bluuebunny/crossref_metadata_2025 huggingface dataset:
Local developmental state and order in China's urban development during transition
Authors: Zhu Jieming
Published: June 2004

Rules and order in urban construction, and thus the relationship between the market and the state, are a fundamental issue for urban development. In China, a transition economy, marketization has been actively promoted under the economic reforms to replace central‐planning and has contributed significantly to the subsequent dynamic urban growth. However, the role of the state in defining an institutional framework for the market is lagging behind. Fiscal deficiency in conjunction with a pro‐growth position undermines the capacity of the local developmental state to exercise effective developmental controls. Without effective state enforcement of rules, market order does not emerge when uncertainty pervades the marketplace. The phenomenon of urban villages and the case of Luohu's redevelopment clearly show that the absence of the state both in constructing the market and as a third‐party gives rise to the logic of the commons or quasi‐commons in the land development market. Inferior and suboptimal developments ensue.

En construction urbaine, les règles et la discipline, donc le rapport entre marché et État, constituent un aspect fondamental de l'aménagement des villes. Dans l'économie de transition chinoise, la commercialisation – activement stimulée par des réformes économiques visant à remplacer la planification centrale – a énormément contribuéà la dynamique de la croissance urbaine. Toutefois, le rôle de l'État dans la définition du cadre institutionnel du marché ne suit pas le rythme. Carences fiscales associées à une position favorable à la croissance empêchent l'État local moteur de développement de contrôler efficacement la croissance. Sans une application étatique effective des règles, il ne naït pas de discipline de marché, l'incertitude régnant. Le phénomène des villages urbains et le cas du réaménagement de Luohu montrent clairement que l'absence de l'État, tant dans l'élaboration du marché qu'en tant que tiers, introduit la logique des terrains communaux ou quasi‐communaux sur le marché de l'aménagement foncier. Il en résulte des équipements de second ordre, inférieurs à la qualité optimale.
The glass menagerie of urban governance and social cohesion: concepts and stakes/concepts as stakes
Authors: Maloutas Thomas , Pantelidou Malouta Maro
Published: June 2004

Social goals and social action are increasingly framed by a host of ambiguously egalitarian notions. The ambiguity of notions like ‘social cohesion’ originates principally in the tentative accommodation of competition and social justice that former radical approaches considered in fundamental contradiction. The social cohesion terminology has become part of political realism and the question is whether such notions are or could be fuelling practices that promote social justice, overcoming the ambiguity/contradiction of the different/competing interpretations nebulously juxtaposed in their fluid definition. This article comments on interrelated ambiguities in the content of social cohesion, governance and tolerance starting with a reformulated goal (social cohesion) which necessitates new means of implementation (‘new governance’) that entail the dominance of non‐conflictual social relations (tolerance). Social cohesion, governance and tolerance are Janus‐faced concepts, full of restrictions and contradictions but also full of possibilities related to the mobilizing potential of their inherently positive meaning. Social cohesion and governance would become real stakes if radical discourse and politics tried to invest them with content and meaning that would effectively transgress their legitimating function of conservative social regulation, and create massive demand for more social justice both in terms of redistributive justice and of democracy.

L'action et les objectifs sociaux sont de plus en plus conditionnés par une foule de notions soi‐disant égalitaires. L'ambiguîté de concepts tels que la cohésion sociale émane surtout de l'essai d'adaptation entre concurrence et justice sociale, considérées précédemment par les approches radicales comme fondamentalement contradictoires. La terminologie de la cohésion sociale s'est peu à peu intégrée au réalisme politique, mais il s'agit de savoir si de telles notions nourrissent ou pourraient nourrir des pratiques favorables à la justice sociale, en éliminant la contradiction/ambiguîté des interprétations diverses/concurrentes vaguement juxtaposées dans le flou des définitions. L'article étudie des ambiguïtés corrélatives contenues dans cohésion sociale, gouvernance et tolérance, en partant d'un objectif reformulé (cohésion sociale) nécessitant des moyens originaux de mise en uvre (‘nouvelle gouvernance’) porteurs de relations sociales non‐conflictuelles (tolérance). Ces trois notions à deux visages sont empreintes de restrictions et contradictions, mais aussi de possibilités liées au potentiel mobilisateur de leur sens intrinsèquement positif. Cohésion sociale et gouvernance deviendraient des intérêts réels si le discours radical et la politique s'efforçaient de leur donner des contenus et significations qui transgresseraient effectivement leur fonction justificative de régulation sociale conservatrice, et créeraient une demande massive pour davantage de justice sociale en termes de justice redistributive et de démocratie.
New Regionalism contested: some remarks in light of the case of the Mezzogiorno of Italy
Authors: Rossi Ugo
Published: June 2004

This article attempts to re‐consider the debate that has recently developed around the so‐called New Regionalism with reference to the studies regarding the emergence of a ‘new’ competitive Mezzogiorno of Italy. The first two sections of the article are devoted to a critical analysis of the literature on the New Mezzogiorno. It is argued that this literature has, on the one hand, fruitfully called attention to the emerging experiences of regional development in the South of Italy; yet, on the other hand, in throwing positive light on local economic development in the South of Italy, it has underestimated the more troublesome phenomena that these experiences reveal, especially from the point of view of capital‐labour relations. The third section of the article is devoted to showing how the limits and contradictions of the new regionalist approach to local development are reflected in the new course of regional policy that has been embraced in Italy in recent years. Finally, in the concluding section, the article argues for a shift towards a critical approach to research on the Italian southern regions and local productive systems.

