The administration of a single bolus of anti-IgM antibody to foetal lambs early in pregnancy produces prolonged B-cell depletion. The present study investigated this depletion by examining the effect, on B-cell development in the ileal Peyer's patches, of varying the timing and dosage of antibody administration and by supplementing anti-IgM with surgical splenectomy. The capacity of a 1 mg bolus of anti-IgM to deplete Peyer's patches of B cells was lost if its administration was deferred until two thirds of the way through pregnancy, but persisted beyond this time if weight-adjusted doses were used. Splenectomy of the foetus performed at an earlier age failed to extend the age at which a 1 mg dose of antibody remained effective. As the concentration of murine immunoglobulin in foetal serum was greatly reduced after 21 days, it is inferred that ongoing suppression of B-cell development is not dependent on the continued presence of murine immunoglobulin. The enduring nature of suppression could be attributable to a limited period during which differentiation of B cells from stem cells normally occurs, although further studies will be needed to investigate this and other possible explanations for the effect of anti-IgM treatment on prenatal B-cell development in sheep.


We have developed a computer-implemented, multivariate Markov chain model to project tuberculosis (TB) incidence in the United States from 1980 to 2010 in disaggregated demographic groups. Uncertainty in model parameters and in the projections is represented by fuzzy numbers. Projections are made under the assumption that current TB control measures will remain unchanged for the projection period. The projections of the model demonstrate an intermediate increase in national TB incidence  followed by continuing decline. The rate of decline depends strongly on geographic, racial, and ethnic characteristics. The model predicts that the rate of decline in the number of cases among Hispanics will be slower than among white non-Hispanics and black non-Hispanics a prediction supported by the most recent data.


