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This is the first of two chapters which address wider organisational aspects of social work stress. Chapter 6 explores those aspects that are largely related to the ways in which social work agencies are organised and managed — the factors that can be improved if the political will to bring about change exists or can be generated. The focus of this chapter, by contrast, is on those aspects of social work that cannot be changed — the factors that are intrinsic to the nature of the social work enterprise.

Pottage and Evans (1992) argue that: ‘A shift from the traditional view of stress as a personal problem located in individuals, towards seeing it as an indicator of the ineffectiveness of work environments, systems and practices is necessary’ (pp. 12–13). This is very much in line with the perspective we have adopted here, based on the view that stress is both an individual problem and an organisational one. Indeed, as our discussions in Chapter 4 suggested, we would even go so far as to say that it is a social and political matter. This chapter therefore examines those aspects of stress which are related to the organisations in which social work staff work. In particular, the focus is on those factors within the organisational context which, depending on how they are handled, can either assist staff in dealing with their pressures, or actually contribute to making those pressures overspill into stress. As McDerment (1988) points out: ‘Organizational contributors to individual suffering cannot be emphasised enough’ (p. 44).

The term ‘stress’ is used in everyday speech in a loose and nonspecific way to refer broadly to the process of coping with life’s pressures and problems and the negative feelings this can generate. However, in order to study stress and its effects, causes and so on, we need a more precise definition — a degree of academic rigour is called for.

Preface.- Acknowledgements.- Introduction.- The Costs of Stress.- Sources of Stress.- Stress, Coping and Personality.- The Social Context.- The Social Work Task.- The Organisational Context.- Prevention and Remedy.- Conclusion.- Bibliography.- Index.

Background: Activating mutations in the receptor tyrosine kinase, KIT, are found in the majority of gastrointestinal stromal tumors (GIST) and further secondary resistance mutations in KIT frequently arise upon treatment with tyrosine kinase inhibitors such as imatinib. KIT and its mutant forms are sensitive clients of HSP90 and it has been suggested that HSP90 inhibition could be an effective treatment for both imatinib-sensitive and imatinib-resistant GIST, which can occur simultaneously in different clones within the same patient. Methods: AT13387 is a fragment-derived, potent HSP90 inhibitor, which is currently being evaluated in clinical trials. To evaluate its anti-tumor activity against GIST, AT13387 was tested in both imatinib-sensitive (GIST882, GIST-PSW) and imatinib-resistant (GIST430, GIST48) in vitro and in vivo GIST models. Results: AT13387 inhibited the proliferation of GIST cell lines at sub-100 nM potencies, irrespective of their sensitivity to imatinib. Treatment of GIST882, GIST430 and GIST48 cells with AT13387 induced HSP70, a marker of HSP90 inhibition, whilst reducing the levels of the client proteins KIT, AKT and their phosphorylated forms. A concomitant decrease in the levels of phospho-ERK and phospho-S6 demonstrated that KIT signaling was being inhibited in all cell lines, whilst an increase in cleaved PARP indicated apoptosis. In contrast, treatment with imatinib inhibited KIT signaling only in the imatinib-sensitive line, GIST882. In vivo, the efficacy of AT13387 was tested in imatinib-sensitive (GIST-PSW) and imatinib-resistant (GIST430) xenograft models. AT13387, dosed once a week, inhibited the growth of both xenografts; depletion of phospho-KIT and inhibition of KIT signaling were again seen in these tumors. As expected, treatment with imatinib caused significant regression of the GIST-PSW tumors but not of GIST430. The combination of imatinib and AT13387 significantly enhanced tumor growth inhibition (T/C 21%) over either of the monotherapies (T/C 30% for AT13387, 46% for imatinib) in the GIST430 xenograft. Importantly, the combination was well tolerated. Conclusions: AT13387 is currently being evaluated in a Phase II GIST trial both as single agent and in combination with imatinib. These results support the potential efficacy of the compound in both imatinib-sensitive and imatinib-resistant GIST and its current testing in this disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A217.