L'article propose une relecture du débat qui s'est récemment développé autour du Nouveau Régionalisme,è partir des travaux concernant l'émergence d'un ‘nouveau’ Mezzogiorno compétitif en Italie. Les deux premières sections de l'article proposent une analyse critique de la littérature sur le Nouveau Mezzogiorno. D'un côté, celle‐ci a permis, de façon fructueuse, d'attirer l'attention sur l'émergence d'expériences de développement régional dans le Sud italien. De l'autre, en jetant une lumière positive sur le développement économique local dans le Sud de l'Italie, cette littérature a sous‐estimé les aspects les plus problématiques que ces expériences révèlent, en particulier du point de vue des relations entre capital et travail. La troisième partie montre combien le nouveau cours pris par les politiques régionales en Italie reflète les limites et les contradictions de l'approche néo‐régionaliste du développement local. En conclusion, l'article se penche sur la nécessité de développer une approche critique à la recherche sur les régions et les systèmes productifs locaux en Italie du Sud.
Port Cities
Authors: Silverstein Paul A.
Published: June 2004

Chris Brenner Work in the New Economy: Flexible Labor Markets in Silicon Valley

Mary Chayko Connecting: How We Form Social Bonds and Communities in the Internet Age

David N. Pellow and Lisa Sun‐Hee Park The Silicon Valley of Dreams: Environmental Justice, Immigrant Workers, and the High‐Tech Global Economy
Caspase‐mediated cleavage and activation of LIM‐kinase 1 and its role in apoptotic membrane blebbing
Authors: Tomiyoshi Go , Horita Yuji , Nishita Michiru , Ohashi Kazumasa , Mizuno Kensaku
Published: June 2004

Actin cytoskeletal reorganization plays a critical role in cell morphological changes, including membrane blebbing during apoptosis. LIM‐kinase 1 (LIMK1) regulates actin cytoskeletal reorganization by phosphorylating and inactivating cofilin, an actin filament‐depolymerizing and ‐severing protein. We now report that LIMK1 is cleaved and activated during anti‐Fas antibody‐induced apoptosis in Jurkat T cells. The cleavage and activation of LIMK1 were blocked by z‐DEVD‐fmk, an inhibitor for caspase‐3 or related proteases, thus indicating that caspase‐3‐like proteases are responsible for LIMK1 cleavage. The caspase‐mediated cleavage of LIMK1 occurs at Asp‐240, a site at the N‐terminal side of the protein kinase domain, which leads to the production of an N‐terminally truncated, constitutively active LIMK1 fragment. Expression of an N‐terminally truncated LIMK1 fragment, LIMK1(241–647), induced membrane blebbing in both Jurkat and HeLa cells, with an extent significantly higher than that of wild‐type LIMK1. Down‐regulation of endogenous LIMK1 expression by small interfering RNA (siRNA) reduced the Fas‐induced membrane blebbing in Jurkat cells. These findings suggest that caspase‐mediated cleavage and activation of LIMK1 play a role in the membrane bleb formation during apoptosis.
Ethical issues in social research: difficulties encountered gaining access to children in hospital for research
Authors: Stalker K. , Carpenter J. , Connors C. , Phillips R.
Published: June 2004

Background  This paper recounts the difficulties experienced when the authors sought access to children in hospital for social research interviews. These were part of a 2‐year study, funded by the Joseph Rowntree Foundation, aiming to explore the numbers, circumstances and experiences of children who spend prolonged periods in health care settings.

Methods  As the intention was to carry out ‘guided conversations’ with 24 young people in various different NHS locations, permission to do so was sought from a multi‐site research ethics committee (MREC), and from several local research ethics committees (LRECs). Agreement was then necessary from NHS trusts, which were asked to nominate a liaison person to help identify and recruit children to the study. Consent was also required from individual parents and children. A series of unexpected delays encountered during this process are discussed in some detail. Eventually a sample of 15 children was achieved.

Discussion  The second part of the paper locates this experience within a wider context, noting that similar difficulties gaining access to children in NHS settings have recently been reported by other social researchers. Several possible reasons for this trend are identified and discussed. These relate to the role of MRECs and LRECs in screening social research proposals, recently implemented legislation about data protection, heightened concerns within the NHS about confidentiality and consent, and increasing awareness of the risk of child abuse in health care settings.

