J. , King‐Jones K. , Lehmann M. , Pujol J.‐P. , Boumediene K.
Published: June 2003

Objective

Interleukin‐1 (IL‐1) and transforming growth factor β1 (TGFβ1) play major roles in osteoarticular diseases, exerting opposite effects on both the catabolism and anabolism of cartilage matrix. Previous findings suggest that IL‐1 and TGFβ1 could function in a feedback interaction. However, the effect exerted by IL‐1 on expression of TGFβ by articular chondrocytes is, so far, poorly understood. The present study was carried out to determine the influence of IL‐1β on the expression of TGFβ1 by bovine articular chondrocytes (BACs) in primary culture.

Methods

BAC primary cultures were treated with IL‐1β, and TGFβ1 messenger RNA (mRNA) steady‐state levels and protein expression were measured by real‐time reverse transcription–polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively. Transient transfection of TGFβ1 gene promoter constructs was performed to delineate the DNA sequences that mediate the IL‐1β effect. Electrophoretic mobility shift assays (EMSAs) and supershift analysis were used to characterize the transcription factors binding to these sequences.

Results

Cultured BACs responded to IL‐1β exposure by exhibiting an increase of TGFβ1 expression at both the mRNA and protein levels. The effect was found to be mediated by a major 80‐bp sequence located between −732 and −652 upstream of the transcription initiation site. EMSA and supershift analysis revealed that the transcription factors activator protein 4 (AP‐4) and AP‐1 specifically bound to the −720/−696 part of this sequence under IL‐1β treatment. Overexpression of AP‐4 in the BAC cultures resulted in stimulation of the transcriptional activity of the −732/+11 TGFβ1 promoter construct through the same IL‐1β–responsive element.

Conclusion

IL‐1β induces an increase of TGFβ1 in articular chondrocytes through activation of AP‐4 and AP‐1 binding to the TGFβ1 gene promoter. These findings may help us understand the role of IL‐1β in the disease process. Notwithstanding its deleterious effect on cartilage, IL‐1 could initiate the repair response displayed by injured cartilage in the early stages of osteoarthritis through its ability to enhance TGFβ1 expression by local chondrocytes.
Epidermal growth factor up‐regulates expression of transforming growth factor β receptor type II in human dermal fibroblasts by phosphoinositide 3‐kinase/Akt signaling pathway: Resistance to epidermal growth factor stimulation in scleroderma fibroblasts
Authors: Yamane Kenichi , Ihn Hironobu , Tamaki Kunihiko
Published: June 2003

Objective

Transforming growth factor β receptors (TGFβRs) are known to be expressed at high levels in several fibrotic diseases, including systemic sclerosis. In the present study, we investigated the mechanism of up‐regulation of TGFβR expression.

Methods

The levels of expression of TGFβR type II (TGFβRII) messenger RNA (mRNA), with or without stimulation by epidermal growth factor (EGF), were evaluated by Northern blot analysis, and the protein levels were determined by immunoblotting. The transcription activity of the TGFβRII gene was examined with luciferase assays using the −1670/+35 TGFβRII promoter luciferase construct.

Results

EGF up‐regulates the expression of TGFβRII mRNA and protein in human dermal fibroblasts. Actinomycin D, an RNA synthesis inhibitor, significantly blocked the EGF‐mediated up‐regulation of TGFβRII mRNA expression, whereas cycloheximide, a protein synthesis inhibitor, did not block this up‐regulation. In addition, EGF treatment did not significantly affect the TGFβRII mRNA half‐life. EGF‐mediated induction of TGFβRII expression was inhibited by treatment of fibroblasts with the selective phosphoinositide 3‐kinase (PI 3‐kinase) inhibitors wortmannin or LY294002, and Akt inhibitor also blocked EGF‐induced expression of TGFβRII. In addition, EGF induced TGFβRII promoter activity, and this induction was significantly blocked by wortmannin, LY294002, or Akt inhibitor. Cotransfection with a dominant‐negative mutant of p85 (the regulatory component of PI 3‐kinase) or Akt significantly reduced the induction of TGFβRII promoter activity by EGF. Moreover, a constitutive active form of p110 (a catalytic component of PI 3‐kinase) induced TGFβRII promoter activity. In addition, scleroderma fibroblasts expressed increased levels of TGFβRII but did not show further up‐regulation of TGFβRII expression by EGF.