In principle, it would seem to be preferable to examine asset demands (and supplies) within the context of a complete multi-asset portfolio model, rather than in single individual equations. The advantage of such an approach is that the allocation of the financial wealth of a sector among a variety of assets (and liabilities) is analysed as an interdependent decision: the demand equations explicitly take into account the fact that a decision to hold funds in a particular form is simultaneously a decision not to hold these funds in an alternative form. Furthermore, by examining the simultaneous response of sets of asset demands to changes in different explanatory variables, it is possible to impose, and to test, additional constraints upon the values that the coefficients in the system should take. For example, if the rate of interest on national savings is raised, it is possible not only to analyse the interest sensitivity of the demand for that asset, but also to see the extent to which the increase in demand is at the expense of the demand for money or other liquid assets. Such information, on the substitutability of different assets, is clearly of use to policy-makers.

The incorporation of proxies for risk and brokerage costs, and other specific tests of the theories outlined in Chapters 2, 3 and 4, are comparatively rare in empirical demand for money studies. Instead, most empirical work has concentrated upon the need to isolate a stable money demand function at the aggregate level, using the key opportunity cost and scale variables discussed in Chapter 5. Most studies published in the 1960s and early 1970s, such as Meltzer (1963), Brunner and Meltzer (1963), Laidler (1966a) and Goldfeld (1973) for the US, and Kavanagh and Walters (1966), Laidler and Parkin (1970) and Goodhart and Crockett (1970) for the UK, were able to find stable and well-determined money demand functions. The precise form of the equations, and the type and period of data used, varied between studies; static long-run equations of the form given in (5.3) were common for annual data, while studies using quarterly data generally estimated short-run equations, such as (5.6) and (5.14), which allowed for adjustment and expectational lags. The results, for the US in particular, were broadly invariant to the precise data period involved and the particular definitions of money, interest rate and scale variable used. Consequently, even though little attempt was made to test for stability in any rigorous manner, nobody seriously questioned the view that stable money demand functions could be isolated. Laidler (1971) was able to claim that, ‘The evidence for Britain certainly points to the existence of a stable demand for money function in that economy. For the United States the evidence is overwhelming, and for Britain it is at the very least highly. suggestive’.1

Mean-variance models are most applicable to asset choice decisions where returns are truly stochastic. When applied to the study of capital-certain assets, the approach is suspect. In particular, when the variances and covariances of the rates of return are small, a mean-variance model implies that most wealth will enter the asset with the highest yield. The diversification of holdings among relatively low risk-low return assets can often only be explained in terms of transactions and liquidation costs, and many studies have considered the portfolio choice problem largely in terms of such factors. This alternative treatment of the demand for money and other assets is often termed the inventory-theoretic approach, because of its similarity to the more general analysis of the demand for inventories; it emanates from the preliminary work of Baumol (1952) and Tobin (1956) on the transactions demand for money. Although these models were developed independently, their conclusions are very similar. In each case, the demand for transactions balances arises from the non-synchronisation of income receipts and expenditures, both of which are perfectly foreseen, and the brokerage costs involved in transferring funds between non-interest-bearing money and interest-earning financial assets, which provide the alternative temporary store of value. The models are important because they attribute a role to the rate of interest in the transactions demand function, a relationship which was ignored by Keynes.

Both the risk-return and transactions cost approaches to portfolio analysis concentrate on particular themes as the basis for asset diversification. This may be deemed to be unduly restrictive; in practice, portfolio holders choose from a large set of assets, with characteristics which can often neither be solely represented by mean-variance space nor differences in liquidity and associated transactions costs. A more theoretically consistent solution lies in the formulation of mixed models, which combine elements of both approaches. However this type of approach is likely to result in demand functions which are not empirically tractable and consequently there have been few attempts to develop such models. Exceptions are the models of Buiter and Armstrong (1978) and Spencer (1984). Buiter and Armstrong utilise the Baumol inventory-theoretic model of money demand, but assume an uncertain return on the bond. The demand for money is shown to depend upon a mixture of transactions and risk-return variables; the former consisting of income and the brokerage fee, and the latter the expected return and the standard deviation of the return on the risky asset.