The recent development and publication of evidence-based clinical practice guidelines (CPGs) for acute low back pain (LBP) has resulted in evidence-based recommendations that, if implemented, have the potential to improve the quality and safety of care for acute LBP. While a strategy has been specified for dissemination of the CPG for acute LBP in Australia, there is no accompanying plan for active implementation. Evidence regarding the cost-effectiveness of active implementation of CPGs for acute LBP is sparse. The IMPLEMENT study will consider the incremental benefits and costs of progressing beyond development and dissemination to implementation.Cost-effectiveness and cost-utility analyses alongside the IMPLEMENT cluster randomised controlled trial (CRCT) from a societal perspective to quantify the additional costs (savings) and health gains associated with a targeted implementation strategy as compared with access to the CPG via dissemination only.The protocol provided here registers our intent to conduct an economic evaluation alongside the IMPLEMENT study, facilitates peer-review of proposed methods and provides a transparent statement of planned analyses.Australian New Zealand Clinical Trials Registry ACTRN012606000098538 The recent development and publication of evidence-based clinical practice guidelines (CPGs) for acute low back pain (LBP) has resulted in evidence-based recommendations that, if implemented, have the potential to improve the quality and safety of care for acute LBP . While aThe purpose of the present paper is to describe methods for the cost-effectiveness analysis alongside the CRCT. Detailed descriptions of methods for development of the targeted implementation strategy and design of the CRCT in the IMPLEMENT study are given elsewhere .It is now well established that development and dissemination of CPGs will not necessarily produce improvements in clinical practice . Clinicaet al. [Despite this imperative, a recent review of 63 economic evaluations and cost analyses conducted alongside rigorous experimental studies of guideline implementation strategies published between 1966 and 1998 concluded that the available economic evidence was lacking in methodological rigour and often drew conclusions that 'must clearly be treated with suspicion' . A signiet al. . The actet al. [et al. conclude that 'it is very likely that the extended implementation strategy incurs extra costs without producing health gains, hence it is very likely to be not cost-effective' [Hoeijenbos et al.  calculatfective' . While cet al. [While the principles of economic evaluation for health care interventions are now well-established, the literature provides relatively few examples of well-executed economic evaluations of implementation strategies and the characteristics of CPGs raise several issues in the estimation and interpretation of cost-effectiveness ,12. The et al.  suggest The costs of guideline development may be substantial and that development and dissemination alone might have relatively little impact on practice patterns . Compariet al. [The second issue concerns the potential for repeated use of various components of the evaluated intervention. The information embedded in a CPG and an implementation strategy is 'non-rival' such that a single use does not diminish the quantity or quality of information available for subsequent use. The development of a CPG therefore amounts to a one-time investment that may find a repeated use in other populations, in subsequent cohorts of practitioners, or in other contexts. Likewise, an implementation strategy may find repeated use in other populations/contexts, in subsequent cohorts, or perhaps even for implementation of another CPG in another disease-area. Drummond et al.  note theet al. [A number of recent findings suggest that cost-effectiveness studies in the public domain may represent a biased sample of the population of economic evaluations ,15. It iet al.  suggest e.g., lower the 'response' required to be classified as a 'responder'), extend the time-horizon  and/or revise the unit cost attached to particular categories of resource use  [Published trial protocols typically include a section headed 'economic analyses' when such analyses are planned, but the description of methods is often insufficiently detailed to achieve the purpose of a protocol. Without detail, it is not possible to distinguish planned analyses from post-hoc 'mining' or 'gaming' and analysts can freely substitute between outcomes (at zero) . Each ofThe impact of moves to improve transparency and rigour in the conduct of modelled and trial-based evaluations will vary depending on the extent of discretion exercised by sponsors over research methods and dissemination of findings, the complexity of the disease-process, and the extent to which evidence gaps necessitate a reliance on assumption and/or lower level evidence . For impThe IMPLEMENT study is a CRCT, with the clusters being a sample of 92 general practices of one or more GPs drawn from a sampling frame of 1,000 general practices within the state of Victoria, Australia. Participating practices will be randomised to either a control group or an intervention group. Enrolling an average of 25 patients per practice will yield 2,300 patients for inclusion in intention-to-treat analyses. A detailed description of the design of the CRCT and of proposed methods for sample selection, randomisation, and analysis of clinical outcomes are provided elsewhere [i.e., whether implementing CPG for acute LBP is cost-saving as compared with dissemination alone), and to determine whether the implementation strategy dominates dissemination alone . The time horizon for inclusion of relevant costs and consequences is set at three months, consistent with the final scheduled follow-up of patients from the CRCT. That is to say, the economic evaluation is explicitly 'within-trial' and any subsequent extrapolation beyond the trial period will be treated as a separate research task.Cost-effectiveness and cost-utility analyses will be conducted alongside the CRCT to quantify the additional costs (savings) and health gains associated with the implementation strategy as compared with dissemination alone from a societal perspective. Specific secondary aims will be to determine whether the incremental costs of the implementation strategy are outweighed by incremental cost-savings associated with any change in practice  of Australia endorsed a CPG for acute LBP . There iIn addition to access via the existing dissemination strategy, the intervention group will receive active implementation of the CPG for acute LBP. The GPs randomised to the intervention arm will receive an implementation strategy specifically designed to address the barriers and enablers for implementation of the CPG. The intervention will concentrate on delivering the CPG's key messages, namely that diagnostic x-rays are rarely necessary in the management of acute LBP and that remaining active reduces pain and disability. The intervention will consist of a series of facilitated face-to-face small group workshops. These workshops will involve a combination of didactic lectures and small group interaction. The delivery of the intervention will be co-ordinated by a project officer and delivered by members of the research team and external facilitators.The program logic of the evaluated intervention and the symptomatology of acute LBP suggest that specific dimensions of HRQoL, such as pain-related disability, physical function, and physical pain are most relevant in capturing variation in health outcomes. However, it is possible that a differential effect might arise between the evaluated intervention and the comparator with respect to dimensions of HRQoL other than physical disability or physical pain. The outcome measures specified below will therefore provide broad coverage of HRQoL.The measures chosen to assess patient outcome are commonly used in trials of interventions for acute LBP and provide broad coverage of HRQoL, including those dimensions of HRQoL that are most likely to be relevant in identifying an effect attributable to the intervention.The RDQ is among the most widely used and well-validated measures of LBP-specific disability. The RDQ has high validity and reliability for use over the telephone and is recommended for inclusion in core sets of measures used in LBP . The RDQAn 11-point scale (0 = no pain to 10 = worst pain ever) has acceptable reliability and validity for self-reported assessment of pain .The AQoL can be used as either a psychometric instrument, yielding a descriptive measure of HRQoL, or a multi-attribute utility instrument that yields a preference-based measure of HRQoL. The AQoL descriptive system includes five latent dimensions with each dimension reflected in three items: illness , independent living , social relationships , physical senses  and psychological well-being . Four of the five dimensions and 12 of the 15 items contribute to the AQoL's preference-based measure of HRQoL, with the illness dimension excluded because it was deemed indicative of an underlying health condition rather than the impact of that health condition on HRQoL . The AQoFollow-up of patient level outcomes is scheduled for seven days and three months after their initial GP consultation for acute non-specific LBP. Table While the patient level outcomes described above are expected to capture all relevant dimensions of health outcome, there are a number of advantages in expressing the results of cost-effectiveness analyses in cost per quality adjusted life year (QALY) terms. Between-group differences in preference-based HRQoL weights derived from the AQoL will be combined with the period of time over which such differences persist to calculate effectiveness in QALY terms. Intervention effects with respect to AQoL scores will be estimated using methods specified for the main analysis of patient level clinical outcome measures, controlling for the same set of pre-specified set of potential confounders . In the et al. note that some costs may simply confirm a result that would be obtained by consideration of a narrower range of costs [Incremental costs will reflect all resource use associated with development of the implementation strategy, delivery of the implementation strategy, and any subsequent changes in practice and subsequent health effects. All research and evaluation costs will be excluded from the cost analysis. Two questions arise in specifying the minimum dataset for the cost analysis. First, can any cost items be excluded from the base-case analysis without biasing our estimate of incremental costs? And, second, for which included costs should we directly collect data from either GPs or patients? Drummond of costs . Volunteet al. note the importance of identifying capital outlays that should be amortised over the lifetime of the asset [Cost items associated with development of the implementation strategy include the cost of recruiting informants to assist development of the intervention, the cost of time in focus groups for informants and facilitators, the opportunity cost of interview and meeting rooms, the cost of time and equipment for analysis and interpretation of focus group data, and the cost of consultation with the GP advisory committee. Drummond he asset . CertainCost items associated with delivery of the implementation strategy include administrative costs associated with coordinating small group workshops, production of materials for workshops, the opportunity cost of venue use, the opportunity cost of travel time, and attendance at workshops for GPs, opportunity cost of pre- and post-workshop reflection for GPs, and labour costs associated with preparation/delivery/facilitation of workshops.Cost items associated with change in clinical practice include direct and indirect health care costs, such as use of x-rays, over-the-counter or prescription analgesics, allied health or GP consults, and the time of volunteer or paid caregivers. Practice change is also expected to impact on direct and indirect costs outside the health sector, including waiting time and travel time to attend treatment, productivity gains due to a change in specific disability, and time lost from work associated with treatment.In measuring resource use associated with development of the implementation strategy, delivery of the implementation strategy, and any subsequent changes in practice and subsequent health effects, data will be collected from the research team, from the enrolled practitioners and from the enrolled patients. Scheduled observations on resource use are listed in Table Resource use associated with the development of the implementation strategy will be costed based on financial and administrative records, as well as a detailed description of the development process obtained from the project manager and project officers. This will require recall over a relatively short period of time as to proportion of an equivalent full-time salary that project staff spent in development of the implementation strategy . Administrative and financial records will provide data as to the number of informants, total person hours spent in focus groups and interviews for informants and facilitators, use of interview and meeting rooms, total person time for analysis/interpretation of findings, and total person hours for advisory committee members.Resource use associated with the delivery of the implementation strategy will be estimated from administrative and financial records detailing resource use associated with the production of materials, total person hours spent in organising and facilitating workshops, total hours GP attendance, venue location and total hours venue hire, and practice location for attending GPs. Time spent by GPs in pre- and post-workshop reflection or self-education will be estimated based on a description of the intervention (rather than self-report) and varied in sensitivity analysis.Resource use associated with a change in clinical practice and subsequent health effects will be based on patient self-report. While GPs may be in a position to report the percentage of LBP patients referred for x-ray, patients' use of allied health care and their use of over-the-counter analgesics cannot be obtained from enrolled practitioners. It is well-known that patient self-report becomes increasingly unreliable as the period of recall increases. "For example, one study found that 10% of patients failed to report that they had been hospitalized when they were interviewed approximately five months after discharge. Even if subjects remember that they have seen a physician or have gone to a hospital, they often will not know what services they received ." For loUnit costs for health service resource use will be as per the Manual of Resource Items for use in submissions to the Commonwealth of Australia's Pharmaceutical Benefits Advisory Committee . Resource.g., average wage rates, cost of services such as childcare or cleaning services required to replace role of homemaker) is frequently used to value the unpaid work of retirees, homemakers, and the unemployed. For example, the Bureau of Transport Economics [Production losses are most frequently valued via the human capital approach, whereby the actual gross earnings of those in paid employment are used to estimate the value of time absent from work due to treatment or illness . Note, hconomics  estimateconomics  and averconomics , and theconomics .et al. employed a friction cost approach to the estimation of productivity gains/losses in their study of guideline implementation for non-specific LBP [Due to the relatively short duration for an episode of acute non-specific LBP and the relatively short duration of follow-up, the difference between human capital and friction cost  estimateific LBP , productAll costs will be inflated to current Australian dollars for the year of study completion. While costs and benefits associated with delivery of the implementation strategy and any subsequent within-trial changes in practice are expected to accrue within a 12 month period, costs associated with development of the implementation strategy are expected to accrue up to 24 months prior to costs associated with delivery of the implementation strategy and any subsequent within-trial changes in practice. All costs and benefits will be converted to present values using an annual discount rate of 5% in the base-case, and annual rates of 3% and 7% in sensitivity analysis.Results from the economic evaluation will be expressed as: additional costs (savings) per point difference in RDQ at seven days and three months; additional costs (savings) per point difference in usual pain at seven days and three months; and additional costs (savings) per QALY gained.Cost-effectiveness acceptability curves (CEACs) will be used to quantify and visualise sampling and parameter uncertainty. The CEAC is derived from the joint density or joint distribution of incremental costs (ΔC) and incremental effects (ΔE) for the intervention of interest against a comparator, and represents the proportion of the density where the intervention is cost-effective for a range of willingness to pay thresholds (λ). The joint density will be obtained via non-parametric bootstrapping from the distribution of observed cost/effect pairs. Because the base-case analysis will include all cost items listed above, a separate CEAC will be calculated using best estimate and upper/lower bound estimates for travel time, time of volunteer caregivers, productivity gains and for other uncertain parameters such as the discount rate. Sensitivity analysis on the CEAC will also adjust estimates of incremental costs and incremental benefits for practice characteristics and patient characteristics to consider the external validity of study findings.Publication and peer-review of protocols for economic evaluation is advisable for much the same reasons as has been advocated elsewhere for trial protocols . PublicaEthical approval for this trial was obtained from the Monash University Standing Committee on Ethics in Research involving Humans (2006/047).Sally Green is a member of the editorial board of Implementation Science. The remaining authors declare that they have no competing interests.DM participated in the design of the trial-based economic evaluation and drafted the protocol. SF, JM, DO'C and SG participated in the design of the trial-based economic evaluation and suggested edits and revisions to the protocol. All authors read and approved the final manuscript.


