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The leading models of disability struggle to fully encompass all aspects of “disability.” This difficulty arises, the author argues, because the models fundamentally misunderstand the nature of disability. Current theoretical approaches to disability can be understood as “nounal,” in that they understand disability as a thing that is caused or embodied. In contrast, this paper presents an adverbial perspective on disability, which shows that disability is experienced as a personally irremediable impediment to daily-living tasks or goals-like-ours. The picture theory of disability technically constitutes a species of relational approach because its analysis references the interplay between an individual and their environment; it differs from other relational accounts, however, by interpreting disability as a certain kind of negative experience—rather than a function of that relationship. This purely descriptive theory makes no normative claims about disability and operates as both a mechanism for the evaluation of the experience of disability and a heuristic device for the proper interpretation of disability. When disability is reframed in this way, the theory offers a particularist perspective which shows if, when, where, and how disability is experienced.

Histatin-5 (Hst5) is a member of the histatin superfamily of cationic, His-rich, Zn(II)-binding peptides in human saliva. Hst5 displays antimicrobial activity against fungal and bacterial pathogens, often in a Zn(II)-dependent manner. In contrast, here we showed that under in vitro conditions that are characteristic of human saliva, Hst5 does not kill seven streptococcal species that normally colonize the human oral cavity and oropharynx. We further showed that Zn(II) does not influence this outcome. We then hypothesized that Hst5 exerts more subtle effects on streptococci by modulating Zn(II) availability. We initially proposed that Hst5 contributes to nutritional immunity by limiting nutrient Zn(II) availability and promoting bacterial Zn(II) starvation. By examining the interactions between Hst5 and Streptococcus pyogenes as a model Streptococcus species, we showed that Hst5 does not influence the expression of Zn(II) uptake genes. In addition, Hst5 did not suppress growth of a ΔadcAI mutant strain that is impaired in Zn(II) uptake. These observations establish that Hst5 does not promote Zn(II) starvation. Biochemical examination of purified peptides further confirmed that Hst5 binds Zn(II) with high micromolar affinities and does not compete with the AdcAI high-affinity Zn(II) uptake protein for binding nutrient Zn(II). Instead, we showed that Hst5 weakly limits the availability of excess Zn(II) and suppresses Zn(II) toxicity to a ΔczcD mutant strain that is impaired in Zn(II) efflux. Altogether, our findings led us to reconsider the function of Hst5 as a salivary antimicrobial agent and the role of Zn(II) in Hst5 function.

The Human Condition is neither a well-defined nor well-described concept—nevertheless, it is generally agreed that human sexuality is a fundamental and constituent part of it. For most able-bodied persons, accessing and expressing one's sexuality is a (relatively) trouble-free process. However, many disabled persons experience difficulty in accessing their sexuality, while others experience such significant barriers that they are often precluded from sexual citizenship altogether. Recognising the barriers to the sexual citizenship of disabled persons, the concept of a Welfare-Funded Sex Doula Program has been advanced — a program specifically aimed at meeting the various (and often complex) sexual needs of disabled people. Below we show how that program can be justified within at least two different moral frameworks, the capabilities approach and liberal utilitarianism, and consider and repudiate arguments against it.

Patients relapsing with T-cell acute lymphoblastic leukemia (T-ALL) face a dismal outcome. The aim of this study was to identify new markers of drug resistance and clinical response in T-ALL. We measured gene expression and drug sensitivity in 15 pediatric T-ALL cell lines to find signatures predictive of resistance to 10 agents used in therapy. These were used to generate a model for outcome prediction in patient cohorts using microarray data from diagnosis specimens. In three independent T-ALL cohorts, the 10-drug model was able to accurately identify patient outcome, indicating that the in vitro–derived drug–gene profiles were clinically relevant. Importantly, predictions of outcome within each cohort were linked to distinct drugs, suggesting that different mechanisms contribute to relapse. Sulfite oxidase (SUOX) expression and the drug-transporter ABCC1 (MRP1) were linked to thiopurine sensitivity, suggesting novel pathways for targeting resistance. This study advances our understanding of drug resistance in T-ALL and provides new markers for patient stratification. The results suggest potential benefit from the earlier use of 6-mercaptopurine in T-ALL therapy or the development of adjuvants that may sensitize blasts to this drug. The methodology developed in this study could be applied to other cancers to achieve patient stratification at the time of diagnosis. Cancer Res; 73(9); 2749–59. ©2013 AACR.

