bluuebunny/crossref_metadata_2025 huggingface dataset:
Bridging the gap
Authors: Doyle Lesley , Garrington Neil
Published: January 2008

The issue of learning loss and lack of continuity, especially as pupils transfer from primary to secondary school, is a source of major concern.
The plight of Australia's teaching principals
Authors: Gamage David
Published: January 2008

This article is based on a project on teaching principals and the management of smaller schools conducted in 1996 and 1997
Managing the gender gap
Authors: Clark David
Published: January 2008

Since 1993 the national media, league tables and more recently OFSTED have alerted those in education to the problem of boys' underachievement.
Managing change in small Scottish primary schools
Authors: McPake Joanna
Published: January 2008

How have headteachers of small primary schools copedis with the large amount of change that the education system has had to cope with over the last decade? While the research focuses on Scotland, most of the conclusions are also relevant elsewhere.
Asian girls and equal opportunities: are schools getting it right?
Authors: Fleming Peter
Published: January 2008

Schools are constantly having to deal with new initiatives from above and respond to challenging situations which arise daily. Under such circumstances it takes determination and commitment on the part of managers and teachers to ensure that Equal Opportunities initiatives remain on course. A regular review of the needs of particular groups within a school is a useful approach. This second article on contemporary issues from Peter Fleming considers the needs of Asian girls.
Leaders as head learners
Authors: Wright Carole
Published: January 2008

This school based research project set out to investigate the School entrance behaviour of five-year-olds. The particular focus was to ascertain any differences between the entry behaviour of boys and girls. The aim was to identify, at the time of entry, children who may find progress in reading difficult to achieve. The author uses this as an example of a collegiate approach to school leadership and the development of a community of learners.
'Management', 'leadership' and schools
Authors: Wilson John
Published: January 2008

The author takes the opportunity simply to raise, not solve, some problems inherent in the concepts marked by `management' and 'leadership' in relation to schools.
The Road Less Travelled
Authors: Mau Rosalind , Lim Levan
Published: January 2008

This article illustrates a professional development process of self knowledge, reflection of self in group dynamics and integration of self into action plans. Fifteen managers completed this professional development process in a Master of Arts (Educational Management) core course in Singapore
Teaching Quality Assurance: Technology is Improving Standards in HE
Authors: Stanton Clare
Published: January 2008

This article reports on the systems used in a university to gather data on student perceptions of teaching quality
BEMAS Annual Conference 1998
Authors: Tomlinson Harry
Published: January 2008

This special edition of Management in Education reports on the proceedings of the BEMAS annual conference held at the University of Warwick in September 1998. The chair of the conference organising committee reports on the keynote presentations and a selection of papers then follow. Further papers may be included in later editions of MiE as appropriate.
Governance & headship: distinctive management perspectives in small primary schools
Authors: Evans Tricia
Published: January 2008

This article draws upon the outcomes from an on-going study of governance and management issues in small primary schools in three LEAs.
Leading parents to fuller involvement
Authors: Bennet Carey
Published: January 2008

Among all of the new school reforms, the changing attitude to parents is in danger of going unnoticed because its implementation is diffuse and potentially unstructured. How is the national context changing in the field of home-school relations ?
Perceptions of the HEADLAMP Scheme
Authors: Gunraj Judith
Published: January 2008

This article continues the work relating to headteachers' perceptions about the HEADLAMP programme begun with Desmond Rutherford at the University of Birmingham, part of which was reported at the 1997 BEMAS Conference (Gunraj and Rutherford, 1998).
Frank Parsons' Contribution to Career Counseling
Authors: Jones Lawrence K.
Published: January 2008

Frank Parsons had a vision of a better world, and he devoted himself tirelessly to its realization. Through his work, in the brief span of time from 1906 to 1908, he founded the vocational guidance movement. This movement was based on his development of the (a) organization known as the Vocation Bureau of Boston, and (b) principles and methods of vocational counseling that guided the counselors in their work. In this article we will consider his vision and how its implementation contributed to career counseling as we know it today.
Parsons' Contribution to Career Assessment
Authors: Zytowski Donald G. , Swanson Jane L.
Published: January 2008

This article presents Parsons' extensive method of assessment and reviews its incorporation of the developing science of psychometrics in the early decades of this century. The utility of self-assessment, also advocated by Parsons, is discussed. It concludes that the validity of Parsons' fundamental ideas, although greatly elaborated in the past 80 years, is affirmed.
A Theoretical and Conceptual Reexamination of Subsystem Politics
Authors: Freeman J. Leiper , Stevens Judith Parris
Published: January 2008

What we focus upon here is essentially the politics of policy making in a political system divided into numerous interests and with a governmental structure that is institutionally and organizationally quite complex. We shall attempt an eclectic examination of some concepts and theories in the literature of ‘subsystem’ politics. By the term ‘subsystem’ we mean political relations among people in special policy areas coming from different institutions and organizations in the larger system. The politics of subsystems consists of relations between the system and the subsystem, as well as relations within the subsystem itself.
Shaping Policy Through the Courts: (1) The British Courts
Authors: Hogwood Brian W.
Published: January 2008

This article centrally argues that the courts in Britain play a role in laying down general rules which is, on occasion, equivalent to the role of Parliament and the legislative process. The next issue will carry a companion piece by Brian Hogwood on the courts and the EEC and the European Convention on Human Rights.
Life in the Whitehall Village
Authors: Bruce-Gardyne Lord
Published: January 2008