Conclusion  Finally, some suggestions for facilitating the access process are discussed. They include the sensitive and appropriate application of research governance frameworks to social research – including studies within health care settings. Ethical considerations and adequate protection of children are vital but, the authors argue, wherever possible children themselves should be encouraged to decide whether or not to participate in research. In addition, unnecessarily complex access procedures may adversely affect research outcomes.
Reviewing measures of outcome: reliability of data extraction
Authors: Haywood K. L. , Hargreaves J. , White R. , Lamb S. E.
Published: June 2004

Rationale, aims and objectives  Although there is wide acceptance of the necessary domains for the evaluation of measures of health outcome, there has been little development or evaluation of methods of data extraction, such as checklists. This study aimed to assess the inter‐rater reliability of data extraction from published articles using a new electronic database developed  for structured reviews  of health outcome  measures.

Methods  Domains considered important in the evaluation of measures of health outcome provided the foundation for a checklist for data extraction using a new electronic database. The database utilized Microsoft Access 2000 software (Microsoft Corporation, 2000). Following training, three independent reviewers extracted data from seven selected articles using the electronic database, and assessed article and measure quality against pre‐defined criteria. Data extraction was compared for consistency and item content. Inter‐reviewer agreement for categorical data was assessed by multiple kappa correlation.

Results  Analysis demonstrated strong agreement between reviewers for all aspects of data extraction. However, lack of clarity in published articles affected the ability to clearly identify measures of outcome.

Conclusions  The high level of inter‐reviewer agreement supports the use of multiple trained reviewers in data extraction for reviews of measures of outcome using the checklist and Access software described. The electronic database supports standardized data extraction from published articles, benefiting from the combination of data extraction and data entry in a single step. Adaptation of the database to support structured reviews of measures of outcome adopted in the evaluation of other health states is proposed.
Evaluating the effectiveness of asthma treatment in real‐life practice
Authors: Pearson Mike , Barnes Neil , Thomas Mike , Tate Helen , Simnett Sarah
Published: June 2004

Rationale, aims and objectives  The randomized controlled trial (RCT) is considered the gold standard methodology for determining the efficacy and tolerability of new treatments. However, RCTs cannot provide information on the effectiveness of interventions as they are used in real life. This study was conducted to investigate the effectiveness of montelukast, a leukotriene receptor antagonist, in the real‐world management of asthma, through a large‐scale, retrospective, observational study: the National Montelukast Survey.

Methods  In order to ensure a robust methodology for the National Montelukast Survey we performed three pilot studies involving a total of almost 400 patients. During the pilots, the design of the study was extensively modified from a simple prescriber questionnaire used in the first pilot to the ‘triangulated’ methodology encompassing the perspectives of patient, prescriber and independent observer used in the National Montelukast Survey. Good levels of interobserver agreement confirmed the robustness of the final methodology.

Conclusions  Achieving a robust methodology was dependent on the extensive piloting. It is possible to collect reliable observational data relating to treatment outcomes. We believe our methods are likely to have more widespread applicability and offer a potential improvement over postmarketing surveillance.
Multi‐item outcome measures for lateral ligament injury of the ankle: a structured review
Authors: Haywood K.L. , Hargreaves J. , Lamb S.E.
Published: June 2004

Objective  To identify and review evidence relating to the measurement properties of published multi‐item outcome measures for the conservative management of lateral ligament injuries of the ankle.

Methods  Systematic literature searches were used to identify measures, which were then assessed against pre‐defined criteria relating to development, item content, reliability, validity and responsiveness.

Results  Seven disease‐specific measures of ankle status [Ankle Joint Functional Assessment Tool, Clinical Trauma Severity Score, Composite Inversion Injury Scale, Kaikkonen Functional Scale (KFS), Karlsson Ankle Function Score (KAFS), Olerud and Molander Ankle Score (OMAS), and the Point System] and two generic measures of health (McGill Pain Questionnaire, Sickness Impact Profile) met the review inclusion criteria. While all measures had been used in acute injuries, only two had also been applied during later stages of recovery (>6 months). The studies covered a comprehensive range of graded ligament injuries. Expert opinion dominated item generation for all measures. All measures lack evidence of test‐retest or internal consistency reliability in patients with ankle sprain. Several measures were assessed for validity through comparison with other measures, but there was limited evidence of construct validity and no formal assessment of responsiveness for any measure.

Conclusion  The disappointing lack of evidence for measurement properties suggests that any measure should be used with caution until appropriate evidence is provided. On the basis of limited evidence, the KFS offers the most promising approach to a combined clinician‐ and patient‐assessment of ankle function, and the KAFS or OMAS if a patient‐assessed evaluation of function is required.
Evidence‐based practice – an incomplete model of the relationship between theory and professional work
Authors: Hancock Helen C. , Easen Patrick R.
Published: June 2004

Rationale, aims and objectives  Current day realities of diminishing resources, reductions in spending and organizational change within health care systems have resulted in an increased emphasis on a multidisciplinary team approach to quality patient care. The movement of nursing towards more autonomous practice combined with the current trend towards ‘evidence‐based practice’ in health care demands increased accountability in clinical decision making. This paper focuses on one aspect of nurses’ clinical decision making within the demands of evidence‐based practice and cardiac surgery. In this field recent advances, combined with increasing demands on health care institutions, have promoted early extubation of post‐operative cardiac patients. While this remains a medical role in many institutions, an increasing number of intensive care units now consider it as a nursing role.