Variations in sterling M3 are often closely associated with changes in sterling bank lending to UK residents. Such lending increased considerably after the removal of direct controls in the Competition and Credit Control reforms of 1971. The company sector, in particular, reduced its traditional reliance on the capital markets in the 1970s and increasingly began to use bank lending as a source of external finance. It is therefore not surprising to find that the breakdown of the broad demand for money function in the 1970s was accompanied by similar problems in the modelling of bank lending equations. Whereas studies based upon data periods covering the 1950s and 1960s, such as Norton (1969) and Artis (1978), had indicated that reasonably stable bank lending equations could be isolated, Cuthbertson and Foster (1982) found that, when later data periods were considered, the isolation of such functions became more problematical. Their study looked at bank lending to industrial and commercial companies, and in particular how such lending was modelled in versions of three large macro models current in the early 1980s.

In comparison to the plethora of empirical studies on the demand for money function, there have been few attempts to model the non-bank private sector’s demand for long-term government securities (gilts). The issue was analysed by Norton (1969) in a pioneering study, while more recent models of the demand for government bonds are developed in Spencer (1981) and Hoggarth and Ormerod (1985). One of the main issues, analysed by these later studies, is the role and importance of expected capital gains in determining the demand for gilts. In each case, an attempt is made to model the relative return on gilts in each period, defined as the long-term rate of interest plus the ex post capital gain over the period, less the rate of interest obtainable on alternative capital-safe short-term assets.1 Various models are used for this purpose, ranging from simple autoregressive forecasting schemes to more sophisticated ‘structural’ models, which relate the relative return to explicit economic information.

Portfolio analysis is concerned with the development of theoretical models designed to analyse the factors affecting the financial assets held by economic agents, together with the empirical testing of these models. The agents may be individuals and firms, in which case we are concerned with the way in which private sector wealth is allocated between different assets, or alternatively financial institutions where the deposits of customers are allocated among competing assets so as to satisfy the balance sheet identity. Such an approach to asset choice decisions has its roots in early studies of the demand for money. In his formulation of the speculative demand for money, Keynes analysed the way in which individuals allocate their given wealth between interest-bearing bonds and money in the form of cash balances which earns no pecuniary return. The choice is based upon the expected holding-period return on bonds, which not only depends upon the interest income, but also upon expectations about movements in the market rate of interest and hence the price of bonds; these expectations will, in turn, be based on what is perceived to be the ‘normal’ rate of interest. If market rates are low, below the ‘normal’ rate, and therefore expected to rise over the holding period, a capital loss is to be expected on bond holding; individuals will sell bonds and hold their entire portfolio in cash, as long as the interest income from bond holding is not enough to offset this expected capital loss. On the other hand, if market rates are high, above the ‘normal’ rate, and expected to fall over the holding period, individuals will expect capital gains from bond holding; they will accordingly transfer their wealth from cash to bonds.

An alternative approach to the modelling of monetary aggregates is that based upon the notion of ‘disequilibrium money’. Artis and Lewis (1974, 1976) were the first to formulate such a concept, in their attempt to explain the breakdown in the UK money demand function in the 1970s. In the traditional approach to estimating money demand equations, it is implicitly assumed that the actual money supply is always equal to the aggregate short-run demand, so that the money market is continually in equilibrium. Such an assumption is uncontroversial when the money stock is demand determined, as is generally assumed to have been the case in the UK in the 1950s and 1960s. However, the assumption appears to be a less applicable characterisation of the UK money market after 1970, particularly for broad money. Artis and Lewis argue that large independent changes in the UK money supply, in the early 1970s, led to a disequilibrium in the money market in which supply exceeded demand. This expansion in the money stock occurred for a number of reasons. An important factor was the Competition and Credit Control reforms, which created a new spirit of competition in the banking system and abolished the direct controls on bank advances. In addition, budget deficits incurred by the government in the early 1970s were largely financed by money creation.