This article is abridged from Lord Bruce-Gardyne's account of his experience as a Treasury Minister published in 1986 under the title Ministers and Mandarins. It is valuable as another Ministerial account of life ‘on the inside’. It is also valuable as a contribution which is based on the experience of the Conservative Government. But above all it is valuable because Lord Bruce-Gardyne started off with a well informed academic view of the Treasury (See J. Bruce-Gardyne and M. Lawson, The Power Game, 1976).
Non-profit Organizations and Urban Policy in Britain and the USA
Authors: Jacobs Brian D.
Published: January 2008

In Britain and the USA, non-profit and charitable organizations have become increasingly important wit/h respect to their role in urban community activity. Governments on both sides of the Atlantic have recognized the value of n)on-profits in promoting community involvement in local initiatives designed to stimulate economic activity and political and social integration. The paper describes American experience and suggests that Britain is also responding to the challenge posed by voluntarism by increasing government intervention in support of non-profits.
Shaping Policy through the Courts: (2) The European Dimension
Authors: Hogwood Brian W.
Published: January 2008

This is the second of a pair of articles on the role of the courts in shaping British public policy. The first article, in the previous issue of this journal, dealt with the British courts. This article examines how British public policy is shaped by two quite distinct systems of law and courts; first, the European Convention on Human Rights, and, second, the European Communities and the work of the European Court of Justice.
The Role of the Test Discount Rate in the NHS
Authors: McGuire A. , Stuart P.
Published: January 2008

In this paper we consider the role of the Test Discount Rate, as recommended by the UK Treasury, in the NHS. We do not intend to discuss the mechanics of discounting. Rather the purpose of the paper is to consider some of the theoretical difficulties associated with the practice of discounting in the public sector generally and the NHS specifically, in the light of the officially endorsed rationale for the use of the TDR in the UK. We believe that the mechanics of discounting are generally well understood in the NHS but that there is little understanding of the theoretical justification for this practice in the health care sector. We therefore believe that this is giving rise to a less than optimal use of the discounting procedure in allocating resources in the NHS.
Planners, Uncertainties and Methodologies
Authors: Keys P.
Published: January 2008

A problem which confronts those involved with planning in all settings is the choice of a methodology to guide the planning process so that it may be effective. There have been numerous attempts to identify those factors in planning situations which influence the style of the planning process and the behavior of planners. The resulting contingency theory is essentially descriptive and recently efforts have been made to build upon this foundation and provide a prescriptive contingency theory of planning. This work is extended here by providing a contingency framework which associates relevant distinctions in planning situations with significantly different levels of uncertainty in the mind of a planner. The framework is able to act as both a descriptive and a prescriptive tool for the analysis of planning situations and the determination of appropriate planning methodologies. An example is given to illustrate its use in each of these modes.
The Keynesian Revolution in Whitehall: A Study in Public Policy
Authors: Barberis Peter
Published: January 2008

This paper examines some of the public policy implications of the debate about the Keynesian Revolution. This it does by testing more recent (revisionist) interpretations which have challenged traditional (Keynesian) beliefs that a revolution took place. It is argued that the notion of a revolution remains broadly serviceable: and that some of the revisionists have overstated their case, while providing valuable correctives to the cruder varieties of Keynesian interpretation.
The Quasi Market in Health Care: Pre-requisites, Problems and Prospects
Authors: Mulholland G , McAlister D
Published: January 2008

This paper evaluates the operation of the quasi market in health care after the implementation of the reforms set out in the White Paper ‘Working for Patients’ (DoH, 1989a), which replaced the largely state run monopoly provision of health and social services by a state financed internal market. Lying behind the reforms was the assumption that the move away from bureaucratic, to market oriented, systems in the allocation of health and social care would lead to improvements in service efficiency, and responsiveness. This was to be achieved by separating state authorities' purchasing and providing roles, and the introduction of contracts. Using the framework developed by Le Grand and Bartlett (1993), this paper assesses the extent to which the internal market for acute services in Northern Ireland is meeting the expected outcome criteria of efficiency, responsiveness, choice, quality and equity. A survey of purchasers and providers of acute hospital services was conducted, followed by in-depth interviews with the stakeholders in the contracting process. Analysis of the quantitative data, and preliminary consideration of the qualitative data, would indicate that the potential benefits are yet to be fully realised.
The ‘Pondlife’ of Executive Agencies:
Authors: Judge David , Hogwood Brian W. , McVicar Murray
Published: January 2008

Agencies attract the attention of MPs unequally. In focusing upon ‘informnatory responsibility’, as a prerequisite of ministerial responsibility in an era of executive agencies, the article reveals that there is no simple model or pattern of informatory responsibility, whether measured by parliamentary questions, letters from MPs, or extent of contact between ministers and agencies. Those agencies which attract the sustained interest of MPs often require elaborate mechanisms of response to deal with the sheer volume of questions and requests for information. In tumrn, this may have pathological organisational consequences for working practices and staffing tasks particularly if the agency is responsible for policy delivery in a politically sensitive area. Conversely, those agencies which attract little or no interest from MPs raise the neglected question of what does ministerial responsibility ‘mean’ in these circumstances? The article concludes that a more exacting perspective of inforinatory accountability is needed: one that places the emphasis not only upon the regularity of the flow of information and upon the consistency of explanation to parliament, but also takes into account the interactions of agencies and their ‘constituencies of accountability’.
Complaints Within Constraints: A Critical Review and Analysis of the Citizen's Charter Complaints Task Force
Authors: Blackmore Martin
Published: January 2008

