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To examine the link between meningococcal C (MenC) vaccine size and immunogenic response, a panel of MenC glycoconjugate vaccines were prepared differing in chain length, molar mass and hydrodynamic volume. The preparations consisted of different lengths of MenC polysaccharide (PS) covalently linked to monomeric purified tetanus toxoid (TT) carrier protein using the coupling reagent ethylcarbodiimide hydrochloride (EDC). Size exclusion chromatography with multi-angle light scattering (SEC-MALS) and viscometry analysis confirmed that the panel ofof MenC-TT conjugates spanned masses of 191,500 to 2,348,000 g/mol, and hydrodynamic radii ranging from 12.1 to 47.9 nm. The two largest conjugates were elliptical in shape, whereas the two smallest conjugates were more spherical. The larger conjugates appeared to fit a model described by multiple TTs with cross-linked PS, typical of lattice-like networks described previously for TT conjugates, while the smaller conjugates were found to fit a monomeric or dimeric TT configuration. The effect of vaccine conjugate size on immune responses was determined using a two-dose murine immunization. The two larger panel vaccine conjugates produced higher anti-MenC IgG1 and IgG2b titres after the second dose. Larger vaccine conjugate size also stimulated greater T-cell proliferative responses in an in vitro recall assay, although cytokines indicative of a T-helper response were not measurable. In conclusion, larger MenC-TT conjugates up to 2,348,000 g/mol produced by EDC chemistry correlate with greater humoral and cellular murine immune responses. These observations suggest that conjugate size can be an important modulator of immune response.

Characteristics and outcomes of exercise-related out-of-hospital cardiac arrests (OHCA) are not well described in Australia.This was a retrospective observational study of non-exercise-related aetiology and exercise-related OHCAs from the Victorian Ambulance Cardiac Arrest Registry between 2008 and 2016, including 12-month quality of life data from 2010 to 2016. Exercise-related OHCA was defined as taking place during or within 1 h of at least moderate intensity exercise. Descriptive statistics and adjusted logistic regression analyses were performed.During the study period there were 482 exercise-related and 33,358 non-exercise-related OHCAs. Jogging/running were the most frequent precipitating sports. The incidence rate of exercise-related OHCA was low (1 per 100,000 person-years). Compared to non-exercise-related aetiology, exercise-related OHCAs were younger (mean 54 versus 70 years, p 0.001) and more likely to present in an initial shockable rhythm (85% versus 18%, p 0.001). Bystander CPR, and bystander or EMS defibrillation at any time, were more common among exercise-related arrests (93% versus 38%, p 0.001 and 91% versus 24%, p 0.001, respectively). A public access defibrillator was used in 24% of shockable exercise-related OHCAs compared with 4% of non-exercise-related OHCAs (p 0.001). After adjustment for arrest characteristics, exercise-related OHCAs were more likely to survive to hospital discharge (50% versus 14%, p 0.001; adjusted odds ratio [AOR] = 1.56, 95% confidence interval [CI] 1.25-1.96, p 0.001) and survive to 12-months with good functional recovery (72% versus 62%, p = 0.012; AOR = 1.57, 95% CI 1.08-2.28, p = 0.018).Exercise-related OHCAs were associated with better short- and long-term prognoses compared to non-exercise-related OHCAs. The underlying factors associated with this survival benefit warrant further investigation.