Changes in the immune competence and levels of suppressore elements were assessed by mitogen stimulation and in vitro antibody production, after resection of a transplantable sarcoma. Spleen cells from tumour-resected animals were found to have depressed responses to conA as well as to the antigens SRBC and DNP-LPS. This inability to respond was gradually overcome and, by Day 21 after resection, spleen cell competence had returned to normal levels. Suppressor cells isolated from the spleens of tumour-resected animals were capable of suppressing the conA response and PFC response of normal syngeneic spleen cells in vitro. The ability to suppress the conA response of normal cells disappeared by Day 1 after resection, while the ability to suppress the anti-SRBC and anti-DNP PFC response of normal cells disappeared by Day 8 and Day 14 respectively. Serum from tumour-resected mice was also found to be suppressive to the conA response of normal spleen cells. The inhibitory material responsible for suppression eluted with the Ig-containing fraction on Sephadex G-150. This inhibitory material gradually disappeared from the serum of tumour-resected mice and was no longer apparent by Day 14. Therefore, it appeared that the return of normal lymphocyte function after tumour-resection was concomitant with the disappearance of splenic suppressor cells and suppressive serum factor.


An overview is presented of the different aspects of the role ofanalytical chemistry in process monitoring and control. On-linemonitoring is currently the most attractive option in this area,especially with unsegmented-flow techniques. In addition toallowing automation of these systems, the variety of ways in whichcalibration and recalibration can be performed allows theiradaptation to any situation by using extremely simple, home-mademanifolds. The most relevant designs are presented and criticallydiscussed in this paper.


A method is presented for the description of a heterogeneous cell population with respect to the volume and density of its cellular components, based on computer analysis of the cell-volume spectra of density-gradient fractions. Display programmes were developed to produce either a perspective plot or an isofrequency contour plot ("fingerprint") of the two-parameter data. The use of sequential density and velocity gradients permitted the separation and study of the properties of any subpopulation. We describe the results of an analysis of cellular heterogeneity in an ovarian carcinoma cell line and in 2 cases of ascites cells from human ovarian carcinoma. The proliferative state (labelling index) and growth potential (culture clonogenicity) of cells from one malignant ascites have been "mapped" in terms of density/volume parameters. The results are discussed in terms of their impact on the view of human ovarian carcinoma as a stem-cell system.


Photoradiation therapy of cancer in the presence of haematoporphyrin derivative is based on a retention of porphyrin in malignant tissue. After long term incubation of NHIK 3025 cells in the presence of 25 microgram ml-1 haematoporphyrin derivative, one fraction is easily removed from the cells by washing with a serum-rich medium. Another fraction remains bound to the cells for a prolonged time. The former does not contribute to the photosensitivity of the cells while the latter, the tightly-bound component, results in a photosensitivity proportional to the cellular contents of porphyrin. Transformed cells are shown to be slightly more sensitive and to retain 25-50% more haematoporphyrin derivative than non-transformed cells. Cytological effects of light absorbed by the tightly-bound component have been studied. The growth of treated cells is similar to that of control cells after a dose-dependent post irradiation lag period. A relatively slow leakage of lactate dehydrogenase (LDH) out of the cells takes place after treatment. The treatment induces a significant increase in the frequency of sister chromatid exchanges (SCE). We conclude that photoactivation of the tightly-bound fraction of haematoporphyrin derivative induces less damage to the outer cell membrane and probably more intracellular damage than irradiation of cells after a short period in contact with the derivative.


Tumour blood flow was characterised in a 'tissue-isolated' rat tumour model, in which the vascular supply is derived from a single artery and vein. Tumours were perfused in situ and blood flow was calculated from simultaneous measurement of (1) venous outflow from the tumour and (2) uptake into the tumour of radiolabelled iodo-antipyrine (IAP). Comparison of results from the two measurements enabled assessment of the amount of blood 'shunted' through the tumours with minimal exchange between blood and tissue. Kinetics of IAP uptake were also used to determine the apparent volume of distribution (VDapp) for the tracer and the equilibrium tissue-blood partition coefficient (lambda). lambda was also measured by in vitro techniques and checks were made for binding and metabolism of IAP using high-pressure liquid chromatography. VDapp and lambda were used to calculate the perfused fraction  of the tumours. Tumour blood flow, as measured by IAP (TBFIAP), was 94.8 +/- 4.4% of the blood flow as measured by venous outflow, indicating only a small amount of non-exchanging flow. This level of shunting is lower than some previous estimates in which the percentage tumour entrapment of microspheres was used. The unperfused fraction ranged from 0 to 20% of the tumour volume in the majority of tumours. This could be due to tumour necrosis and/or acutely ischaemic tumour regions. For practical purposes, measurement of the total venous outflow of tumours is a reasonable measure of exchangeable tumour blood flow in this system and allows for on-line measurements. Tracer methods can be used to obtain additional information on the distribution of blood flow within tumours.


The novel fluorinated 2-nitroimidazole SR-4554 is undergoing preclinical development as a magnetic resonance spectroscopy and imaging probe for hypoxic tumour cells. We have used electron energy loss spectroscopic analysis (EELS) to show selective reduction and differential subcellular localisation of SR-4554 in human ovarian multicellular spheroids. SR-4554 was demonstrated to be metabolised by these A2780 cells under hypoxic but not under normal aerobic cell culture conditions. The EELS technique illustrated that the relative amount of drug within the cytoplasm of cells from both the inner region (150-160 microns from edge) and outer edge of the spheroid did not differ significantly after an initial 3 h incubation with drug. In contrast, an 8-fold differential between the amount of drug retained in the cytoplasm (primarily ribosomes and endoplasmic reticulum) of cells from the inner vs outer regions of the spheroids was observed following a subsequent 2 h 'chase' culture in drug-free medium. Within cells from the hypoxic region of the spheroid, SR-4554 was mainly associated with the endoplasmic reticulum, nucleus and the cytoplasmic side of intracellular vesicles and also to a lesser extent with the nuclear periphery. Interestingly, the drug was only weakly associated with the mitochondria and plasma membrane of the cells. The characteristics of cellular and subcellular distribution of SR-4554 are consistent with the hypothesis that 2-nitroimidazole compounds undergo hypoxia-mediated enzymatic reduction to reactive species. These reactive species are selectively retained in the cells in which they are metabolised through covalent association with subcellular components. These findings provide additional support for the clinical development of the drug as a non-invasive probe for tumour hypoxia and at the same time illustrate the utility of the EELS technique for examining the heterogeneity of drug distribution both between and within cells.