Method  This paper explores the realities of nurses’ clinical decision making through a discussion of current practice in the extubation of patients following cardiac surgery. In addition, it considers the implications of current practice for both nurse education and the continued development of clinical nursing practice.

Conclusion  The findings indicate that evidence‐based practice appears to be an incomplete model of the relationship between theory and professional work.
Provider‐perceived barriers and facilitators for ischaemic heart disease (IHD) guideline adherence
Authors: Powell‐Cope Gail M. , Luther Stephen , Neugaard Britta , Vara John , Nelson Audrey
Published: June 2004

Rationale, aims and objectives  Clinical practice guidelines have become a standard way of implementing evidence‐based practice, yet research has shown that clinicians do not always follow guidelines.

Method  As part of a larger study to test the effects of an intervention on provider adherence to ischaemic heart disease (IHD) guidelines, we conducted five focus groups at three Veterans Administration Medical Centers with 32 primary care providers, cardiologists, and internists to identify key barriers and facilitators to adherence of the guidelines. Using content analysis, responses were grouped into categories.

Results  The main perceived advantages of using the IHD guidelines were improvements in quality and the cost of care. Perceived barriers were the lack of ability of guidelines to manage the care of any one individual patient, the difficulty of accessing guidelines, and high workloads with many complex patients. While providers agreed on the benefits of aspirin, beta‐blockers and angiotensin converting enzyme inhibitors, barriers for use of these medications were lack of consensus about contraindications, difficulty in providing follow‐up during medication titration, and lack of patient adherence. Sources of influence for guideline use were: professional cardiology organizations, colleagues, mainly cardiologists, and key cardiology journals. However, most providers acknowledged that following guidelines was a personal practice decision.

Conclusions  While results validated the influences of using clinical practice guidelines, our results highlight the importance of ascertaining guideline‐specific barriers for building effective interventions to improve provider adherence. An advisory panel reviewed results and, using a modified nominal group process, chose implementation strategies targeting key barriers.
National Clinical Sentinel Audit of Evidence‐based Prescribing for Older People
Authors: Batty G. M. , Grant R. L. , Aggarwal R. , Lowe D. , Potter J. M. , Pearson M. G. , Jackson S. H. D.
Published: June 2004

Objectives  To audit the performance of hospitals in evidence‐based prescribing.

Setting  All hospitals in England were invited to participate. The audit was completed in 62 hospitals.

Subjects  Prescribing and clinical data were collected on 100 consecutive medical inpatients aged ≥ 65 years at each site, enabling evaluation of eight prescribing indicators before and after intervention. The data were collected using a specifically designed database.

Interventions  The results of the first audit were available immediately from the software and a national report with locally identifiable information was returned to hospitals. Hospitals were encouraged to design and deliver their own intervention strategy. A questionnaire was sent to all hospitals to document prioritization of indicators.

Results  Generic names were used for 36 061 (82.6%) in 1999 and 39 188 (86.4)% in 2000. In 1999, 50% (3074) of patients had documentation of allergy status. This increased to 60% (3684) in 2000. For 21.2% of patients prescribed paracetamol in 1999 and 18.1% in 2000, the prescription was written such that it was possible to exceed the maximum recommended dose of 4 g in 24 hours. Long‐acting hypoglycaemic drugs were prescribed to 29 patients in 1999 and 20 patients in 2000. Anti‐thrombotics were used appropriately for 54% (520/966) of patients in atrial fibrillation in the first audit and 57% (579/1019) in the second audit. The appropriate use of aspirin increased from 91% (595/651) to 94% (725/772) and the appropriate use of benzodiazepines dropped from 49% (537/1088) to 47% (460/966) between the audits. For three indicators, the allocating of a high priority translated into a bigger improvement between the audits.

Conclusions  Local ownership of data and the quality improvement process, and provision of national benchmarking data did not result in a significant improvement in prescribing in the second audit.
Adjusting for publication bias: modelling the selection process
Authors: Preston Carrol , Ashby Deborah , Smyth Rosalind
Published: June 2004

Rationale, aims and background  Systematic review with meta‐analysis, a statistical technique for combining results of several studies, is progressively being used to guide decisions in medicine. Publication bias is acknowledged as a threat to the validity of systematic reviews and its existence may lead to inappropriate decisions about patient management or health policy. It is said to occur when the results of research available in the literature are not representative of the totality of all research. The selection mechanism that causes publication bias is complex, yet despite an extensive literature of empirical research identifying risk factors for publication, little work has been done to improve models of selection.

Methods  Methods that adjust combined meta‐analytic estimates for publication bias are compared and applied to a systematic review of oral rehydration solution in the treatment of dehydration. Within a weighted distributions framework models of the selection process are considered and developed further.