In June 1993 a Task Force within the Citizen's Charter Unit of the Cabinet Office initiated a review of complaints procedures in public sector organisations. Its work included an appraisal of private sector complaints handling practice to see if there were any lessons that could be usefully applied to the public sector. Its Main Report (1995) contained a number of interesting observations, some of which appear to challenge the logic of the structural reforms to the public sector. Effective complaints mechanisms require that all complaints, including those pertaining to policy, need to be dealt with by those who deliver services. A commitment to implementing the Task Force's recommendations would have resource implications and would involve changes in organisational culture and management style including the empowerment of front-line personnel. In terms of empowering citizens however, the Task Force's impact is likely to be minimal due to the constraints within which delivery agencies operate.
Spain, its regions and the EU ‘LEADER’ initiative: some critical perspectives on its administration
Authors: Barke Michael , Newton Michael
Published: January 2008

This paper examines the development of the EU's LEADER Initiative for integrated rural development. It is argued that the policy process, specific to the LEADER Initiative, has to be understood in terms of the development of a ‘policy community’ in Brussels and beyond, engaged in policy developments informed by a clear ‘integrationist’ philosophy. The paper goes on to examine the administrative arrangements created within Spain to implement the EU's LEADER Initiative for integrated rural development. The intention of the scheme's initiators in Brussels was that, in order to facilitate ‘grass-roots’, local development initiatives, the regional and provincial levels of administration would not be involved in the programme and that administration would take place through one national agency (IRYDA in the case of Spain). A questionnaire survey and a series of in-depth interviews with appropriate officials at the European, national, regional and local (CEDER) levels revealed that, in several of the Spanish regions (autonomous communities), there has been a considerable degree of involvement in the Initiative but that such intervention varies quite widely. It is argued that it was inevitable that some Spanish regions (e.g. the Basque Country) would seek ‘hands on’ involvement in the scheme because of their suspicion of any centralised, national level of administration. Other regions with little experience of rural development (e.g. Extremadura) have been very closely involved with IRYDA throughout, whereas in Andalusia, where rural development plans were already significantly advanced before the adoption of LEADER, the regional authority appears to have had a minimal involvement. It is clear that officials in IRYDA have not followed the intentions of Brussels and, in their relationship to the regional authorities, have been extremely flexible in their implementation of LEADER 1. However, at the European level, LEADER 2 is now under way and contains a requirement that regional levels of administration be involved in the programme. It is argued that these findings support the view that policy implementation may be seen as part of the policy process, whereby the realities of implementation force changes in the nature of policy itself in ways not originally envisaged by the i nstigators.
Why bureaucrats can't always do what Ministers want: multiple accountabilities in Westminster democracies
Authors: Polidano Charles
Published: January 2008

Politicians and public servants are commonly depicted as being in a unilinear power relationship. However, senior officials are subject to accountability relationships with various central government authorities in addition to ministers. Multiple accountabilities can work at cross-purposes and prevent bureaucrats from complying with ministerial directions, however legitimate those directions may be. One aim of recent public management reform has been to do away with some of these accountabilities. But they have only been replaced by others. Multiple accountabilities are an inescapable part of the reality of government.
Quasi-Government in Britain: The Origins, Persistence and Implications of the Term ‘Quango’
Authors: Cole Michael
Published: January 2008

Discussion about quasi-government usually involves the term ‘quango’. There is, however, no generally accepted definition of this concept or any widespread understanding of the way in which in the term has influenced the debate about quasi-governmental bodies. In this paper the origins and development of ‘quango’ are explored and its persistence and dominance of the quasi-government lexicon assessed. The implications of the term for the debate about the numbers of quasi-governmental bodies, the growth in their numbers, public appointments to them and their accountability are examined. Overall, the paper concludes that the indiscriminate use of ‘quango’ has helped to blur the distinction between different types of bodies and has produced generalisations that are often difficult to sustain. Debate about quasi-governmental issues such as public appointments and accountability should, therefore, focus on the relevant quasi-governmental characteristics rather than any specific definition of quasi-government.
Assuring the quality of UK Local Government services: a case study of school meals catering
Authors: Bailey Stephen J.
Published: January 2008

This article analyses the changing nature of quality assurance issues for the UK school meals service and presents the results of research into the impact on this service of the compulsory competitive tendering (CCT) regime. It considers the institutional and policy context within which the school meals service operates and shows how that context has qualified the maxim that the consumer knows best. Schools and their pupils have had little input into contract specifications for the school meals service. However, increased local discretion regarding the nutritional standards of school meals, the decentralisation to schools of responsibility for managing their own budgets and the growth of fast food’ catering outlets outwith school premises are, in combination, increasing the power of school managers and of pupils themselves relative to that of the central offices and committees of local education authorities. Hence, the balance of power between different stakeholder groups is changing, so modifying perceptions of what constitutes quality of service.
Plain English and Public Administration
Authors: Watson Robert P. , Lynch Thomas D.
Published: January 2008