The therapeutic monoclonal antibody (mAb) TGN1412 (anti-CD28 superagonist) caused near-fatal cytokine release syndrome (CRS) in all six volunteers during a phase-I clinical trial. Several cytokine release assays (CRAs) with reported predictivity for TGN1412-induced CRS have since been developed for the preclinical safety testing of new therapeutic mAbs. The whole blood (WB) CRA is the most widely used, but its sensitivity for TGN1412-like cytokine release was recently criticized. In a comparative study, using group size required for 90% power with 5% significance as a measure of sensitivity, we found that WB and 10% (v/v) WB CRAs were the least sensitive for TGN1412 as these required the largest group sizes (n = 52 and 79, respectively). In contrast, the peripheral blood mononuclear cell (PBMC) solid phase (SP) CRA was the most sensitive for TGN1412 as it required the smallest group size (n = 4). Similarly, the PBMC SP CRA was more sensitive than the WB CRA for muromonab-CD3 (anti-CD3) which stimulates TGN1412-like cytokine release (n = 4 and 4519, respectively). Conversely, the WB CRA was far more sensitive than the PBMC SP CRA for alemtuzumab (anti-CD52) which stimulates FcγRI-mediated cytokine release (n = 8 and 180, respectively). Investigation of potential factors contributing to the different sensitivities revealed that removal of red blood cells (RBCs) from WB permitted PBMC-like TGN1412 responses in a SP CRA, which in turn could be inhibited by the addition of the RBC membrane protein glycophorin A (GYPA); this observation likely underlies, at least in part, the poor sensitivity of WB CRA for TGN1412. The use of PBMC SP CRA for the detection of TGN1412-like cytokine release is recommended in conjunction with adequately powered group sizes for dependable preclinical safety testing of new therapeutic mAbs., Highlights • Sensitivity of different CRA formats determined by power analysis of group sizes. • PBMC solid phase CRAs were highly predictive for TGN1412 but not alemtuzumab. • Whole blood CRAs were predictive for alemtuzumab but poorly predictive for TGN1412. • TGN1412 cytokine release was inhibited by glycophorin A and red blood cells.

There is an urgent unmet need for human tissue bioassays to predict cytokine storm responses to biologics. Current bioassays that detect cytokine storm responses in vitro rely on endothelial cells, usually from umbilical veins or cell lines, cocultured with freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. These assays therefore comprise cells from 2 separate donors and carry the disadvantage of mismatched tissues and lack the advantage of personalized medicine. Current assays also do not fully delineate mild (such as Campath) and severe (such as TGN1412) cytokine storm-inducing drugs. Here, we report a novel bioassay where endothelial cells grown from stem cells in the peripheral blood (blood outgrowth endothelial cells) and PBMCs from the same donor can be used to create an autologous coculture bioassay that responds by releasing a plethora of cytokines to authentic TGN1412 but only modestly to Campath and not to control antibodies such as Herceptin, Avastin, and Arzerra. This assay performed better than the traditional mixed donor assay in terms of cytokine release to TGN1412 and, thus, we suggest provides significant advancement and a definitive system by which biologics can be tested and paves the way for personalized medicine.

Inactivated polio vaccines, which have been used in many countries for more than 50 years, are produced by treating live poliovirus (PV) with formaldehyde. However, the molecular mechanisms underlying virus inactivation are not well understood. Infection by PV is initiated by virus binding to specific cell receptors, which results in viral particles undergoing sequential conformational changes that generate altered structural forms (135S and 80S particles) and leads to virus cell entry. We have analyzed the ability of inactivated PV to bind to the human poliovirus receptor (hPVR) using various techniques such as ultracentrifugation, fluorescence-activated cell sorting flow cytometry and real-time reverse transcription-PCR (RT-PCR). The results showed that although retaining the ability to bind to hPVR, inactivated PV bound less efficiently in comparison to live PV. We also found that inactivated PV showed resistance to structural conversion in vitro , as judged by measuring changes in antigenicity, the ability to bind to hPVR, and viral RNA release at high temperature. Furthermore, viral RNA from inactivated PV was shown to be modified, since cDNA yields obtained by RT-PCR amplification were severely reduced and no infectious virus was recovered after RNA transfection into susceptible cells. IMPORTANCE This study represents a novel insight into the molecular mechanisms responsible for poliovirus inactivation. We show that inactivation with formaldehyde has an effect on early steps of viral replication as it reduces the ability of PV to bind to hPVR, decreases the sensitivity of PV to convert to 135S particles, and abolishes the infectivity of its viral RNA. These changes are likely responsible for the loss of infectivity shown by PV following inactivation. Techniques used in this study represent new approaches for the characterization of inactivated PV products and could be useful in developing improved methods for the production and quality control testing of inactivated polio vaccines. Measuring the antigenicity, capsid stability, and RNA integrity of inactivated PV samples could help establishing the optimal balance between the loss of infectivity and the preservation of virus antigenicity during inactivation.