Vector-borne diseases for which transmission occurs exclusively between vectors and hosts can be modeled as spreading on a bipartite network.Ixodes ricinus ticks on mice and lizards from two independent studies are well described by a scale-free distribution compatible with an asymptotically vanishing epidemic threshold. The commonly used negative binomial, instead, cannot describe the right tail of the empirical distribution.In such models the spreading of the disease strongly depends on the degree distribution of the two classes of nodes. It is sufficient for one of the classes to have a scale-free degree distribution with a slow enough decay for the network to have asymptotically vanishing epidemic threshold. Data on the distribution of The extreme aggregation of vectors on hosts, described by the power-law decay of the degree distribution, makes the epidemic threshold decrease with the size of the network and vanish asymptotically. Many natural, social and technological systems can be described in terms of self-organized networks of interacting entities. These networks often display topological properties, such as scale-free degree distributions, community structure and small-world phenomenon, which set them apart from simpler networks such as lattices and random networks see e.g. .In particular, the spreading of a transmissible disease can be studied by modeling the population as a network of individuals, in which an edge is placed between two individuals if there is the possibility of transmission between them. It was shown In some cases of practical interest modeling the propagation of the disease requires the introduction of a bipartite network In this work we introduce another context in which bipartite networks provide the natural framework to study epidemic spreading, namely those vector-borne diseases in which transmission occurs exclusively between vectors and hosts. The aim of this study is twofold: first, we show that the analysis of bipartite networks performed in Ixodes ricinus on their hosts. These ticks can transmit the pathogens responsible for Lyme disease (Borrelia burgdorferi) and the tick-borne encephalitis (TBE) virus  to have a scale-free distribution of contacts  To determine the degree distribution of the bipartite network we analyzed field data on the distribution of the number of ticks (nymphs and larvae) found on hosts (mice and lizards), represented in the model by the degree distribution of host nodes. Exhaustive empirical surveys have shown that macroparasites, and in particular ticks, are aggregated across host populations. This aggregative behavior has important implications for the population and evolutionary dynamics of the parasite and its host right tail of the distribution better than the commonly used negative binomial distribution in both empirical datasets. The power-law distribution is compatible with both datasets , B. burgdoferiApodemus spp. and Podarcis spp. The animals were infested only by immature ticks Ixodes ricinus. The number of mice and lizards examined are reported in The “Tuscany” dataset contains infestation data from field work conducted in a natural reserve in Le Cerbaie hills, Pisa province, central Italy. This area is characterized by Mediterranean vegetation, an optimal habitat for ticks and their hosts The “Slovakia” dataset refers to the distribution of larvae and nymphs on mice, obtained from The power-lawThe goodness-of-fit tests were based on the empirical distributions of the Kolmogorov-Smirnov statistic obtained by Monte Carlo methods as explained in


Experiments were conducted to determine the dose response of rat bladder urothelium to a range of different single and fractionated intravesicular doses of the carcinogen, N-methyl-N-nitrosourea (MNU). A dose-related response of bladder-tumour incidence to single graded doses of MNU was found, and a threshold does suitable for use of multistage carcinogenesis experiments was derived from these data. For any given total dose of MNU, the tumour incidence was greater if the MNU had been administered in several small fractions than if it had been administered in fewer larger ones. Extending the interval between doses did not reduce the tumour incidence. It is argued that these results support the multistage theory of carcinogenesis. The histopathology and cell-surface alterations which characterize the development of MNU-induced bladder cancer are described and the contribution of hyperplasia and calculi are discussed.


The construction of a microcomputer-controlled electrode switch foruse in potentiometric determinations is described. This can be coupled to most of the analytical equipment usually found in laboratories, to enable a setting up of automatic systems capable of performing sequential determinations with several ion-selectiveelectrodes. The assessment of its analytical usage and behaviour are discussed.


Prostatic intraepithelial neoplasia (PIN) has been considered as a precursor of prostatic cancer. Few reports have dealt with the long-term follow-up of PIN lesions, and there is still a lack of proof that PIN is a true premalignant lesion. The objective of this study was to evaluate PIN in the transition/central zone as a marker for subsequent development of prostatic cancer. The PIN status of tissue specimens from 789 men without prostate cancer was determined in 508 transurethral resections and 281 transvesical prostatic enucleations. All slides were reviewed blind and independently by two pathologists. The patients were followed for an average of 11 years, and the incidence of subsequent cancer and cause-specific survival were analysed. Thirty-six cases of clinical prostatic cancer occurred among the cohort of 789 men through follow-up. No association between the presence of PIN in the transition/central zone and subsequent cancer development was found. There was also no difference in survival related to PIN status among the subsequent cancer patients.


Serial transplantation of an HCG-producing human testicular teratoma in immune-deprived mice is described. The xenografted tumour was compared to the tumour of origin in histology, immunohistochemistry  autoradiography, marker production and growth rate. It is concluded that the xenograft retained the characteristics of the original tumour with the exception of a reduction in HCG-producing elements at transplantation beyond 5 serial passages.


Pre-concentration of analytes, or matrix removal to overcomeinterferences using mini- or micro-columns of exchange media prior to atomic spectrometric detection is becoming increasingly more common. This paper is a review of some of the more recent applications of chelating, ion exchange and other resins and gelsthat have been used to accomplish this.


This paper addresses some serious issues about personnel morale,fears and hopes associated with and attributed to the laboratoryrobot. The introduction of the laboratory robot into the laboratoryis examined from a managerial perspective. Human-rights androbot-rights issues are identified and addressed. Real worldexamples of how the integration of two high through-put robotsaffected the routine of a major industrial food laboratory arediscussed.


In this study, the immunohistochemical expression of a new inducible elastase inhibitor, SKALP (skin-derived anti-leucoproteinase)/elafin, in the tissue of squamous cell carcinoma and uninvolved oesophageal mucosa was studied using a polyclonal rabbit anti-serum against SKALP/elafin. The results were compared with the immunohistochemical staining of proliferating cell nuclear antigen (PCNA) and the TUNEL assay in serial sections. In non-malignant oesophageal mucosa, the expression of SKALP/elafin was localized in the cells of the stratified zone overlying the PCNA-positive basal zone. In oesophageal cancer, the incidence of the expression was significantly related to the degree of the differentiation of the tumour. Characteristically, the expression was almost limited in tumour cell nests that had a clear squamous phenotype. In tumour cell nests, the expression of SKALP/elafin was localized in the cells overlying PCNA-expressing cells and no expression was found in the cells that expressed PCNA; DNA fragmentation was often observed in the same cell layers as those in which SKALP/elafin immunoreactivity was found. This enzyme inhibitor is speculated to be involved in the induction of the cell differentiation and apoptosis of human squamous cell carcinoma cells of the oesophagus.


Human bronchoalveolar macrophages were separated from other free lung cells by density sedimentation on Percoll gradients. They were then tested for cytotoxicity against the human lung adenocarcinoma cell line A549, using a Selenomethionine-75 post-labelling assay. The cytotoxicity of the macrophages increased as the effector:target cell ratio was increased, approaching 100% at 20:1. There was no significant difference in the cytotoxicity of macrophages isolated from the lungs of bronchial-carcinoma or non-carcinoma patients. The highly cytotoxic nature of the macrophages was not due to selection of a more potent cytotoxic subpopulation of macrophages on the Percoll gradient, nor to a generally elevated activation of the macrophages due to the pathological conditions in the patients' lungs. An attempt to determine whether low concentrations of macrophages could potentiate target-cell growth proved negative. Cytotoxicity of macrophages for cultured lung target cells was not restricted to A549 cells and is not in accordance with the view that defective bronchoalveolar macrophage cytotoxicity contributes to the emergence of bronchial neoplasia.