Conclusion

These results indicate that EGF‐mediated induction of TGFβRII expression occurs at the transcription level, does not require de novo protein synthesis, and involves the PI 3‐kinase/Akt signaling pathway, and that abnormal activation of EGF‐mediated signaling pathways, including PI 3‐kinase or Akt, might play a role in the up‐regulation of TGFβRII in scleroderma fibroblasts.
Influence of stimulatory and suppressive DNA motifs on host susceptibility to inflammatory arthritis
Authors: Zeuner Rainald A. , Verthelyi Daniela , Gursel Mayda , Ishii Ken J. , Klinman Dennis M.
Published: June 2003

Objective

To examine whether systemic administration of immunostimulatory and immunosuppressive oligodeoxynucleotides (ODNs) alter host susceptibility to inflammatory arthritis.

Methods

Normal BALB/c mice were treated systemically with CpG ODNs or suppressive ODNs, and then challenged intraarticularly with CpG DNA. The onset and magnitude of the resulting inflammatory response was monitored.

Results

Systemic delivery of CpG ODNs significantly increased susceptibility to local inflammation, whereas systemic treatment with suppressive ODNs reduced this susceptibility. CD11c+ cells played a key role in mediating host sensitivity to arthritis. These cells were the dominant source of tumor necrosis factor α production in CpG‐stimulated animals and transferred resistance to arthritis from mice treated with suppressive ODNs.

Conclusion

Systemic exposure to immunostimulatory and immunosuppressive DNA influences host susceptibility to local inflammatory challenge. Current findings raise the possibility that suppressive ODNs may be useful in the prevention/treatment of proinflammatory diseases.
Long‐term anti–tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion
Authors: Straub Rainer H. , Pongratz Georg , Schölmerich Jürgen , Kees Frieder , Schaible Thomas F. , Antoni Christian , Kalden Joachim R. , Lorenz Hanns‐Martin
Published: June 2003

Objective

New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti‐TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti‐TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic–pituitary–adrenal (HPA) axis. This longitudinal anti‐TNF therapy study was designed to assess these effects in RA patients.

Methods

RA patients were given 5 infusions of anti‐TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin‐6 (IL‐6), adrenocorticotropic hormone (ACTH), 17‐hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients.

Results

Upon treatment with anti‐TNF, we observed a fast decrease in the levels of serum IL‐6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti‐TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long‐term anti‐TNF therapy.

Conclusion

Long‐term therapy with anti‐TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who have not previously received prednisolone treatment. These changes are indicative of normalization of the HPA axis and must therefore be considered as evidence of an additional antiinflammatory influence of anti‐TNF treatment in patients with RA.
Promising outcome of a hip school for patients with hip dysfunction
Authors: Klässbo Maria , Larsson Gerry , Harms‐Ringdahl Karin
Published: June 2003

Objective

To evaluate, in an exploratory study, a hip school led by physical therapists for patients with hip dysfunction including pain.

Methods

Physicians in primary care and orthopedic units consecutively recruited patients by residential area to a treatment group (T group; n = 77) and a control group (C group; n = 68), mean age 61.8 years, 59 men, 86 women. Ninety‐nine of the 145 subjects had radiologic hip osteoarthritis. Outcome measures were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Nottingham Health Profile (NHP).

Results

After hip school (6 months) the T group showed greater reduction on the subscales of pain and activity limitations (WOMAC) than the C group. The subscales sleep disturbances, pain, and physical mobility (NHP) showed improvement for the T group compared with at start. The results for the T group persisted after an additional 6 months.

Conclusion

A hip school may reduce pain and activity limitations and improve health‐related quality of life for patients with hip dysfunction including pain.
Development of a work instability scale for rheumatoid arthritis
Authors: Gilworth Gill , Chamberlain M. Anne , Harvey Andrew , Woodhouse Amanda , Smith Jacqui , Smyth M. Glyn , Tennant Alan
Published: June 2003

Objectives

To explore the concept of work instability (WI), a state in which the consequences of a mismatch between an individual's functional abilities and the demands of his or her job could threaten continuing employment if not resolved, in people with rheumatoid arthritis (RA). To develop the Work Instability Scale (WIS).

Methods

WI in people with RA was explored through qualitative interviews, which were then used to generate items for the WIS.

Results

Through Rasch analysis and validation against a gold standard of expert vocational assessment, a short 23‐item, self administered, RA WIS was developed.

Conclusion

The WIS can be scored in 3 bands indicating low, medium, and high risk of work disability.