Language is more than a means of oral or written communication. It shapes the way we think and it is through the lens of language that problems and issues are conceptualized. It is thus useful to analyze the language of government. Moreover, the language used by public administrators might be a source of the problems facing bureaucracy and the hostility the public feels for bureaucracy. What exists in government is an institutionalized misuse of language, comprised of jargon, abstractions, acronyms, and a confusing amalgamation of syntax and doublespeak. This article examines the language of ‘bureaucratese’ by identifying common elements of bureaucratese and the problems associated with its use.
Lean Supply: a Strategy for Best Value in Local Government Procurement?
Authors: Erridge Andrew , Murray J. Gordon
Published: January 2008

Developments in government procurement policy and private sector practice towards a more strategic role provide the context for an examination of the proposals on Best Value in local government. Lean supply is proposed as a means of obtaining better value from suppliers and achieving the goals of better quality, more efficient services and continuous improvement. Empirical evidence is presented from a postal survey of local government purchasing officers, interviews with selected respondents and experiments based upon ‘live’ contracts. Whilst the survey identifies as obstacles a lack of understanding of lean supply and the culture of local government, the interviews and experiments give a much more positive flavour to the prospects for lean supply, and hence Best Value within local government. The paper concludes that lean supply is most applicable for major expenditure items, that the enthusiasm and drive of a ‘champion’ and recognised purchasing professional assist with introducing the concepts and that ‘marketing’ of purchasing's value added contribution assists in overcoming barriers. However, the lean supply model derived from the private sector requires adaptation both in its operational practices and philosophical underpinnings to fit with the local government context.
Stylistics, criticism and mythrepresentation again: squaring the circle with Ray Mackay's subjective solution for all problems
Authors: Short Mick , Freeman Donald C. , van Peer Willie , Simpson Paul
Published: January 2008

This article is a response to an article by Ray Mackay (1996) which constitutes an attack on stylistic analysis in general, and the writings of the above authors and Ron Carter in particular. Mackay's article (in Language and Communication) accuses stylistics of 'scientificness' and claims that its attempt to provide objective analyses of literary texts is futile.1 We suggest that Mackay has misrepresented what stylisticians have said about objectivity, and that his understanding of objectivity, science and the nature of text-interpretative argument is seriously flawed.
Differential regulation of LPS-induced IL-1β and EL-1 receptor antagonist mRNA by IFNα and IFNγ in murine peritoneal macrophages
Authors: Sivo J. , Salkowski C.A. , Politis A.D. , Vogel S.N.
Published: January 2008

IL-1 and its naturally occurring receptor antagonist, IL-1ra, are primarily synthesized by cells of the monocyte-macrophage lineage. The balance of the relative amounts of these secreted cytokines has major importance in the pathophysiology of various inflammatory disorders, especially bacterial sepsis and some autoimmune diseases. While both the agonist and the antagonist genes belong to the same family, IL-1β and IL-1ra are differentially regulated. In the present study, we examined the effects of macrophage activating factors, bacterial lipopolysaccharide (LPS), IFNα, and IFNγ, on the regulation of IL-1ra and IL-1β mRNA levels in thioglycollate-elicited mouse peritoneal macrophages. LPS-treatment of cultured macrophages resulted in a 3 to 4-fold increase in IL-1ra mRNA which peaked between 6-12 h, then started to decline but remained well above background levels at 24 h. In comparison to IL-1ra, the LPS-induced increase in IL-1β mRNA was larger, peaked earlier (at 2-4 h), and sharply decreased thereafter. In vivo analysis of mRNA from LPS-injected mice showed a similar temporal pattern of IL-1β and IL-1ra gene expression in bone marrow, spleen, and liver. In contrast to the effects of LPS, treatment with IFNα and IFNγ alone failed to affect the expression of either IL-1ra or IL-1β mRNA in vitro. However, in combination with LPS, IFNα and IFNγ had differential effects on the induction of these cytokines: IFNγ, but not IFNα, augmented the expression of LPS-induced IL-1ra. Conversely, both IFNα and IFNγ suppressed the induction of IL-1β mRNA by LPS. Thus, while IFNα only affects LPS-induced IL-1β gene expression, IFNγ exerts opposing effects on the LPS-induction of the agonist and antagonist, illustrating the complex role of interferons during the inflammatory process.
Augmentation of anti-cytokine immunotherapy by combining neutralizing monoclonal antibodies to interferon-γ and the interferon-γ receptor: protection in endotoxin shock
Authors: Bucklin S.E. , Russell S.W. , Morrison D.C.
Published: January 2008

We have employed neutralizing monoclonal antibodies to mouse interferon-γ (IFNγ) and to the receptor for mouse IFNy in studies designed to assess the protective efficacy of each of these monoclonals, administered either separately or in combination, in endotoxin-induced lethality. While pretreatment with either antibody alone, at doses of 200 μg per mouse, provided limited protection (70-50% lethality) in comparison to non-neutralizing antibody controls (100% lethality), the two monoclonal antibodies administered together provided a substantially greater level of protection (17% lethality). Although administration of 100 μg per mouse of either monoclonal alone was not protective (more than 65% lethality), a combination of both antibodies at this dose provided significant protection (19% lethality). In addition, administration of both antibodies 30 min post-endotoxin challenge also demonstrated significant protection in comparison to single antibody immunotherapy. In vitro studies using mouse peritoneal macrophages stimulated with LPS and IFNy have established confirmatory data for a synergistic effect of neutralizing antibody to IFNy and the IFNγ receptor in inhibiting macrophage activation as assessed by production of nitric oxide. These results provide a strong rationale for dual targeting of ligand and receptor in single cytokine immunotherapy.
Properties of US Standard Endotoxin (EC-5) in human male volunteers
Authors: Hochstein H.D. , Fitzgerald E.A. , McMahon F.G. , Vargas R.
Published: January 2008