Conclusions  Weighted distributions offer a flexible approach that allows the potential to modify the selection function to incorporate other factors. Methods that adjust combined estimates should not be used to provide an alternative answer but to consider the robustness of the combined estimate to publication bias.
Attitudes and knowledge of primary care professionals towards evidence‐based practice: a postal survey
Authors: O'Donnell Catherine A.
Published: June 2004

Objectives  To describe the attitudes, awareness and use of evidence across key professional groups working in primary care.

Methods  A postal questionnaire was sent to all lead/chairs, general managers, clinical governance leads, lead nurses, lead pharmacists and public health practitioners working in local health care cooperatives in Scotland.

Results  289 (66.1%) health care professionals responded, ranging from 51% of general managers to 80% of lead nurses. All professional groups supported evidence‐based practice. General practitioners (GPs) were less likely to agree that they had the skills to carry out literature reviews or appraise evidence compared to nurses and public health facilitators (36% vs. 75% vs. 80%; 51% vs. 64% vs. 70%). Access to the internet and bibliographic databases was good for all groups but GPs used a narrower spectrum of evidence‐based journals, relying mainly on medical literature. Only nurses and public health practitioners appeared to have any understanding of qualitative research terms. Public health practitioners were also least likely to view guidelines or protocols developed by others as the best source of evidence for primary care. The major perceived barrier to practising evidence‐based practice was time. Consequently the most important facilitator was protected time, but increased resources (financial and staff) and training were also cited. Professional groups other than GPs perceived inter‐professional boundaries as a barrier and suggested multi‐professional teamworking and learning as potential supports for evidence‐based practice.

Conclusions  While all professional groups welcome and support evidence‐based practice, there are clear differences in the starting point and perspectives across the groups. These need to recognized and addressed to ensure that learning the skills of evidence‐based practice and implementing evidence are effective. This will also enhance the ability of primary care organizations to develop robust mechanisms for supporting key aspects of clinical governance.
A multidisciplinary guideline for the acute phase of stroke: barriers perceived by Dutch neurologists
Authors: Van Der Weijden Trudy , Hooi Jurenne D. , Grol Richard , Limburg Martien
Published: June 2004

Rationale, aims and objectives  Guidelines for stroke management should improve quality of care. Dissemination of guidelines, however, does not guarantee guideline adherence. The aim of this paper is to investigate barriers for guideline adherence to bring about suggestions for possible implementation strategies.

Method  Questionnaire survey among all Dutch neurologists working on neurology wards in general hospitals during the year 2000 in The Netherlands.

Results  The neurologists expressed a high degree of agreement with the diagnostic and preventive recommendations, but expressed doubts with regard to the therapeutic recommendations, especially for the recombinant tissue plasminogen activator therapy. In general, barriers at the organizational and the multidisciplinary team level were most prominent.

Conclusions  Active implementation of the guidelines seems necessary. Implementation strategies should be focused on the different sources of barriers: the caregiver, the patient and the organization of care.
Clinical trials: deliberations on their essence and value
Authors: Schelling Franz A.
Published: June 2004

Rationale, aim & objectives  In the context of the evidence‐based medicine (EBM) movement, the clinical trial has come to be hailed as the ultimate source of medical knowledge, and especially of clinical pharmacology. By subjecting the premises of this procedure to a thorough analysis, the author hopes to achieve a sound rating of its epistemological significance in the context of medical research.

Method  Current claims on the basic importance of the evidence provided by standardized clinical trials are confronted with conflicting observations concerning their current application in medical practice. The stereotyped trials of present research in multiple sclerosis serve as an example to illustrate this point.

Results  Traditional assumptions concerning the validity of standardized clinical trials are based on an illusion of absolute objectivity and reliability. Apart from being subject to tough publish (conveniently)‐or‐perish and commercial influences, the results of clinical trials, especially drug trials, are of limited informative value in diverse respects, such as (i) clinical trials do not identify every possible drug reaction for every instance of a disease; (ii) their results never allow the prediction of the efficacy of a specific drug in any given individual; (iii) clinical trials have no inherent potential to provide concrete insights into the nature and cause(s) of a definite morbid condition; and (iv) extensions of clinical drug trials to ever‐larger study groups indicate serious problems in basic theoretical respects.

Conclusion  A clinical trial cannot indicate a certain prevention or cure for any particular instance of a disease, and the correctness of its individual predictions is always only contingent. This can be explained by the fact that the correspondence between the nature of each of all pathological conditions presented by the different members of a clinical trial population and by the individual patients being treated according to the results of the trial is never complete.
Is there life after evidence‐based medicine?
Authors: Porta Massimo
Published: June 2004