Dear Sir,Fibrolipomas belong to the family of fat-containing lesions and are benign tumor variants of lipomas characterized by the presence of adipose tissue and abundant amounts of fibrous tissues. They are well-separated from the surrounding tissues and usually occur in adults. These le2A 62-year-old female presented with a giant mass in the abdominal wall . The firet al. in the back region.[Neural fibrolipoma is a benign tumor comprised of hypertrophied, fibrofatty tissue with intermixed nerve tissue and fibrolipomatous hamartoma of the nerve usually seen in infants and children. Althoughk region. For a lik region. In the f


These are the first fully evaluated gold(III) complexes. The activity and reactions   of the diacetato-complex bear a resemblance to cisplatin, and some of the relevant chemistry is    discussed. Preliminary screening data for C,P-chelated tertiary phosphine derivatives of gold(III) are presented.A review is given of the background to and results of the succesful pharmacological testing of         [AuX


The Bayesian methodology described in this paper has the inherentcapability of choosing, from calibration-type curves, candidateswhich are plausible with respect to measured data, expertknowledge and theoretical models (including the nature of themeasurement errors). The basic steps of Bayesian calibration arereviewed and possible applications of the results are described inthis paper. A calibration related to head-space gas chromatographicdata is used as an example of the proposed method. Thelinear calibration case has been treated with a log-normaldistributed measurement error. Such a treatment of noise stresses theimportance of modelling the random constituents of any problem.


The main difference between the reviewed paper and my scientific point of view is the acceptance of bisphosphonate therapy (BT) in daily practice for patients with advanced prostate cancer. Bisphosphonate therapy has been shown to alleviate pain which certainly has an impact on patients' quality of life and skeleton-related events (SRE) at 15 months and two years follow-up . Reduction in fractures translates directly into diminished hospitalization, costs and improves the patients' well-being.Contrary, the authors mean that the use of bisphosphonates is not established.Nevertheless, taxan-based chemotherapy (docetaxel) is the first treatment shown to increase overall survival in patients with hormone-resistant prostate cancer and is today's standard treatment of patients in Western countries. Secondary hormone treatment and administration of bisphosphonates are other established alternatives for palliation of symptoms in patients with hormone-resistant prostate cancer. The existing data support this general statement, but use of bisphosphonates should be restricted to certain conditions such as recommended by the NUCG : BT should be considered in patients with advanced prostate cancer as part of the palliative compassionate care treatment to reduce pain, SRE and use of opiates. Taxan-based chemotherapy should have priority without the combination of BT. The efficacy of combined treatment should be tested in trials such as the ongoing NEPRO study . Patients with fractures should get BT every four weeks and orally calcium/vitamin D supplement.


Mortality rates from cancer of the prostate in successive periods from 1908 to 1978 in Australia, and 1911 to 1977 in England and Wales, have been examined for trends with time and birth cohort. Age-specific rates and a proportional hazards model, designed to isolate the effect of birth cohort from those of calendar year and age, were used in the analysis. During the period of study, age-standardized mortality rose more than 5-fold in Australian men compared to just over 3-fold in men in England and Wales. In both countries the increases occurred almost entirely before 1960, with relative stability in age-standardized rates since then. The trends in mortality with year of birth were similar in the two sets of data. The risk of death from prostate cancer increased with successive birth cohorts to reach a peak in men born around 1865-1880 in Australia and men born around 1876-1896 in England and Wales. Males born later experienced a continuing reduction in rates, with the exception of age groups between 50 and 69 in which a further increase has appeared, starting with cohorts born after 1910. On the basis of current knowledge of the aetiology of prostate cancer, possible relationships between changes in sexual practices and prostate-cancer risk in successive generations have been explored. It is suggested that lowered sexual activity during the Great Depression may account for the recent cohort-based increases in mortality in middle-aged men.


A previously described defect of in vitro monocyte maturation in patients with squamous-cell carcinoma of the lung (SCC) has been investigated further. The maturation of patients' monocytes in pooled normal human serum was significantly better than in autologous serum. Conversely, the maturation of normal control monocytes was significantly depressed in patients' serum. The defect has been shown to be due to the presence of an inhibitory factor, rather than the lack of a necessary component in the patients' serum. Artificially aggregated gamma-globulin inhibited monocyte maturation in vitro, but the presence of immune complexes in the serum of many patients with SCC did not correlate well with the depression of in vitro maturation of monocytes from the same patient. Similarly, pregnancy-associated alpha 2-glycoprotein, in increased amounts in the serum of patients with SCC, showed no correlation with monocyte maturation. The addition of soluble extracts of tumour, but not of surrounding normal lung tissue significantly inhibited monocyte maturation. The results suggest that the defective monocyte maturation in patients with SCC is at least in part due to serum inhibitory factors, which are likely to be a heterogeneous group.


To assess the impact of preventive measures by the food industry, we analyzed food monitoring data as well as trends in the incidence of listeriosis estimated through three independent sources: the National Reference Center of Listeriosis; a laboratory-based active surveillance network; and two consecutive nationwide surveys of public hospital laboratories. From 1987 to 1997, the incidence of listeriosis decreased by an estimated 68%. A substantial reduction in the proportion of Listeria monocytogenes-contaminated products was observed at the retail level. The temporal relationship between prevention measures by the food industry, reduction in L. monocytogenes-contaminated foodstuffs, and reduction in listeriosis incidence suggests a causal relationship and indicates that a substantial part of the reduction in illness is related to prevention efforts.


Two cohorts of women born in 1914-18 and 1929-33 who participated in a cervical screening programme have been followed for over 40 years. Age-specific incidence rates of squamous carcinoma of the cervix by rank of smear and length of interval between smears are reported. The younger cohort, who had undergone more frequent screening, had lower rates of invasive disease. From these incidence rates, estimates of false-negative rates and regression rates for carcinoma in situ have been made. The false-negative rate was estimated to be about 15%. Regression seemed more frequent in younger than in older women. For the younger cohort it was estimated to be 72% and in the older 47%. A comparison of the rates of in situ carcinoma with those of invasive disease suggests that the screening of the younger cohort reduced the rate of invasive disease to at least one-half or one-third of what it would have been if screening had commenced later. Rates of disease appear less dependent on age than previously thought and are consistent with causation by an infective agent.


Lonidamine or 1-[ methyl]-1H-indazole-3-carboxylic acid, studied in a battery of in vitro and in vivo tests currently used for the screening of anti-tumour agents affecting cell division, has been shown to have a narrow spectrum of anti-tumour activity. The significance of this finding is discussed in the light of previous investigations suggesting that lonidamine affects mitochondrial function and not cell replication. Hyperthermia has been shown to sensitize tumour cells to lonidamine. This observation indicates that in combination with hyperthermia lonidamine has some potential for the treatment of cancer; moreover, it suggests that hyperthermia might reproduce a metabolic condition occurring in some stages of the disease. The blood levels corresponding to the anti-tumour action of lonidamine in animals are in the range of those detected in patients treated with the drug.


This paper describes an automatic system which measures the effectof temperature variations on the response of ion-selective electrodes (hysteresis curves). The system is managed by a computer program which plots hysteresis curves following a pre-established temperature cycle, from setting and controlling the temperature of thewater-bath, to acquiring the response potentials of up to five electrodes after temperature stabilization.


Emphasis is given to the effect of tumour burden on production of the monokines and of the eicosanoids and on the production of these compounds by the tumour cells. Finally, the therapeutic implications drawn from animal studies and clinical trials is discussed.Cytokines and eicosanoid products of macrophages play an essential role in expression of antitumour activity of macrophages either in a cell-to-cell contact system between the effector and the target cell or as cell-free soluble products. In this review the relationship between three main monokines, namely TNF-α, IL-1 and IL-6 and the interrelationship between these monokines and eicosanoids (PGE


Although most diseases due to pathogenic mycobacteria are caused by Mycobacterium tuberculosis, several other mycobacterial diseases-caused by M. ulcerans (Buruli ulcer), M. marinum, and M. haemophilum-have begun to emerge. We review the emergence of diseases caused by these three pathogens in the United States and around the world in the last decade. We examine the pathophysiologic similarities of the diseases  and common reservoirs of infection (stagnant or slow-flowing water). Examination of the histologic and pathogenic characteristics of these mycobacteria suggests differences in the modes of transmission and pathogenesis, though no singular mechanism for either characteristic has been definitively described for any of these mycobacteria.