There has been a great interest in endotoxin testing using both Limulus amebocyte lysate (LAL) and the rabbit pyrogen test. It is often difficult to relate the results to the actual biological potency of endotoxin in man. There is a need to have the US Standard Endotoxin (Lot EC-5) tested in human volunteers so that rabbit and human data can be compared.

Human male volunteers were divided randomly into 5 groups of 12. Each group was given an intravenous injection of Lot EC-5 at a level of either 0, 2, 4, 8, or 16 endotoxin units (EU) per kg of body weight. The oral temperature was taken and recorded every 15 min for 8 h. The pyrogenic properties of the US Standard Endotoxin in humans over the test period were determined. The results indicated that there is a direct correlation between EU/kg administered and temperature rise. The threshold pyrogenic dose (≥ 1.0°F rise in 50% of volunteers) in this study is approximately 4.1 EU/kg.
Bacterial endotoxins and pathogenesis of Gram-negative infections: current status and future direction
Authors: Morrison D.C. , Danner R.L. , Dinarello C.A. , Munford R.S. , Natanson C. , Pollack M. , Spitzer J.J. , Ulevitch R.J. , Vogel S.N. , McSweegan E.
Published: January 2008

100 years after the discovery of a bacterial 'endotoxin', 50 years after the introduction of antibiotics and 25 years after the routine use of intensive care units to support septic shock patients, Gram-negative infections continue to account for significant morbidity and mortality. In the coming decade, basic research on the structure/function of LPS, the cytokine cascade, and receptor-mediated intracellular signalling responses to LPS and cytokines will provide a greater understanding of the molecular, cellular and systemic responses to endotoxin and infection. New therapeutic agents now emerging from research, and better designed clinical trials to assess those agents will contribute to the next significant decline in sepsis- and shock-related morbidity and mortality. This article summarizes the findings of a workshop convened at the National Institutes of Health (NIH) to examine current research on endotoxin and Gram-negative septic shock.
Protection against oxygen toxicity by lipid A: role of Mn superoxide dismutase
Authors: Berg J.T. , Tang G. , Tsan M.F.
Published: January 2008

Previous studies have shown that diphosphoryl lipid A (DPL), but not monophosphoryl lipid A (MPL), protects rats against lethal hyperoxia. However, the mechanism of DPL-induced 02 resistance is not clear. In this study, we demonstrated that tracheal insufflation of 5 μg endotoxin (LPS) or DPL, but not MPL, markedly prolonged the survival of rats exposed to 100% O2. LPS was more protective than DPL, while DPL induced more alveolar inflammatory response and tumor necrosis factor (TNF) release. Both LPS and DPL caused a selective enhancement of pulmonary Mn superoxide dismutase (SOD) mRNA without affecting levels of CuZnSOD and catalase mRNAs. In contrast, MPL caused some release of TNF into the alveolar space, but did not produce an inflammatory response and had no effect on pulmonary MnSOD mRNA. These results support a potential role for pulmonary MnSOD in LPS- and DPL-induced 02 tolerance.
Cross-tolerance between bacterial endotoxin and group B Streptococcus in neonatal rats
Authors: Mancuso G. , Blandino G. , Cusumano V. , Alba Merendino R. , Rocca P. , Teti G. , Cook J.A.
Published: January 2008

Although endotoxin tolerance can be induced in newborns, potential cross-tolerance to group B Streptococcus (GBS), a common Gram-positive neonatal pathogen has not been investigated. In the present study we tested the hypothesis that endotoxin or recombinant tumor necrosis factor (rTNFα) can induce tolerance to lethal injection of heat-killed GBS in rat newborn pups and vice versa. The effect of such cross-tolerance on endogenous generation of plasma TNFα was subsequently evaluated. Rat pups (18-24 h old) were pretreated intracardially (i.c.) with either phosphate buffered saline (PBS), Salmonella enteritidis endotoxin (30 μg/kg) or rTNFα (35, 70 or 140 μg/kg). The pups were pretreated for either 4, 24, 48, 96 or 240 h prior to a lethal heat-killed GBS challenge. The susceptibility of the neonates to GBS-induced mortality was dependent on the duration of the pretreatment period. At 4 h of pretreatment with endotoxin or TNF, GBS-induced mortality was augmented relative to the PBS group. However, by 24-48 h the endotoxin and TNF pretreated neonates became more resistant to GBS-induced mortality. In a converse of the above experiment, neonates were pretreated with heat killed GBS (0.7 mg/kg) or rTNFα (70 μg/kg) and sensitivity to endotoxin was determined at 4-240 h after pretreatment. The data were qualitatively similar to endotoxin pretreatment. The 4 h GBS or TNF pretreatment rendered the neonates more susceptible to endotoxin-induced mortality. However, by 24-48 h the pretreatment groups were more resistant (P < 0.05) to endotoxin than the PBS controls. Plasma TNFα levels were increased (P < 0.05) 2 h after challenge i.c. with lethal heat-killed GBS or S. enteritidis endotoxin. In the 4 h pretreatment groups that received either GBS or endotoxin and then challenged with endotoxin or GBS, respectively, the plasma TNFα response was markedly augmented (P < 0.05). By 48 h of pretreatment, however, the plasma TNFα response in these groups to the stimuli was significantly reduced (P < 0.05) compared to the PBS pretreated groups. Therefore, plasma TNFα parallels lethality induced by GBS or endotoxin pretreatment. The ability of GBS and endotoxin to induce cross tolerance suggests that common pathophysiological pathways are involved in these syndromes.
A hamster anti-idiotype monoclonal antibody, mimicking the inner-core region of Gram-negative bacterial lipopolysaccharide (LPS), stimulates LPS inner-core-specific serum antibodies in hamsters
Authors: Field S.K. , Morrison D.C.
Published: January 2008