Aim To determine if cytokine release with a solid phase assay is predictive of adverse responses for a range of therapeutic mAbs. Methods Cytokine ELISAs and a multi-array system were used to compare responses generated by different therapeutic mAbs using a solid phase assay. Flow cytometry was employed to determine the cellular source of those cytokines. Results Only TGN1412 and muromonab-CD3 stimulated CD4+ T-cell mediated cytokine release characterized by significant (all P < 0.0001) IFNγ, TNFα, IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17 and IL-22 release, comparable with T-cell mitogen. Significantly greater (P < 0.0001) IL-2 release with TGN1412 (2894–6051 pg ml−1) compared with muromonab-CD3 (62–262 pg ml−1) differentiated otherwise comparable cytokine responses. Likewise, TGN1412 stimulated significantly more (P = 0.0001) IL-2 producing CD4+ T-cells than muromonab-CD3 and induced Th1, Th2, Th17 and Th22 subsets that co-release this cytokine. Significant TNFα release was observed with bevacizumab (P = 0.0001), trastuzumab (P = 0.0031) and alemtuzumab (P = 0.0177), but no significant IL-2 release. TGN1412 and muromonab-CD3 caused pro-inflammatory cytokine release despite significantly (both P < 0.0001) increasing numbers of T-cells with a regulatory phenotype. Conclusions The severity of the adverse response to TGN1412 compared with muromonab-CD3 and other therapeutic mAbs correlates with the level of IL-2 release.

SUMMARY The molecular basis of common variable immunodeficiency (CVID) is undefined, and diagnosis requires exclusion of other diseases including X-linked lymphoproliferative disease (XLP). This rare disorder of immunedysregulation presents typically after Epstein–Barr virus infection and results from defects in the SAP (SLAM associated protein) gene. SAP mutations have been found in a few patients diagnosed previously as CVID, suggesting that XLP may mimic CVID, but no large-scale analysis of CVID patients has been undertaken. We therefore analysed 60 male CVID and hypogammaglobulinaemic patients for abnormalities in SAP protein expression and for mutations in the SAP gene. In this study only one individual, who was found later to have an X-linked family history, was found to have a genomic mutation leading to abnormal SAP cDNA and protein expression. These results demonstrate that SAP defects are rarely observed in CVID patients. We suggest that routine screening of SAP may only be necessary in patients with other suggestive clinical features.

The unexpected outcome of the clinical trial of the superagonistic CD28 mAb TGN1412 (IgG4κ) continues to stimulate interest. We show that TGN1412 binds similarly to human and cynomolgus macaque FcγR, eliminating the possibility that differences in Fc-mediated interactions with FcγR contributed to the failure of preclinical testing in macaques to predict toxicity in humans. The influence of the Fc domain and C region structure on the in vitro functional activity of TGN1412 was investigated using F(ab′)2 and Fab fragments derived from TGN1412 recovered from the trial and recombinant TGN1412 subclass variants and mutants. Superagonistic activity, as measured by cytokine release and proliferation, was assessed by exposing PBMCs to immobilized mAbs/fragments or to aqueous mAbs/fragments in the presence of HUVEC monolayers. Removing the Fc generally curtailed or abolished PBMC activation. However, eliminating detectable FcγR-binding of the IgG4 by mutation (L235E) did not abrogate activity. Stabilizing the “wild-type” IgG4 hinge (S228P) enhanced activity without increasing FcγR binding, which could only partially be explained by inhibition of Fab arm–exchange. Subclass switching the IgG4 mAb to IgG1 decreased activity, whereas switching to IgG2 markedly increased activity. We conclude that the C region strongly influences in vitro CD28-mediated superagonistic signaling. Superagonism requires an intact Fc, as shown by the absence of activity of TGN1412 Fab and F(ab′)2 fragments, but, notably, appears to be relatively independent of FcγR-binding properties. We propose that the Fc, potentially through restricting flexibility, maintains a favorable V region conformation to allow superagonistic activity. These findings have important implications for Ab design strategies.