This paper describes the epidemiology of Hodgkin's disease occurring in parts of the United Kingdom between 1984 and 1986. The cases were carefully diagnosed and the data rigorously cross-checked as part of the larger Leukaemia Research Fund Data Collection Survey of all lymphoid and haematogenous malignancies. The age-specific rates show the lack of an older adult second peak. Spatial variation is examined in some detail. At county and district levels there is little heterogeneity in the distribution of cases. However, at the electoral ward level there were real differences for the younger age group (0-34).


One of the vital                        activities performed by telomeres is the protection of chromosome ends. This                        allows cells to distinguish the tip of linear chromosomes from sites of DNA                        damage, and to prevent end-to-end chromosome fusions. The protective function                        of telomeres is lost when telomeres become critically short; a condition that                        is frequently found in aging cells . In mamm


A mathematical model was developed to improve understanding of the biodistribution and microscopic profiles of drugs and prodrugs in a system using enzyme-conjugated antibodies as part of a two-step method for cancer treatment. The use of monoclonal antibodies alone may lead to heterogeneous uptake within the tumour tissue; the use of a second, low molecular weight agent may provide greater penetration into tumour tissue. This mathematical model was used to describe concentration profiles surrounding individual blood vessels within a tumour. From these profiles the area under the curve and specificity ratios were determined. By integrating these results spatially, average tissue concentrations were determined and compared with experimental results from three different systems in the literature; two using murine antibodies and one using humanised fusion proteins. The maximum enzyme conversion rate (Vmax) and the residual antibody concentration in the plasma and normal tissue were seen to be key determinants of drug concentration and drug-prodrug ratios in the tumour and other organs. Thus, longer time delays between the two injections, clearing the antibody from the blood stream and the use of 'weaker' enzymes (lower Vmax) will be important factors in improving this prodrug approach. Of these, the model found the effective clearance of the antibody outside of the tumour to be the most effective. The use of enzyme-conjugated antibodies may offer the following advantages over the bifunctional antibody-hapten system: (i) more uniform distribution of the active agent; (ii) higher concentrations possible for the active agent; and (iii) greater specificity (therapeutic index).


As a popular simulation of photon propagation in turbid media, the main problem of Monte Carlo (MC) method is its cumbersome computation. In this work a table-based random sampling simulation (TBRS) is proposed. The key idea of TBRS is to simplify multisteps of scattering to a single-step process, through randomly table querying, thus greatly reducing the computing complexity of the conventional MC algorithm and expediting the computation. The TBRS simulation is a fast algorithm of the conventional MC simulation of photon propagation. It retained the merits of flexibility and accuracy of conventional MC method and adapted well to complex geometric media and various source shapes. Both MC simulations were conducted in a homogeneous medium in our work. Also, we present a reconstructing approach to estimate the position of the fluorescent source based on the trial-and-error theory as a validation of the TBRS algorithm. Good agreement is found between the conventional MC simulation and the TBRS simulation.


This paper describes the development of fully-automated synthesis systems for preparing and isolating various kinds of pharmaceuticalcompounds. The systems are versatile, and are able to performmost of the chemical reactions currently used in organic chemistry,with the exception of hydrogenation which requires high pressure.An additional benefit is the very user-friendly software.


A randomized controlled trial (RCT) comparing primary-care-centred follow-up of breast cancer patients with the current standard practice of specialist-centred follow-up showed no increase in delay in diagnosing recurrence, and no increase in anxiety or deterioration in health-related quality of life. An economic evaluation of the two schemes of follow-up was conducted concurrent with the RCT. Because the RCT found no difference in the primary clinical outcomes, a cost minimization analysis was conducted. Process measures of the quality of care such as frequency and length of visits were superior in primary care. Costs to patients and to the health service were lower in primary care. There was no difference in total costs of diagnostic tests, with particular tests being performed more frequently in primary care than in specialist care. Data are provided on the average frequency and length of visits, and frequency of diagnostic testing for breast cancer patients during the follow-up period. © 1999 Cancer Research Campaign


The activity of theophylline and disodium cromoglycate was tested on adriamycin-induced histamine release in vitro and on adriamycin cardiotoxicity in vivo. Both substances significantly inhibited the release of histamine induced by 100 micrograms ml-1 of adriamycin on rat peritoneal cells and produced significant protection against adriamycin-mediated acute and chronic cardiotoxicity in mice. N-acetylcysteine, a free radical scavenger, successfully used in the prevention of the cardiomyopathy, was also found to be an inhibitor of histamine release induced by adriamycin and compound 48/80 on rat peritoneal cells. This study further supports the hypothesis that the release of histamine may be involved in the pathogenesis of anthracycline cardiotoxicity.


The incidence of ovarian, cervical, lung and prostatic cancer was higher in second-generation Irish living in England and Wales than in all other persons in England and Wales. A higher incidence of ovarian cancer was not found in first-generation Irish. Differences in socioeconomic status did not explain these patterns.


This report highlights the association of a tumour in an acalculous gall bladder with an anomalouspancreatico-biliary junction (PBJ) and a type IVa choledochal cyst. Cholecystectomy and Rouxen-Y hepatico-jejunostomy (RHJ) was performed after division of the common bile duct (CBD)and excision of the dilated segment. The details of the case are presented and the role of an abnormalPBJ in gall bladder carcinogenesis is discussed.


As of June 1998, four randomized trials have been completed comparing the combination of paclitaxel and cisplatin with a cisplatin-based control arm. The results of three of these trials are available; one has been published as a full paper, the other two in abstract form only. Two of the reported trials  provide clear evidence that cisplatin combined with paclitaxel is a more effective regimen than one using the same dose of cisplatin combined with cyclophosphamide. The results of the third reported trial (GOG-132) are rather different, suggesting that a higher dose of single-agent cisplatin may be as effective as the paclitaxel/cisplatin combination tested in the other two trials. A number of explanations for these unexpected results have been proposed: false-positive results in GOG-111 and the Intergroup trial; false-negative results in GOG-132; high crossover in GOG-132 (including crossover before progression); the cyclophosphamide in the control arm of GOG-111 and the Intergroup trial had a negative impact on outcome in the control group in these trials; the higher dose of cisplatin when used as a single agent in GOG-132 had a positive impact on outcome for the control group in this trial. These explanations are discussed in detail, and their implications explored.


The glycosaminoglycan (GAG) content of stomach carcinoma tissue was compared with that of non-neoplastic mucosa. GAG synthesis was also studied, by an analysis of 35S-labelled material after incubation of tissue segments in medium containing 35SO4. No significant difference was found between the amount of GAG and its components in the medullary carcinoma tissue and in non-neoplastic mucosa, but GAG synthesis of the carcinoma tissue was at a much higher rate than that of the non-neoplastic mucosa. In the autoradiograph, high 35S uptake in the carcinoma cells was observed. The GAG content of the scirrhous-carcinoma tissue was about twice that of medullary carcinoma.