We have earlier described the development of an Ab2β anti-idiotype antibody specific for idiotypic determinants of a BALB/c mouse IgG3 monoclonal antibody (MAbY1-4A6) directed against the conserved inner-core 2-keto-3-deoxyoctulosonate (Kdo) residue of Salmonella minnesota rough mutant Re lipopolysaccharide (Re-LPS) [Field S, Pollack M, Morrison D C. Microb Pathog 1993; 15: 103-120]. Immunization of both inbred and outbred mice with MAb4G2 protected these animals against subsequent lethal challenge with S. minnesota Re-LPS. Here we demonstrate that hamsters immunized with the anti-idiotype MAb4G2 generate serum antibodies which cross-react with a variety of forms of LPS, as evidenced by specific dose-dependent binding to R and S chemotype LPS as assessed by ELISA and specific binding to antibiotic-treated, whole bacterial culture supernatants and to LPS-containing fractions in sucrose gradient velocity-sedimentation-fractionated, antibiotic-treated bacterial culture supernatants. Competitive inhibition assays using MAb4G2-elicited hamster antibodies (Ab3 or Ab1') and the Kdo-specific MAbY1-4A6 (Ab1) were carried out to assess the Kdo epitope-specificity and Ab1'-like properties of the hamster αMAb4G2 antibodies (Ab3). Hamster αMAb4G2 serum antibodies and the Ab1 MAbY1-4A6 express similar epitope specificities for both the MAb4G2 and Re-LPS antigens, confirming the Kdo epitope-specificity of these Ab1' serum antibodies. These data further establish that MAb4G2 is a true internal surrogate image of the conserved inner-core Kdo epitope of LPS.
Synthesis and purification by HPLC of des-O-acyl partial structures of Escherichia coli Re lipopolysaccharide
Authors: Fukase K. , Kurosawa M. , Kusumoto S.
Published: January 2008

Four compounds corresponding to partial structures of Re-type lipopolysaccharide (LPS) were synthesized for precise investigation of immunological properties of the 3-deoxy-D- manno-2-octulosonic acid (Kdo)-containing inner core and lipid A regions of LPS. The synthetic compounds lack all the ester-bound acyl groups which are present in natural LPS but known to be not essential for the antigenicity. The simplest compound is N,N'-diacylated glucosamine β1-6 disaccharide 4'-monophosphate 2 which corresponds to the des- O-acyl derivative of 1-dephospho lipid A. The other three contain one or two Kdo moieties linked to 2. The most complex one is a tetrasaccharide equivalent to the des- O-acylated 1-dephosphorylated derivative of LPS from Escherichia coli Re-mutant. Syntheses were performed by stepwise condensation of appropriately protected sugar moieties and final hydrogenolytic deprotection. The synthetic des- O-acyl LPS analogs were effectively purified by means of reversed phase HPLC to give homogeneous preparations.
Regulation of endotoxin mitogenicity in murine spleen cells by tumor necrosis factor α
Authors: Jakobs D.M. , Schade F.U.
Published: January 2008

In the present study the role of tumor necrosis factor α (TNFα) in endotoxin-induced mitogenicity of mouse spleen cells was examined. TNFα was found to enhance endotoxin-induced proliferation of spleen cells. However, in the absence of endotoxin, tumor necrosis factor treatment was without effect. An antiserum against TNFα completely abolished the mitogenic effect of endotoxin in spleen cell cultures. This inhibition was reversed by exogenously added TNFα. The TNFα production in spleen cell cultures reached a maximum after 6 h. When the antiserum was added to cultures at various time intervals following endotoxin addition, maximal inhibition was observed at a time point 6 h after the start. These data suggest that TNFα has a function in endotoxin-induced mitogenicity of murine spleen cells.
Endotoxin induced cytotoxicity of macrophages is due to apoptosis caused by nitric oxide production
Authors: Yamamoto Y. , He P. , Klein T.W. , Friedman H.
Published: January 2008