The failure of regulatory science to keep pace with and support the development of new biological medicines was very publically highlighted in March 2006 when the first-in-man Phase I clinical trial of the immunomodulatory CD28-specific monoclonal antibody (mAb) TGN1412 ended in disaster when all six volunteers suffered a life-threatening adverse reaction termed a ‘Cytokine Storm’. The poor predictive value of standard pre-clinical safety tests and animal models applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays and animal models that are both sensitive and predictive of clinical outcome in man. The non-predictive result obtained from pre-clinical safety testing in cynomolgus macaques has now been attributed to a lack of CD28 expression on CD4+ effector memory T-cells that therefore cannot be stimulated by TGN1412. In contrast, high levels of CD28 are expressed on human CD4+ effector memory T-cells, the source of most TGN1412-stimulated pro-inflammatory cytokines. Standard in vitro safety tests with human cells were also non-predictive as they did not replicate in vivo presentation of TGN1412. It was subsequently shown that, if an immobilized therapeutic mAb-based assay or endothelial cell co-culture assay was used to evaluate TGN1412, then these would have predicted a pro-inflammatory response in man. New in vitro assays based on these approaches are now being applied to emerging therapeutics to hopefully prevent a repeat of the TGN1412 incident. It has emerged that the mechanism of pro-inflammatory cytokine release stimulated by TGN1412 is different to that of other therapeutic mAbs, such that standard pro-inflammatory markers such as TNFα and IL-8 are not discriminatory. Rather, IL-2 release and lymphoproliferation are optimal readouts of a TGN1412-like pro-inflammatory response.

Two methods for predicting the risk of pro-inflammatory clinical infusion reactions during monoclonal antibody therapy were evaluated. In the first, the antibody of interest is immobilised by air-drying onto 96-well plates prior to the addition of human peripheral blood mononuclear cells (PBMCs). In the second, the antibody is added in aqueous phase to a co-culture of human PBMCs and human endothelium-derived cells. In both methods the cells are incubated with the antibody to allow the accumulation of pro-inflammatory cytokines, quantified by enzyme-linked immunosorbent assay (ELISA). The antibodies associated with clinical infusion reactions, Herceptin, Campath-1H and TGN1412, gave the largest responses taking into account the data for all readouts (tumour necrosis factor-α, TNF, interleukin-6, IL-6, IL-8, IL-2 and cell proliferation) for both methods. Overall, the antibodies tested could be ranked as follows: Tysabri

The failure of preclinical testing to predict the severity of the cytokine storm experienced by the recipients of the superagonistic anti-CD28 monoclonal antibody (mAb) TGN1412 during its Phase 1 clinical trial prompted the development of new in vitro experimental approaches for mimicking in vivo cytokine release and lymphoproliferation. Peripheral blood mononuclear cells (PBMC) presented to TGN1412 immobilised on plastic has previously been shown to stimulate a pro-inflammatory cytokine response. The aim of the present study was to investigate a 'co-culture' model for the detection of TGN1412-like immunomodulatory activity in which TGN1412 was presented to PBMC in the presence of monolayers of endothelium-derived cells and other cell types, followed by measurement of cytokine levels in the culture supernatants and proliferation of PBMC. Culturing PBMC with TGN1412 over primary human umbilical vein endothelial cells (HUVEC) and HUVEC-derived cell lines retaining classic endothelial markers, but not cell lines of non-endothelial origin, mediated the specific release of IL-6, IL-8 and TNFα, and proliferation of PBMC. Low levels of IL-2 and IFNγ were also detected in supernatants with most donors of PBMC. An anti-CD28 mAb agonist, i.e., not a superagonist like TGN1412, did not stimulate cytokine release or proliferation of PBMC in co-cultures. In conclusion, co-culture experiments for TGN1412-specific cytokine release required cells of endothelial origin. However, the profile of released cytokines in co-cultures did not mirror that in the clinical trial participants or the responses from PBMC exposed to TGN1412 immobilised on plastic, suggesting that TGN1412 stimulation of PBMC can occur through more than one mechanism.