Recent years have witnessed the rising star of evidence‐based medicine (EBM) as an approach towards rationalizing clinical practice in the face of an exponentially growing body of knowledge. Along with it, however, a sense of unease is rising among practising doctors, as they feel that well‐intentioned principles may be increasingly applied to disease management, with its economic and cost‐cutting implications, rather than disease cure or treatment. There is a fear that any procedure, however time‐honoured, that was not or cannot be subjected to randomized controlled clinical trial, may some day be discouraged, more or less strongly, based on statistical rather than clinical considerations. Resistance to EBM ranges from a ‘we‐know‐best’ uncompromising non‐acceptance to a ‘you‐may‐be‐right‐sometimes‐but‐don’t‐ever‐tell‐me‐what‐to‐do’ sort of openness. The problem is one of measure, in more than one sense: measure of how effective individual practitioners are in treating their patients, measure of how useful EBM is, measure in promoting what may become a dogmatic application of probability laws to the very improbable practice of medicine, measure in siding with the supporters of health care on a budget. There is much that EBM can give to clinical medicine by its ability to organize complex data sets for the ultimate benefit of patients, but there is also much that can stifle practice by forcing a dogmatic implementation, rather than a flexible common sense approach, of its principles.
Hospital doctors’ self‐rated skills in and use of evidence‐based medicine – a questionnaire survey
Authors: Oliveri Roberto S. , Gluud Christian , Wille‐Jørgensen Peer A.
Published: June 2004

Rationale, aims and objectives  Problems in understanding basic aspects of evidence‐based medicine (EBM) may form barriers to its implementation into clinical practice. We examined hospital doctors’ skills in EBM terms and related these skills to their use of information sources, critical appraisal, and implementation of EBM into clinical practice.

Methods  A self‐administered questionnaire was sent to all hospital doctors (n = 376) at a university hospital in Denmark, including 12 questions on methodological terms frequently used in evidence‐based literature plus one non‐existing dummy term. Furthermore, participants were asked about their use of various information sources, self‐rated skills of critical appraisal of standard scientific literature, and level of implementation of evidence‐based principles in daily clinical settings. Based on the answers to the 12 evidence‐based methodological terms, we calculated a familiarity score.

Results  Proportion of responding was 60% (n = 225), but representative for all hospital doctors regarding background data. Ten doctors (4.4%) could define and explain all 12 methodological terms. The majority of all doctors showed interest in knowing more about the terms. Fifty‐six per cent knew the dummy term. Doctors mainly consulted traditional and possibly insufficient sources (textbooks, colleagues, scientific journals) when searching for clinical evidence. The Cochrane Library was the least consulted information source and had never been consulted by 49%. Only 18% always practised EBM. More reliance on PubMed and The Cochrane Library as information sources, more competence of critical appraisal, and more frequent practise of EBM were significantly (P < 0.001) associated with a higher familiarity score. Compared to seldom or never users of The Cochrane Library, frequent users had significantly higher academic degree (P = 0.01), familiarity score (P < 0.001),  and  use of PubMed (P = 0.0004).

Discussion and conclusions  Most hospital doctors seem to lack knowledge of key methodological evidence‐based medicine terms. This may form a barrier when consulting EBM sources and to the implementation of EBM into clinical practice.
The doctor, his patient, and the computerized evidence‐based guideline
Authors: Lipman Toby
Published: June 2004

This paper explores some of the issues raised by the finding in a randomized controlled trial (RCT) that general practitioners (GPs) taking part failed to use a computerized evidence‐based guideline, nor did it have any impact on patient outcomes. GPs are expected to ‘make an initial decision on every problem [patients] may present’ and to address psychological and social problems in addition to biomedical ones. The computerized guideline imposed an external, largely biomedical, agenda that superseded the patient’s. This disrupted the normal pattern of GP consultations and it was therefore ignored. Guidelines for any particular disease are effective if backed up by a detailed programme of education and audit. However, the large number of different conditions seen in general practice means that it is impractical to have such programmes for more than a small fraction of the clinical workload. The reductionist assumptions underlying the construction of evidence‐based guidelines from systematic reviews lead to inflexible recommendations on the management of disease. Anthropologists and sociologists make an important distinction between scientifically defined diseases and the culturally constructed experience of illness. Because GPs deal with patients suffering illness that may or may not result from disease, disease‐centred guidelines often conflict with their needs and wishes. The development of evidence‐based medicine (EBM) was intended as a tool to help doctors make sense of evidence in the context of individual patients’ problems. Few GPs are skilled in it, and it has been appropriated by powerful expert groups such as guidelines developers and the pharmaceutical industry. It is suggested that more understanding of EBM by GPs leads to better informed decision making by them and their patients.
Interrelationships among physicochemical properties, absorption and anthelmintic activities of 2‐desoxoparaherquamide and selected analogs
Authors: Johnson S. S. , Coscarelli E. M. , Davis J. P. , Zaya R. M. , Day J. S. , Barsuhn C. L. , Martin R. A. , Vidmar T. J. , Lee B. H. , Conder G. A. , Geary T. G. , Ho N. F. H. , Thompson D. P.
Published: June 2004