The mean-variance, or risk-return, approach to portfolio analysis is based upon the premise that the investor in allocating his wealth between different assets takes into account, not only the returns expected from alternative portfolio combinations, but also the risk attached to each such holding. This risk is usually assumed to arise out of uncertainty over future asset prices, and can occur in any asset where the expected holding period is less than the term to maturity. Stocks and shares fall into such a category because prices vary according to market conditions, with the risk of capital losses potentially high. However, even the returns from interest-paying capital-certain money deposits may involve an element of uncertainty over the holding period, if the interest rate is subject to market variability. In formal terms, the mean-variance approach assumes that the investor maximises the expected utility obtainable from his portfolio holding, expressed in terms of expected return and risk, subject to the restriction imposed by his budget constraint. Expected return is measured by the mean of the probability distribution of portfolio returns and risk by the standard deviation or variance of the distribution, which provides a measure of the dispersion of possible returns around the mean value. A large standard deviation implies a high probability of big deviations from expected returns, both positive and negative. Such an approach to portfolio analysis stems from Markowitz’s (1952, 1959) studies of efficient portfolio selection and Tobin’s (1958) paper on liquidity preference.

Deregulated AKT signalling is implicated in cancer. The preclinical characterization of AKT inhibitors and development of PD biomarkers are vital prior to clinical trials. Invasive techniques for clinical PD analyses pose ethical and logistical issues, hence hair follicles may represent a non-invasive option. The pyrazole AT7867 and pyrrolopyrimidine CCT128930 are novel ATP-competitive AKT inhibitors from different chemical series developed at The Institute of Cancer Research in collaboration with Astex Therapeutics (Cambridge, UK). AT7867 and CCT128930 have IC50 values against AKT2 of 17nM and 6nM respectively. Growth inhibitory IC50 (GI50) values were 2.4μM and 6.3μM in PTEN-null U87MG glioblastoma cells as measured by SRB assay. Cellular studies of both compounds in U87MG cells were carried out by Meso Scale Discovery (MSD) ELISA, western blot (WB) and immunofluorescence. These showed an initial induction of phosphorylated (p) Ser473 AKT as expected with ATP-competitive AKT inhibitors, and inhibition of downstream AKT targets, including pSer9 GSK-3β, pThr246 PRAS40, pSer127 YAP and pSer235/236 S6RP, indicating AKT pathway blockade. Interestingly, CCT128930 inhibited phosphorylation of AKT targets GSK-3β, S6RP and PRAS40 at lower concentrations (0.5-1µM), compared to AT7867 (5-10µM) in U87MG cells. Phosphorylation was also inhibited at earlier time points with equipotent doses (3XGI50) of CCT128930 versus AT7867. CCT128930 also caused a predominant G0/G1 phase arrest, while AT7867 resulted in a predominant G2 arrest in U87MG cells at equipotent doses (3XGI50), using BrdU and PI staining and flow cytometry. We report for the first time in vivo efficacy with intraperitoneally (ip) or orally administered AT7867 in PTEN-null MES-SA uterine sarcoma and U87MG mouse xenograft models; and ip administered CCT128930 in HER2-overexpressing BT474 breast cancer and U87MG xenografts, which correlated with in vivo pharmacokinetics (PK) and PD biomarker modulation of pSer9 GSK-3β and pSer235/236 S6RP using WB and MSD. Hair follicles were developed as a robust surrogate PD biomarker, with pThr246 PRAS40 as a PD readout. This assay was validated with healthy volunteer hair follicles, which were treated ex vivo with CCT128930. A significant decrease in pThr246 PRAS40 (p In conclusion, by employing an integrated PK and PD biomarker-driven drug discovery strategy, we have developed 2 novel and potent AKT inhibitors with antitumor activity, and have validated a robust surrogate biomarker assay for AKT inhibition for use in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4481.