Background and purpose In 2006, a life-threatening 'cytokine storm', not predicted by pre-clinical safety testing, rapidly occurred in all six healthy volunteers during the phase I clinical trial of the CD28 superagonist monoclonal antibody (mAb) TGN1412. To date, no unequivocal explanation for the failure of TGN1412 to stimulate profound cytokine release in vitro or in vivo in species used for pre-clinical safety testing has been established. Here, we have identified a species difference almost certainly responsible for this disparate immunopharmacology. Experimental approach Polychromatic flow cytometry and intracellular cytokine staining were employed to dissect the in vitro immunopharmacology of TGN1412 and other therapeutic mAbs at the cellular level to identify differences between humans and species used for pre-clinical safety testing. Key results In vitro IL-2 and IFN-γ release from CD4+ effector memory T-cells were key indicators of a TGN1412-type response. This mechanism of cytokine release differed from that of other therapeutic mAbs, which can cause adverse reactions, because these other mAbs stimulate cytokine release primarily from natural killer cells. In contrast to humans, CD28 is not expressed on the CD4+ effector memory T-cells of all species used for pre-clinical safety testing, so cannot be stimulated by TGN1412. Conclusions and implications It is likely that activation of CD4+ effector memory T-cells by TGN1412 was responsible for the cytokine storm. Lack of CD28 expression on the CD4+ effector memory T-cells of species used for pre-clinical safety testing of TGN1412 offers an explanation for the failure to predict a 'cytokine storm' in humans.

TGN1412 is a "superagonistic" CD28 monoclonal antibody (IgG4) that caused serious adverse events at its first time in human clinical trial. In the present study, different in vitro methods for detecting and quantifying unwanted pro-inflammatory activity of therapeutic monoclonal antibodies (mAbs) such as TGN1412 are described. The antibody of interest is immobilised by wet-coating or air-drying onto polypropylene or polystyrene 96-well plates prior to the addition of human peripheral blood mononuclear cells (PBMCs). The cells are incubated for 16-24h with the immobilised antibody which allows the accumulation of pro-inflammatory cytokines, quantified by enzyme-linked immunoabsorbent assay (ELISA), in response to the antibody. Cytokine responses stimulated by TGN1412 immobilised by air-drying onto polypropylene and polystyrene plates were much larger than responses to TGN1412 wet-coated onto polypropylene and polystyrene plates, respectively. In additional experiments with other mAbs associated with clinical reactions, air-dried mAbs stimulated larger tumour necrosis factor-alpha (TNF) responses than antibodies added in aqueous phase. Also, TGN1412 air-dried onto plastic plates stimulated large proliferative responses of 3-day cultures of lymphocytes. It was concluded that immobilising mAbs by air-drying offers a useful in vitro method for detecting and quantifying pro-inflammatory activities of therapeutic mAbs.

This is the first part of Professor Eastwood’s paper given as the AUA Annual Guest Lecture on 24 October 2007.

The CD28-specific mAb TGN1412 rapidly caused a life-threatening “cytokine storm” in all six healthy volunteers in the Phase I clinical trial of this superagonist, signaling a failure of preclinical safety testing. We report novel in vitro procedures in which TGN1412, immobilized in various ways, is presented to human white blood cells in a manner that stimulates the striking release of cytokines and profound lymphocyte proliferation that occurred in vivo in humans. The novel procedures would have predicted the toxicity of this superagonist and are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system. Data from these novel procedures, along with data from in vitro and in vivo studies in nonhuman primates, suggest that the dose of TGN1412 given to human volunteers was close to the maximum immunostimulatory dose and that TGN1412 is not a superagonist in nonhuman primates.

This article is written by the chairman and a panel member of the UK Benchmarking Group in Earth Science, Environmental Science and Environmental Studies. In it we have discussed the broad “purpose” of benchmarking and the timescale and remit afforded to the group. As far as the benchmark statement itself is concerned, we have reviewed the statement section by section concentrating especially both on the rationale underpinning each section and the way in which the statement may be used for the purpose of academic review. Finally, we have looked briefly at the process of academic review itself, in so far as it is understood at the moment. Although we are confident that the Benchmarking Group as a whole would agree with the vast majority of this article, nonetheless it must be seen as representing only our own views.