The interrelationships between physicochemical properties, absorption and potency of 2‐desoxoparaherquamide and five analogs, representing a new anthelmintic class, were evaluated in in vitro and in vivo assays. At pH 7.5, rates of drug absorption by the gastrointestinal nematode Haemonchus contortus and jird small intestine, parameterized by the permeability coefficient, Pe, ranged from 1.2–2.4 × 10−4 cm/min (nematode) to 2.5–5.5 × 10−3 cm/min (jird). In the jird intestine, absorption was pH‐dependent, with Pe at pH 7.5 being twice that at pH 4.5, reflecting the negative influence of protonation on transport of these weakly basic molecules. Each compound rapidly paralyzed H. contortus during in vitro exposure to therapeutically relevant concentrations (1–10 μm). The kinetics of drug action on motility in vivo mirrored their in vitro effects; motility concentrations were reduced in nematodes collected from jird stomach 3 h following oral drug dosing, by which time ≥50% clearance of the parasites had occurred. The nematode/medium partition coefficient K ranged from 10.1 to 16.1, consistent with the lipophilic nature of the compounds. The time required to reduce motility in vitro by 50% (t50*) and Pe were used to determine Cn*, the concentration of drug in the nematode at t50*, as an indicator of intrinsic potency. In the jird, the apparent potencies of the compounds were insensitive to route of administration (i.e. oral = i.v. = i.p. = i.m.) for H. contortus and two other gastrointestinal nematodes, Ostertagia ostertagi and Trichostrongylus colubriformis; topical administration, however, required three to 10‐fold higher doses for equivalent efficacy.
Lipoprotein processing is required for virulence of Mycobacterium tuberculosis†
Authors: Sander P. , Rezwan M. , Walker B. , Rampini S. K. , Kroppenstedt R. M. , Ehlers S. , Keller C. , Keeble J. R. , Hagemeier M. , Colston M. J. , Springer B. , Böttger E. C.
Published: June 2004

Lipoproteins are a subgroup of secreted bacterial proteins characterized by a lipidated N‐terminus, processing of which is mediated by the consecutive activity of prolipoprotein diacylglyceryl transferase (Lgt) and lipoprotein signal peptidase (LspA). The study of LspA function has been limited mainly to non‐pathogenic microorganisms. To study a potential role for LspA in the pathogenesis of bacterial infections, we have disrupted lspA by allelic replacement in Mycobacterium tuberculosis, one of the world's most devastating pathogens. Despite the presence of an impermeable lipid outer layer, it was found that LspA was dispensable for growth under in vitro culture conditions. In contrast, the mutant was markedly attenuated in virulence models of tuberculosis. Our findings establish lipoprotein metabolism as a major virulence determinant of tuberculosis and define a role for lipoprotein processing in bacterial pathogenesis. In addition, these results hint at a promising new target for therapeutic intervention, as a highly specific inhibitor of bacterial lipoprotein signal peptidases is available.
New Listeria monocytogenes prfA* mutants, transcriptional properties of PrfA* proteins and structure–function of the virulence regulator PrfA
Authors: Vega Yolanda , Rauch Markus , Banfield Mark J. , Ermolaeva Svetlana , Scortti Mariela , Goebel Werner , Vázquez‐Boland José A.
Published: June 2004

PrfA, a transcription factor structurally related to Crp/Fnr, activates Listeria monocytogenes virulence genes during intracellular infection. We report two new PrfA* mutations causing the constitutive overexpression of the PrfA regulon. Leu‐140Phe lies in αD adjacent to the DNA‐binding motif in the C‐terminal domain, like a previously characterized PrfA* mutation (Gly‐145Ser). Ile‐45Ser, in contrast, maps to the N‐terminal β‐roll, a structure similar to that of the Crp cAMP binding site. The in vitro transcriptional properties of recombinant PrfA*I45S and PrfA*G145S were compared to those of PrfAWT at two differentially regulated PrfA‐dependent promoters, PplcA and PactA. The two PrfA* mutations increased the affinity for the target DNA to a different extent, and the differences in DNA binding (PrfA*G145S > PrfA*I45S >>> PrfAWT) correlated with proportional differences in transcriptional activity. The use of the PrfA* proteins revealed that PplcA had a greater affinity for, and was more sensitive to, PrfA than PactA. RNA polymerase (RNAP) initiated transcription independently of PrfA at PplcA, but not at PactA, consistent with bandshift experiments suggesting that PplcA has a greater affinity for RNAP than PactA. Thus, differences in affinity for both PrfA and RNAP appear to determine the different expression pattern of PrfA‐regulated promoters. Modelling of the PrfA* mutations in the crystal structure of PrfA and comparison with structure–function analyses of Crp, in which similar mutations lead to constitutively active (cAMP‐independent) Crp* proteins, suggested that PrfA shares with Crp an analogous mechanism of cofactor‐mediated allosteric shift. Our data support a regulatory model in which changes in PrfA‐dependent gene expression are primarily accounted for by changes in PrfA activity.
Are rhoptries in Apicomplexan parasites secretory granules or secretory lysosomal granules?
Authors: Ngô Huân M. , Yang Mei , Joiner Keith A.
Published: June 2004