AT13387 is a novel small molecule inhibitor of HSP90. a member of a family of molecular chaperones. Previously we highlighted an association between the high affinity binding of AT13387 to the N-terminal ATPase domain of HSP90 and the duration of target inhibition in tumor cell lines in vitro. Further, AT13387 was shown to inhibit HSP90 and deplete client proteins in tumor xenografts longer than other, lower affinity inhibitors in the class. Here we have expanded the investigation to a wider number of tumor cell lines and to in vivo xenograft models and demonstrate that AT13387 has an extended pharmacodynamic action in tumors compared to other HSP90 inhibitors. We reason that the cumulative effects of these properties allow for less frequent dosing thus maximising efficacy whilst minimising systemic exposure and the potential for side effects. This study reports extended inhibition of HSP90 by AT13387 in a wider range of tumor cell lines in vitro. A 24hr exposure of A375 (melanoma) cells to AT13387 suppressed the expression of client proteins for 72 hrs or more. However in other cell lines such as NCI-H1975 (lung) and BT474 (breast), the suppression of client proteins by AT13387 was found to last in excess of 7 days. The pharmacodynamic action of AT13387 in vivo has been compared with that of 17-AAG and SNX-5422 in A375 and NCI-H1975 xenografts in nude mice. Following a single dose of each agent, we have investigated and compared the time course of the suppression of levels of several client proteins (e.g. AKT, CDK4) and the phosphorylation of key growth/survival signalling components (e.g. pERK, pS6, pAKT). These effects were rapidly induced in tumors following treatment with AT13387 and levels remained suppressed for up to 96 hrs. The durability of the AT13387 effects was significantly greater than for the other competitor compounds. Investigation of tumor growth in these models demonstrated that the longer pharmacodynamic action of AT13387 ensured that efficacy could be maintained on a once weekly schedule, whereas such a schedule for the other agents resulted in a significant loss of their anti-tumor effects. These data provide further support for the potential benefit of long acting HSP90 inhibitors as a way of maintaining anti-tumor effects whilst minimising potential for undesirable effects associated with systemic exposure. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A217.

Hand–arm vibration is becoming a major risk in construction, leading both to lost productivity and expensive injury claims. Neil Thompson of Speedy Hire says civil engineers can help by advising on the correct choice of tools, particularly now that independent tool test data is available online.

By mid-1975 the Canadian Parliament will enact one of the most progressive and far-reaching statutes of its kind: a major revision to the Combines Investigation Act of 1889. In addition, a new Foreign Investment Review Act to prevent foreign competition in Canada, and a Canada Development Corporation to establish domestic monopoly and oligopoly structures in a number of industries, will produce a profound but as yet unpredictable effect on Canada's competitive environment.

A review of some methods that have recently been proposed to improve the temporal coherence of SASE output is presented. These methods do not require any external laser seed field, or the use of the so-called self-seeding methods, where the SASE radiation is optically filtered and improved at an early stage of the interaction before re-injection and amplification to saturation. By using methods that introduce an additional relative propagation between the electron beam and the radiation field, the localised collective interaction, which leads to the formation of the ‘spiking’ associated with normal SASE output, is removed. The result is output pulses which are close to the fourier transform limit without the need for any external seeds or intermediate optics. We acknowledge STFC MoA 4132361; ARCHIE-WeSt HPC, EPSRC grant EP/K000586/1; John von Neumann Institute for Computing (NIC) on JUROPA at Julich Supercomputing Centre (JSC), under project HHH20.

Consideration is now being given in the UK to the provision of an advanced facility at lower energy to complement the DIAMOND x-ray light source. The proposed solution, 4GLS, is a superconducting energy recovery linac (ERL) with an output energy around 600 MeV, delivering both CW beam currents up to 100 mA and alternatively high charge bunches for FEL applications. Production and manipulation of short electron bunches (fs) is a vital part of the source specification. In addition to beam lines from undulator sources in the ERL recovery path there will be three FELs: two will be oscillator types in the infrared and VUV respectively, and the third will be a high gain system for XUV output. The project is outlined, together with its status and the R&D challenges posed. A funded prototype based on a 50 MeV ERL is also described.

The Free-Electron Laser (FEL) is a cutting-edge, accelerator-based instrument that has the potential to provide simultaneous access to the spatial and temporal resolution of the atomic world. In a FEL, ultra-short electron bunches from an accelerator are passed through a long undulator magnet to generate coherent light. Recently, scientists from SLAC demonstrated the first generation of attosecond hard X-ray pulses, using the Linac Coherent Light Source. Now, as described in the review article by Alan Mak et al. [1], researchers are proposing developments that will make the FEL a fully coherent, singlecycle (attosecond) X-ray laser. The new concepts build upon a strong nexus between linear accelerators, FELs and quantum lasers, to produce extreme attosecond pulses with controllable waveforms.