An examination of employment change based upon an exploratory classification of Northern Ireland's environmental industry is undertaken. Results show that, in 1993, some 12 900 persons or around 2.1% of the total civilian employment in the region were working in a ‘green production sector’. By using a range of data sources it is suggested that significant opportunities for employment expansion currently exist. Indeed, a total of between 4000 and 6000 new environmental jobs could be created in Northern Ireland by the year 2003. Most of the growth is anticipated in the traditional areas of recycling and re-use, pollution treatment and control and energy conservation. In a small and peripheral European economy these figures have important implications for the development of the local labour market. To this end, a series of recommendations is put forward that could help Northern Ireland maximize the employment potentials offered by these types of environmental activity. Copyright © 2001 John Wiley & Sons, Ltd and ERP Environment.

This article offers a reinterpretation of the public career and work of E. P. Thompson. Much of the current critical work on Thompson assumes that he had two, largely separate, careers, one as an historian, the other as a political activist. As a result his historical writing is generally considered in isolation from an equally large and influential body of political writings, which represented interventions in contemporary debates from the struggle of the Yugoslav partisans in the 1940s to the campaigns for nuclear disarmament in the 1980s. The present article attempts an historical reading of Thompson’s political writings, reconsiders his achievement as an historian, and seeks to offer a more integrated and critical reading of his historical and political vision.

One does not have to be a card-carrying postmodernist to understand that historical periods do not possess inherent characteristics. ‘Eras of Reform’, ‘Ages of Revolution’, ‘Triumphs of Reform’, and ‘Centuries of Reformation’ exist only in, and as, texts. They represent, in the simplest of forms, readings of the past. The nomenclatures we employ to demarcate and characterise particular historical moments embody fundamental ideological assumptions, encapsulating an idée fixe, and exposing the crux of the creative—or, if you prefer, the scholarly—process. Traditionalists might already be crying foul, insisting that our titles, or period characterisations, reflect rather than impute salience. History, as Geoffrey Elton might have instructed us, reports rather than constructs the past. The writing of history, Elton suggested in 1967, ‘amounts to a dialogue between the historian and his materials. He supplies the intelligence and the organising ability, but he can interpret and organise only within the limits set by his materials. And those are the limits created by a true and independent past.’ Revealingly, though, our book titles generally describe or construct processes, rather than recall events; and processes are abstractions whose full meaning, as Vico told us long ago, is apparent only in retrospect. Of course the Reformation happened, but not in the same way as the Battle of Trafalgar happened. Thus describing the sixteenth century as ‘The Age of Reformation’ orders the experience of the European West in a very particular way. It was also, and some might say equally, an age of exploration, of empire, of inflation, of hunger, and of the explosion of print culture.

Environmentally based economic development and employment opportunities in Northern Ireland are identified and predicted over the medium term to the year 2000. The results show that in 1993 about 1.9% of the total Northern Ireland workforce (11 500 workers) was employed within a ‘green production sector’. Using an innovative economic modelling technique it is suggested that there are significant employment generation opportunities available and a total of up to 15 000 new jobs could be created in Northern Ireland's green economy by the turn of the century. Moreover, and on the basis of these findings, four recommendations are offered which could help maximize the employment potentials afforded by environmental activity.

Re-reading much of Edward Thompson's work, I have been struck afresh by how deeply English his cast of mind was. It was not so much that his scholarly work focused almost exclusively on English subjects, but rather that his reading of English history so often verged on a celebration of English exceptionalism. The finest summary of Thompson's reading of long-run developments in English historical formation remains his 1965 essay 'The Peculiarities of the English', that wonderfully controlled polemic where Thompson married intellectual virtuosity and theoretical plasticity to so telling an effect.1 If this 1965 essay hinted at the great arch of Thompson's historical vision, the rest of his oeuvre offered stonework of a very distinctively English kind.2 Now it is true that some Thompsonian concepts have travelled, the idea of 'moral economy' most notably, but even his most generally influential theoretical formulations were rooted in the English popular experience and in English archival sources. Whether or not Thompson died in the faith of a 'Muggletonian Marxist' I am not competent to judge, but only the most English of Radicals could have defined himself as such in New York in 1968.3 All of this is crucially relevant both to Thompson's reading of the French Revolution and to the way in which he sought to situate the French Revolution in English history. Throughout his work Thompson constantly and emphatically played down the significance of 1789 for English history.