The club‐shaped rhoptries in Apicomplexan parasites are one of the most unusual secretory organelles among the eukaryotes, containing unusual lipid and protein cargo that is specialized for intracellular parasitism. Rhoptries have traditionally been viewed strictly as regulated secretory granules. We discuss in this article recent data on the cargo, function and biogenesis of rhoptries in two parasitic model systems, Toxoplasma and Plasmodium. Current findings suggest that rhoptries receive products from both biosynthetic and endocytic pathways and, therefore, they are most analogous to secretory lysosomal granules found in mammalian cells.
In UV‐irradiated Saccharomyces cerevisiae, overexpression of Swi2/Snf2 family member Rad26 increases transcription‐coupled repair and repair of the non‐transcribed strand
Authors: Bucheli Miriam , Sweder Kevin
Published: June 2004

Summary Nucleotide excision repair (NER) in eukaryotes is a pathway conserved from yeast to humans that removes many bulky chemical adducts and UV‐induced photoproducts from DNA in a relatively error‐free manner. In addition to the recognition and excision of DNA damage throughout the genome (GGR), there exists a mechanism, transcription‐coupled nucleotide excision repair (TCR), for recognizing some types of DNA damage in the transcribed strand of genes in Escherichia coli, yeast and mammalian cells. An obstacle in the repair of the transcribed strand of active genes is the RNA polymerase complex stalled at sites of DNA damage. The stalled RNA polymerase complex may then mediate recruitment of repair proteins to damage in the transcribed strand. Proteins enabling TCR are the Cockayne syndrome B (CSB) protein in humans and its yeast homologue Rad26. Both CSB and Rad26 belong to the Swi2/Snf2 family of DNA‐dependent ATPases, which change DNA accessibility to proteins by altering chromatin structure. To address how Rad26 functions in yeast repair, we used the genetic approach of overexpressing Rad26 and examined phenotypic changes, i.e. changes in NER. We found that repair of both the transcribed and the non‐transcribed strands is increased. In addition, overexpression of Rad26 partially bypasses the requirement for Rad7 in GGR, specifically in the repair of non‐transcribed sequences. As TCR takes place in very localized regions of DNA (i.e. within genes) in wild‐type cells, we propose that overexpression of recombinant Rad26 increases accessibility of the damaged DNA in chromatin for interaction with repair proteins.
Specificity of streptolysin O in cytolysin‐mediated translocation
Authors: Meehl Michael A. , Caparon Michael G.
Published: June 2004

Summary Cytolysin‐mediated translocation (CMT) is a recently described process in the Gram‐positive pathogen Streptococcus pyogenes that translocates an effector protein of streptococcal origin into the cytoplasm of a host cell. At least two proteins participate in CMT, the pore‐forming molecule streptolysin O (SLO) and an effector protein with the characteristics of a signal transduction protein, the Streptococcus pyogenes NAD‐glycohydrolase (SPN). In order to begin to elucidate the molecular details of the translocation process, we examined whether perfringolysin O (PFO), a pore‐forming protein related to SLO, could substitute for SLO in the translocation of SPN. When expressed by S. pyogenes, PFO, like SLO, had the ability to form functional pores in keratinocyte membranes. However, unlike SLO, PFO was not competent for translocation of SPN across the host cell membrane. Thus, pore formation by itself was not sufficient to promote CMT, suggesting that an additional feature of SLO was required. This conclusion was supported by the construction of a series of mutations in SLO that uncoupled pore formation and competence for CMT. These mutations defined a domain in SLO that was dispensable for pore formation, but was essential for CMT. However, introduction of this domain into PFO did not render PFO competent for CMT, implying that an additional domain of SLO is also critical for translocation. Taken together, these data indicate that SLO plays an active role in the translocation process that extends beyond that of a passive pore.
A distinctive dual‐channel quorum‐sensing system operates in Vibrio anguillarum
Authors: Croxatto Antony , Pride John , Hardman Andrea , Williams Paul , Cámara Miguel , Milton Debra L.
Published: June 2004

Summary Many bacterial cells communicate using diffusible signal molecules to monitor cell population density via a process termed quorum sensing. In marine Vibrio species, the Vibrio harveyi‐type LuxR protein is a key player in a quorum‐sensing phosphorelay cascade, which controls the expression of virulence, symbiotic and survival genes. Previously, we characterized Vibrio anguillarum homologues of LuxR (VanT) and LuxMN (VanMN) and, in this study, we have identified homologues of LuxPQ (VanPQ) and LuxOU (VanOU). In contrast to other Vibrio species, vanT was expressed at low cell density and showed no significant induction as the cell number increased. In addition, although the loss of VanO increased vanT expression, the loss of VanU, unexpectedly, decreased it. Both VanN and VanQ were required for repression of vanT even in a vanU mutant, suggesting an alternative route for VanNQ signal transduction other than via VanU. VanT negatively regulated its own expression by binding and repressing the vanT promoter and by binding and activating the vanOU promoter. The signal relay results in a cellular response as expression of the metalloprotease, empA, was altered similar to that of vanT in all the mutants. Consequently, the V. anguillarum quorum‐sensing phosphorelay systems work differently from those of V. harveyi and may be used to limit rather than induce vanT expression.