Bacterial LPS is one of the most powerful immunostimulators in nature and causes a wide spectrum of acute pathophysiological effects recognized as toxic properties. At the cellular level, LPS also is cytotoxic for a variety of cells. However, the molecular mechanisms responsible for LPS cytotoxicity are not well understood. In this study, possible mechanisms of LPS cytotoxicity for mouse macrophages were examined in comparison with the effect of detoxified LPS (DeLPS). Mouse peritoneal exudate macrophages cultured with 10 μg/ml of LPS for 48 h evinced approximately 40% cell death as measured by the tetrazolium dye reduction assay. Co-treatment of the macrophages with IFNγ enhanced LPS-associated toxicity so that as little as 0.1 μg/ml of LPS induced a significant toxicity. In contrast, neither DeLPS alone nor the combination of DeLPS and IFNγ induced any cytotoxicity even at a high concentration of DeLPS, such as 100 μg/ml, and a relatively long incubation period such as 72 h. Examination of nitric oxide (NO) production demonstrated a dose-response production of NO in culture supernatants of LPS treated macrophages but not in DeLPS macrophages. However, when the macrophages were primed with IFNγ and stimulated with LPS, more NO production was observed as compared to stimulation with LPS alone. Macrophages were cultured with LPS in the presence of anti-IFNβ; cytotoxicity as well as NO production was significantly reduced. Treatment with the NO inhibitor, NG-monomethyl-L-arginine, completely blocked production of NO and, furthermore, diminished the cytotoxicity induced by either the combination of IFNγ and LPS or LPS alone. Investigation of the possible mechanism of LPS induced cytotoxicity implicated the involvement of apoptosis as shown by DNA fragmentation. Furthermore, treatment with the NO inhibitor completely blocked DNA fragmentation induced by LPS and IFNγ. The data obtained suggest that LPS-induced cytotoxicity of macrophages may be due to apoptosis caused by excessive production of NO.
Taxol: a promising endotoxin research tool
Authors: Manthey C.L. , Vogel S.N.
Published: January 2008

Recently, endotoxin research has benefited from the cross fertilization of two fields of study. Investigation into the cellular actions of the anticancer drug, taxol, has suggested novel tools with which to investigate the signaling apparatus that mediates macrophage activation by bacterial lipopolysaccharide. 2 In turn, this research may ultimately cause a re-examination of the belief that microtubules are the singular molecular target for taxol and suggest additional potential mechanisms for the antineoplastic actions of taxoids. The aim of this chapter is to review the actions of taxol on macrophages and the evidence that taxol engages the LPS signaling apparatus. Microtubule-independent targets for taxol are proposed, as is the use of taxol as a novel tool for endotoxin research.
Structural investigation of the lipopolysaccharide from Proteus mirabilis R45 (Re-chemotype)
Authors: Vinogradov E.V. , Thomas-Oates J.E. , Brade H. , Holst O.
Published: January 2008

Five phosphorylated saccharides were isolated from the deacylated then N-acetylated lipopolysaccharide (LPS) of Proteus mirabilis R45 (Re-chemotype) by anion-exchange chromatography. Their structures were determined by 1- and 2-dimensional 1H- and 3C-nuclear magnetic resonance spectroscopy as α-Kdo-(2-4)-[β-L-Ara pNAc-(1-8)-]-α-Kdo-(2-6)-β-D-GIc pNAc-(1-6)-α-D-GIc pNAc 1-phosphate (1), α-Kdo-(2-4)-[β-L-Ara pNAc-(1-8)-]-α-Kdo-(2-6)-β-D-Glc pNAc-(1-6)-α-D-Glc pNAc 1,4'-bisphosphate (2), α-Kdo-(2-4)-α-Kdo-(2-6)-β-D-Glc pNAc-(1-6)-α-D-Glc pNAc 1-phosphate (3), α-Kdo-(2-4)-α-Kdo-(2-6)-β-D-Glc pNAc-(1-6)-α-D-GlcpNAc 1,4'-bisphosphate (4), and β-L-Ara pNAc 1-phosphate (5) (ArapNAc, 4-acetamido-4-deoxy-L-arabinopyranose; Kdo, 3-deoxy-D-manno-octulopyranosonic acid). Compounds 1-5 were obtained from deacylated LPS in a molar ratio of ~1.1:0.8:1.1:1.0:0.6 as determined by high-performance anion-exchange chromatography. Although we cannot exclude that in the deacylated LPS (without N-acetylation) the molar ratio may be different, the result can be taken as indication that in LPS about 50% of the 4'-phosphates of lipid A are substituted by (β-L-AraρN. Furthermore, our data prove that the first Kdo in the carbohydrate chain is partially substituted by a second residue of ArapN.

The de-O-acylated LPS was additionally investigated using fast atom bombardment and B/E linked scan mass spectrometry which confirmed the above findings and also identified minor amounts of another LPS species possessing a third pentosamine residue.
Design of a semi-synthetic (polymyxin-B•NHS-LC-biotin)4lavidin tetramer and evaluation of its ability to inhibit lipopolysaccharide induced TNFα synthesis
Authors: Coyne C.P. , Moritz J.T.
Published: January 2008

A method is described for the semi-synthetic production of (polymyxin-B•NHS-LC-biotin) 4lavidin tetramer. In phase I of semi-synthesis procedures, polymyxin-B was reacted with NHS-LC-biotin reagent resulting in the generation of the reactive intermediate, polymyxin-B•NHS-LC-biotin.