One of the more interesting developments in recent historical writing has been a reconsideration of the debates over poor law reform. In the sharply-demarcated world of post-war scholarship, the poor law fell clearly, if somewhat problematically, into the domain of social history. For obvious contemporary reasons, post-war social history devoted a good deal of scholarly energy to constructing a history of social policy. Much of this work was problematized in terms of the then orthodox agenda of the welfare state. The dominant questions concerned modes of assessing entitlements, mechanisms for delivering welfare, and the bureaucratic characteristics of the old and new poor laws. Despite its considerable empirical merits, this kind of social history was inhibited by its methodological and problematic certainties. To a large extent this was a social history which defined itselfagainsttraditional political history, offering a narrative of social policy formation which, whilst not eliminating political processes from its account, tended to marginalize their normative significance. One extreme formulation was Sydney Checkland's ‘socially innocent state’. Here the loss of ‘social innocence’ on the part of the British state is evaluated directly in terms of its willingness to develop the kind of social agenda and administrative machinery characteristic of modern wellfarism. For Checkland in particular, social policy was conceived almost exclusively in terms of state-driven programmes of ‘social improvement’. The old poor law, with its pattern of local management, discretionary administration, and paternalist social vision flatly contracted the statutorily-articulated welfarism which Checkland took to be axiomatic to a coherently-conceived social policy. In terms of statutory authority and administrative machinery, Checkland saw the new poor law as a critical move towards a more coherently-constructed state social policy.

Whether he traced historic truths with zeal,Whether he traced historic truths with zeal,For the state's guidance or the public weal;Or fancy, disciplined by curious art,Informed his pen; or wisdom of his heart;Or judgements, sanctioned in the patriotic mindBy reverence for the rights of all mankind:Wide were his aims, yet in no human breastCould private feelings meet in holier rest.[From William Wordsworth's public epitaph on Robert Southey]The language of politics is, by its very nature, both imprecise and artificial. Its meaning is shaped, not so much by linguistic conventions, but by the very political processes of which language constitutes the essential currency. One can, therefore, only understand the nuances of a given political vocabulary when one relocates it within those historical and political frameworks that it both animated and circumscribed. Once political language is viewed as central to the political process, one can begin to appreciate the extent to which even the basic vocabulary of politics must itself be plastic. One might indeed go further and suggest that the dynamism of a given political system is reflected in organic transformations in the political language it employs. These transformations are most apparent in the radically different meanings that are imputed to terms such as “legitimate” and “constitutional,” on the one hand, or “liberty” and “equality,” on the other. The process of political evolution can be traced as clearly in the development of political vocabulary as it can in the reform of political institutions. It is hardly surprising, therefore, that one of the principal impacts of the French Revolution in Britain lay in its stimulating a renewed struggle over the language of politics.4 Nowhere was that struggle more apparent than in the transformed language of patriotism that emerged from the debates of the 1790s.

1. Small scale sand removal (loads of 0.5 to 10 tonnes) is a persistent environmental problem on beaches within Areas of Outstanding Natural Beauty in Northern Ireland. 2. This study provides the first objective assessment of the problem in the British Isles, examining both the physical and biological impacts on the beach and the cultural background. These approaches are combined to indicate possible management strategies. 3. About 5000 to 6000 tonnes of sediment (sand and gravel) was ‘drawn’ from the eleven beaches in the study area during 1990. The rate and magnitude of sediment removal varied between and within sites, by day of the week and by season. 4. There are two direct impacts to the shoreline environment. First, over a long period, the amount of sediment removed is enough to cause serious erosion on some smaller beaches. Up to 80% of shoreline recession can be explained by sand lost through extraction. Second, extraction appears to lead to an impoverished beach fauna. More indirect impacts include the loss of aesthetic quality (important in an area reliant on tourism), disturbance of wildlife, damage to and possible reduction of access provision, and impairing the ability of the shoreline to develop foredunes. 5. The views of the coastal community are quite polarized. One group (about 55%) wish to see sand removal cease, while the remainder (45%) do not. Interviews with people actually taking sand suggest that they do not see their actions as damaging the environment. 6. Several options for future management are discussed. It would appear that a management prescription for each site, backed by legislation, might relieve the problem.