The ADC data transfer and manipulation routinewas written in Assembler code and in high-level language; thegraphics package and data treatment package is in Basic. For thevarious sampling speeds, all of the program can be written usingBasic-Assembler or completely in Assembler if a high samplingrate is needed. Several numerical treatment methods for chemicalkinetics have been utilized to smooth the data from experiments.A microcomputer-interfaced data acquisition system for chemicalkinetics  hasbeen developed. Analogue signals from instruments used in kineticsexperiments are amplifed by a wide-range adjustable high-gainoperational amplifier and smoothed by an op-based filter, and thendigitized at rates of up to 10The computer-interfaced system for second-order chemical kineticstudies was applied to the determination of the rate constant of thesaponification of ethyl acetate at 35°C. For this specific problem,an averaging treatment was used which can be called an intervalmethod. The use of this method avoids the diffcully of measuringthe starting time of the reaction. Two groups of experimental dataand results were used to evaluate the systems performance. All of theresults obtained are in agreement with the reference value.


The incidence of lymphomata in CBA mice is low and furthermore is unaltered by transplantation at the early blastocyst stage and being born from the lymphoma-prone AKR. The number of C-type murine leukaemia virus particles in CBA derived in this manner and milk-fostered by AKR mice in no way differs from normal CBA. The results suggest that the oncogenic Gross virus does not pass through either the transplacental or transmammary routes, or alternatively that viral replication in the CBA was in some way inhibited. Both possibilities have still to be distinguished.


In the development of test methods for solid dosage forms, manual test procedures for assay and content uniformity often precede the development of automated test procedures. Since the mode of extraction for automated test methods is often slightly different from that of the manual test method, additional validation of an automated test method is usually required. In addition to compliance with validation guidelines, developers of automated test methods are often asked to demonstrate equivalence between the manual and automated test methods. There are problems associated with using the traditional zero-difference hypothesis tests (such as the Student's t-test) for demonstrating equivalence. The use of the Westlake Interval and Schuirmann's Two One-sided test as more rigorous methods of demonstrating equivalence is discussed.


Although it is now widely endorsed that children should as far as possible rate their own health related quality of life (HRQL), there are situations where proxy information on child HRQL may be useful, especially where a child is too ill or young to provide their own HRQL assessment. There is limited availability of generic HRQL scales that have a parallel child and parent version and that are reliable, valid, brief, comprehensible and suitable for use in UK populations. The aims of this study were therefore to develop and validate a parent version of the anglicised Manchester-Minneapolis Quality of Life child form (MMQL-UK (CF)) and to determine the level of association between the child and parent versions of this form.This study was undertaken concurrently with the anglicisation and validation of the MMQL, a measure of HRQL developed for use with children in North America. At that time, no parent version existed, so the MMQL form for children (MMQL-UK (CF)) was used as the basis for the development of the MMQL-UK parent form (PF). The sample included a control group of healthy children and their parents and five exemplar groups; children diagnosed with asthma, diabetes or inflammatory bowel disease and their parents, children in remission from cancer and their parents and children in public care and their carers. Consistency of the MMQL-UK (PF) components were assessed by calculating Cronbach's alpha. Validation of the parent questionnaire was undertaken by comparing MMQL-UK (PF) component scores with comparable components on the proxy PedsQL™ quality of life scales, comparing MMQL-UK (PF) component scores between parents of healthy and chronic disease children and by comparison of component scores from children and their parents or carers. Reproducibility and responsiveness were assessed by retesting parents by follow-up questionnaires.A total of 874 children (completing MMQL-UK (CF)) and 572 parents or carers (completing MMQL-UK (PF)) took part in the study. The internal consistency of all the MMQL-UK (PF) components exceeding the accepted criterion of 0.70 and the construct validity was good with moderate correlations being evident between comparable components of the MMQL-UK (PF) and the proxy PedsQL™. Discriminant validity was demonstrated with significant differences being identified between parents of healthy children and those with chronic conditions. Intra-class correlations exceeded 0.65 for all MMQL-UK (PF) components demonstrating good reproducibility. Weak to moderate levels of responsiveness were demonstrated for all but social functioning. The MMQL-UK (PF) showed moderate parent-child correlation with the MMQL-UK (CF) for all components. The best correlations were seen for those components measuring the same construct .The MMQL-UK (PF) showed moderate to good correlations with the MMQL-UK (CF) component scores. The MMQL-UK (PF) will be of use when comparing child and parent/carer perception of the impact of a child's condition on their HRQL or where the child is too ill or young to provide their own report. The measurement of health-related quality of life (HRQL) is increasingly becoming part of the overall assessment of a patient's health both in the clinical and the research setting, as it provides a more complete picture of the health of the patient. Measuring HRQL includes assessing the patient's perceptions of their physical, emotional and social health and function that can supplement clinical information on their health status.It is now widely endorsed that children as far as possible should rate their own HRQL ,2. HowevThere are conflicting views regarding the benefits of using proxies for measuring HRQL. There is some doubt as to whether proxy reports provide an accurate reflection of the child's HRQL ,6-8. PatWhen measuring the HRQL of children it may be necessary or desirable to obtain reports from their parents . CliniciIn spite of this, may measures of child HRQL do not include parallel parent versions ,18. For This questionnaire was originally developed in the US for use with child cancer survivors . The oriPedsQL™ measurement system is a modular approach to measuring HRQL in children and adolescents and their parents which is rapidly becoming established in the US and Europe ,22. AnglThis study was carried out in the context of a wider study to anglicise and shorten the Manchester-Minneapolis Quality of Life Survey for children (MMQL-UK (CF)). The MMQBefore wider administration of the MMQL-UK (PF) could take place, the phrasing of the questions from the child form had to be modified to make them adult oriented. This was done by qualitative methods. An opportunistic sample of 15 parents of school children (age range 10–18) were recruited for interviews from a local school known to one of the researchers (PU) for development of the MMQL-UK (PF). During the interviews parents were asked to comment on the wording and structure of the questionnaire as well as completing a draft parent form. Interviews were carried out either at the home or at Swansea University, depending on the preference of the parent.The newly developed MMQL-UK (PF) was then compared with the shortened and anglicised version of the MMQL-UK (CF). This paper concentrates specifically on the validation of the MMQL-UK (PF) and comparison with the child (CF) version. The Anglicisation and validation of the MMQL-UK (CF) is reported elsewhere . AlthougChildren and their parents or carers who met the inclusion criteria . The control group were healthy children (and their parents) who were not currently using health care resources for any serious condition. Participants were given a screening questionnaire prior to participation that included a section about health status. Anyone who was identified as having a health problem was excluded from participation in the study. Permission to approach schools was obtained from the Directors of Education in each Local Education Authority, before selecting schools via multi-stage sampling. Information was sent to head teachers of sampled schools, inviting their school to participate. A researcher visited schools expressing an interest, to discuss the project further and arrange for data collection. Written information for parents, parental consent forms and parent questionnaires were supplied for each child to take home. Parents were asked to complete their questionnaires at home and return them to school by a specified date, along with consent for their child to complete the questionnaires. It was emphasised that completion of questionnaires should not involve consultation with the child. For those children that had parental consent, re-explanation and completion of questionnaires followed in class a week later, under the supervision of the researcher.In both subject and control groups, children with moderate to severe learning difficulties and children and parents for whom English was not their first language were excluded from the study.The study was approved by the Welsh Multi-centre Research Ethics Committee (MREC). Informed consent was sought from all children (subjects and controls) and their parents or those with parental responsibilities (for children less than 16 years of age), following oral and written explanation of the study.Data were analysed using the Statistical Package for Social Sciences (SPSS) version 11.4.The internal consistency of the MMQL-UK (PF) components were assessed by item-total correlations and Cronbach's alpha . QuestioThe construct validity of the MMQL-UK (PF) components were assessed by comparing them with the appropriate parent PedsQL™ quality of life scales. If the components were valid measures of HRQL, they would be expected to show significant small to moderate levels of correlation with each of the PedsQL™ scales, with the largest correlations being seen between the PedsQL™ scales measuring physical, social, emotional and school function and the comparable MMQL-UK (PF) components.The discriminant validity of the MMQL-UK (PF) was assessed by comparison of component scores between parents whose children were being treated and the parents of the control group. Our a priori hypothesis was based on identifying moderate to large differences in effect size between each exemplar and the control group . If the The relationship between the MMQL-UK (CF) and MMQL-UK (PF) was determined using Pearson's correlation. If the two reports measure the same concept, then moderate correlation would be expected between the component scores of the MMQL-UK (CF) and the MMQL-UK (PF).Following initial completion of the MMQL-UK (PF) by parents of the exemplar group children, they were asked to complete a second 'retest' questionnaire the next time their child visited clinic. This was a maximum of three months after the first assessment. In addition to completing the MMQL-UK (PF), the parents of children were asked to rate whether they thought their child's health had changed  since the first questionnaire was completed. Those parents reporting no change were included in the reproducibility analysis. Reproducibility was assessed using intra-class correlation co-efficient .The responsiveness of the MMQL-UK (PF) was assessed by using the scores of the exemplar group parents who reported a change in their child's health. The response ratio (mean change in scores for subjects reporting a change divided by the standard deviation of the subjects reporting no change) was used to quantify the responsiveness . The larIn order to have a parallel proxy report, question selection for the parent form replicated that for the child form. A total of 29 questions were selected for the anglicised and shortened MMQL-UK (CF) and MMQL-UK (PF) with five proposed components: physical appearance, school functioning, social functioning, emotional functioning and physical functioning.874 children and 572 parents completed the MMQL-UK (CF) and MMQL-UK (PF). The internal consistency of the MMQL-UK (PF) was excellent, with all components exceeding the accepted criterion of 0.70  was good, with significant correlations being evident between the MMQL-UK (PF) and the proxy PedsQL™ on those scales measuring similar constructs, i.e physical functioning, emotional functioning, social functioning and school functioning (see Table Table Intra-class correlations ranged from 0.65–0.91 for the MMQL-UK (PF) components demonstrating good reproducibility for the questionnaire ) was successfully developed based on the anglicised and shortened child version which has been recently validated in the UK (MMQL-UK (CF)). The parGood internal reliability was found for the MMQL-UK (PF), with alphas exceeding 0.70 for all the components, thus making them acceptable for group comparisons . ConstruDiscriminant validity was demonstrated for the MMQL-UK (PF) proxy report with differences being noted in HRQL by parents of healthy children and children with chronic health conditions and carers of children in local authority care. The reproducibility and responsiveness of the MMQL-UK (PF) were indicated by good test-retest results. The relationship between the MMQL-UK (CF) and MMQL-UK (PF) was confirmed by moderate correlations indicating that the two reports measure the same concept.The availability of a proxy report is important as there may be occasions when a child is either unable or unwilling to complete a HRQL measure. However interpretation of proxy reports should be undertaken with caution as they may not accurately reflect the child's view, particularly for some components. However if they are used in conjunction with a clinical consultation or other objective assessments they could potentially provide useful information on the health of the child .It should be recognised that both child and proxy ratings have value but the question is to clarify how differences in perception of HRQL arise between the child and the proxy . It has It is recommended that parent proxy reports be available for child HRQL measures, a condition that the PedsQL™ also fulfils. The availability of proxy-reports in addition to child reports may be more desirable than reports from the child alone. In medical consultations, the clinicians often look to the parents for guidance regarding medical decision making in relation to their children . The parFurther studies are needed to determine the accuracy of the MMQL-UK (PF) proxy reports compared with the MMQL-UK (CF) child reports in other conditions and different age groups of children. The usefulness of the MMQL-UK (PF) in assessing longitudinal outcomes of children also warrants further attention.This study established the reliability and validity of a new MMQL proxy report (MMQL-UK (PF)). The MMQL-UK (PF) showed good correlations with the child form (MMQL-UK (CF)) in healthy children, those in public care and those suffering from chronic conditions.Health related quality of life (HRQL), Minneapolis-Manchester Quality of Life Instrument (MMQL), Child Form (CF), Youth Form (YF), Parent Form (PF), Inflammatory Bowel Disease (IBD), Bone Marrow Transplant (BMT), Acute Lymphoblastic Leukaemia (ALL), Multi-centre Research Ethics Committee (MREC), Statistical Package for Social Sciences (SPSS), United Kingdom (UK)The author(s) declare that they have no competing interests.HAH was the primary author on the manuscript and was responsible for methodological and statistical support throughout the study and analysis of the final study results. JGW secured funding and led the study, provided methodological support throughout and was involved in writing the manuscript. PU was the primary researcher, was responsible for co-ordinating and managing the study on a day-to-day basis, for data collection and collation, data analysis and input into writing the manuscript. WYC provided methodological and statistical support throughout the study, was involved in the final study analysis and was involved in writing the manuscript. AM provided clinical support for the study, was involved in designing the study and was involved in writing the manuscript. CE was involved in designing the study, provided methodological support throughout and was involved in writing the manuscript. SJ was involved in designing the study and was involved in writing the manuscript. MEM Jenney provided clinical support, was involved in designing the study, provided methodological support throughout and was involved with writing the manuscript. ITR provided methodological and statistical support throughout the study. All authors read and approved the final manuscript.