In phase II of the conjugation procedure, the polymyxin-B•NHS-LC-biotin complex was combined with purified avidin producing the tetramer complex, (polymyxin-B•NHS-LC-biotin) 4lavidin. A 'long-chain' biotinylation reagent, NHS-LC-biotin minimized steric hinderance phenomenon thereby maximizing the binding of multiple lipopolysaccharide molecules.

Binding avidity of (polymyxin-B•NHS-LC-biotin) 4lavidin for lipopolysaccharide was established with the application of fluorescein isothiocyanate Escherichia coli (055:B5) lipopolysaccharide conjugate (FITC-LPS). Applying a tissue culture based biological assay, (polymyxin-B•NHS-LC-biotin) 4lavidin was capable of inhibiting Salmonella minnesota (RS) lipopolysaccharide induced synthesis of tumor necrosis factorα (TNFα).
Limulus amebocyte lysate (LAL) detection of endotoxin in human blood
Authors: Novitsky T.J.
Published: January 2008

Limulus amebocyte lysate (LAL) has been applied to the detection of endotoxin in human serum, plasma and blood since the early 1970s. Although the diagnostic potential of LAL for endotoxemia was recognized immediately, the assay's modest sensitivity and specificity (for Gram-negative sepsis/bacteremia) were perceived as limiting the clinical usefulness of LAL. In an attempt to overcome these drawbacks, many studies have been conducted since the initial work by Levin and his colleagues. Numerous attempts have been made to improve the sensitivity of the assay by changing the formulation of the LAL and assay methodology. The original gel-clot method has for the most part been replaced with turbidimetric or chromogenic methods. The amount of endotoxin detectable within a 1 h incubation period has gone from the nanogram to the picogram range. Since blood (plasma) components interfere with the test, various methods to remove inhibition and/or enhancement have been developed. The chloroform extraction technique of Levin and co-workers has been replaced with acid extraction or with dilution and heating. Partitioning of endotoxin in blood may also influence the assay (recovery). Many recent investigators use platelet-rich plasma instead of ordinary plasma, while a few studies have used whole blood. Even with all the improvements, the specificity and related diagnostic usefulness of the LAL assay for Gram-negative sepsis remain an obstacle for regulatory acceptance. This may have more to do with our understanding of the septic process than with the ability of LAL to detect endotoxin. Although a recent study indicates that the type of Gram-negative bacteremia may be a critical determinant for clinical utility of the LAL test, the presence of endotoxin is not highly predictive of Gram-negative sepsis and vice versa. However, with the potential availability of anti-endotoxin therapy, the diagnosis of endotoxemia, with or without bacteremia, may be extremely important for timely and effective treatment modalities. It is concluded that the LAL test and accompanying sample preparation has evolved into a clinically useful test for the detection of circulating endotoxins and even its modest predictability for sepsis may have some clinical utility.
Lipopolysaccharide binding protein (LBP) as a marker of protein leakage in cerebrospinal fluid
Authors: Heumann D. , Gallay P. , Barras C. , Albrecht H. , de Flaugergues J.C. , Steck A. , Glauser M.P.
Published: January 2008

The presence of functional lipopolysaccharide binding protein (LBP) was investigated in cerebrospinal fluid (CSF) samples of patients with neurological disorders. LBP was detected in CSF by RIA and by a bioassay that measures the ability of LBP to present LPS to human monocytes. Mean concentration of LBP was 1.72 μg/ml in normal CSF, i.e. 1/10 of the concentration measured in normal plasma. LBP concentration was found to be increased in CSF of patients with neurological disorders associated with increased protein levels in CSF, in patients with meningitis/encephalitis and with compressing tumors. LBP levels correlated with protein levels, but not with the clinical presentation. Even in normal CSF, LBP was present in concentrations sufficient to trigger maximal activation of monocytes upon LPS challenge, as measured by tumor necrosis factor induction of mRNA and protein synthesis. The role played by LBP in CSF remains to be determined. However, because it is present and functionally fully active, LBP could play a detrimental role in CSF in the presence of low concentrations of LPS during episodes of Gram-negative infections.
Effects of bactericidal/permeability-increasing protein on endotoxin-induced fever and Escherichia coli-induced shock in rabbits
Authors: Porat R. , Paddock H.N. , Cominelli F. , Marra M.N. , Scott R.W. , Schwaitzberg S.D. , Dinarello C.A.
Published: January 2008

Binding of bactericidal/permeability-increasing protein (BPI) to endotoxin inhibits endotoxin-triggered responses. We investigated the effects of BPI on endotoxin fever and E. coli-induced septic shock in rabbits. Pre-incubation of endotoxin with BPI blocked fever compared to control rabbits (n = 6). A marked reduction in fever was also observed when BPI was injected before endotoxin. E. coli-challenge resulted in 66% mortality (n = 6); pre-treatment with BPI resulted in survival of all animals (n = 3). Mean arterial blood pressure was higher in BPI-treated compared to control rabbits. Comparable leukopenia and thrombocytopenia was observed with either BPI or vehicle treatment. Tumor necrosis factor (TNF) and interleukin-1 receptor antagonist were similarly elevated in both BPI- and saline-treated rabbits. However, in BPI treated rabbits, peak TNF levels were 34 % lower compared to saline controls ( P < 0.05). Further studies are warranted to assess whether BPI may have therapeutic potential for the treatment of septic shock.