The morbidity of high-dose chemotherapy has been considerably reduced by the use of autologous peripheral blood progenitor cell reinfusion. Most studies have used myeloid colony-stimulating factors after stem cell reinfusion, making it difficult to determine the relative contribution of each of these variables to the early recovery of blood cells. The financial implications of colony-stimulating factor use are an area of concern as dose intensification in chemosensitive malignancies is increasingly employed. We have studied 19 consecutive patients receiving high-dose chemotherapy with and without filgrastim  after stem cell infusion to examine its effect on the kinetics of blood cell recovery, the complications of myelosuppression and the associated costs. Analysis of the two treatment groups reveals that administration of filgrastim 10 micrograms kg-1 day-1 following stem cell reinfusion does not further accelerate haemopoietic recovery, fails to reduce the incidence of neutropenic fever or antibiotic usage and significantly increases the cost of the procedure. The results of this study do not support the routine use of filgrastim after high-dose chemotherapy and peripheral blood stem cell reinfusion.


Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is currently based on phenotypical analysis of an expanded pedigree. Diagnostic guidelines ('Amsterdam criteria') proposed by the International Collaborative Group on HNPCC are often too stringent for use with small families. There is also the possibility of false-positive diagnosis in large pedigrees that may contain chance clusters of tumours. This study was conducted to determine the effect of family size on the probability of diagnosing HNPCC according to the Amsterdam criteria. A total of 1052 patients with colorectal cancer were classified as HNPCC or non-HNPCC according to the Amsterdam criteria. Associations between this diagnosis and the size of the first-degree pedigree were evaluated in logistic regression and linear discriminant analyses. Logistic regression showed a significant association for family size with the Amsterdam-criteria-based HNPCC diagnosis. Linear discriminant analysis showed that HNPCC diagnosis was most likely to occur when first-degree pedigrees contained more than seven relatives. Failure to consider family size in phenotypic diagnosis of HNPCC can lead to both under- and overestimation of the frequency of this disease. Small pedigrees must be expanded to reliably exclude HNPCC. Positive diagnoses based on assessment of eight or more first-degree relatives should be supported by other clinical features.