All bacteria possess homeostastic mechanisms that control the availability of micronutrient metals within the cell. Regulatory cross-talks between different metal homeostasis pathways within the same bacterial organism have been reported widely. In addition, there have been previous suggestions that some metal uptake transporters can promote adventitious uptake of the wrong metal. This work describes the cross-talk between the Cu homeostasis pathway and the Zn, Mn, and Fe pathways in Group A Streptococcus (GAS). Using a ΔcopA mutant strain that lacks the primary Cu efflux pump and thus traps excess Cu in the cytoplasm, we show that Cu stress leads to strong downregulation of Zn and Mn uptake genes, and mild downregulation of Fe uptake genes. This effect is associated with depletion of cellular Zn levels, but not those of Mn or Fe. Co-supplementation of the culture medium with Zn and, to a lesser extent, Mn, but not Fe alleviates key Cu stress phenotypes, namely bacterial growth and production of the fermentation end-product lactate. However, neither Zn nor Mn treatment influences cellular Cu levels or Cu availability in Cu-stressed cells. In addition, we show that the Zn and Mn uptake transporters in GAS do not promote Cu uptake. Taken together, the results strengthen and extend our previous proposal that mis-repression of Zn uptake genes and cellular Zn depletion are key mechanisms of Cu stress in GAS. By comparison, although Mn homeostasis in GAS is perturbed during Cu stress, the relationship between the two metals is yet to be defined.GRAPHICAL ABSTRACT

A range of dialkylimidazolium organotrifluoroborate ionic liquids were prepared by anion metathesis from newly available potassium organotrifluoroborate salts, and their physical properties were ch...

Background Intra-abdominal hypertension (IAH) is common in critically ill patients and is associated with increased morbidity and mortality. High positive end-expiratory pressures (PEEP) can reverse lung volume and oxygenation decline caused by IAH, but its impact on alveolar overdistension is less clear. We aimed to find a PEEP range that would be high enough to reduce atelectasis, while low enough to minimize alveolar overdistention in the presence of IAH and lung injury. Methods Five anesthetized pigs received standardized anesthesia and mechanical ventilation. Peritoneal insufflation of air was used to generate intra-abdominal pressure of 27 cmH2O. Lung injury was created by intravenous oleic acid. PEEP levels of 5, 12, 17, 22, and 27 cmH2O were applied. We performed computed tomography and measured arterial oxygen levels, respiratory mechanics, and cardiac output 5 min after each new PEEP level. The proportion of overdistended, normally aerated, poorly aerated, and non-aerated atelectatic lung tissue was calculated based on Hounsfield units. Results PEEP decreased the proportion of poorly aerated and atelectatic lung, while increasing normally aerated lung. Overdistension increased with each incremental increase in applied PEEP. “Best PEEP” (respiratory mechanics or oxygenation) was higher than the “optimal CT inflation PEEP range” (difference between lower inflection points of atelectatic and overdistended lung) in healthy and injured lungs. Conclusions Our findings in a large animal model suggest that titrating a PEEP to respiratory mechanics or oxygenation in the presence of IAH is associated with increased alveolar overdistension.

IonoSolv pretreatment using protic ionic liquids has shown impressive biomass fractionation performance and ionic liquid recyclability. Lignin condensation during ionoSolov pretreatment can lower its economic value and potentially limit the valorisation of lignin to produce high value materials. Organosolv pretreatment is known for generating a high-quality lignin fraction with a large potential for value-added applications. In this study, a hybrid fractionation process was designed based on ionoSolv and organosolv pretreatments, and was tested on two representative feedstocks, Miscanthus and pine. Compared to ionoSolv processing, the hybrid pretreatment displayed an improved fractionation performance by generating a cellulose-rich pulp which was more enzyme-accessible, and by removing a higher proportion of lignin. Saccharification yields reached 89% and 74% for Miscanthus and pine, respectively. The process was also able to maintain its high fractionation performance up to 50 wt% biomass loading. HSQC spectroscopy and GPC were used to characterise the isolated lignin. Alcohol induced α-alkoxylation took place during lignin fractionation and obstructed the lignin condensation, resulting in an improved quality lignin. A technoeconomic analysis was conducted for this new hybrid pretreatment, showing lower energy consumption for the IL regeneration step at a high organic solvent concentration, suggesting lower environmental impact and higher economic potential. This ionoSolv-organosolv pretreatment could be a milestone for the development of the current ionoSolv pretreatment at commercial scale.

We present analytic threshold formulae applicable to both dispersive (time-domain) and diffractive (pattern-forming) instabilities in Fabry-Perot Kerr cavities of arbitrary finesse. We do so by extending the gain-circle technique, recently developed for counter-propagating fields in single-mirror-feedback systems, to allow for an input mirror. In time-domain counter-propagating systems walk-off effects are known to suppress cross-phase modulation contributions to dispersive instabilities. Applying the gain-circle approach with appropriately-adjusted cross-phase couplings extends previous results to arbitrary finesse, beyond mean-field approximations, and describes Ikeda instabilities., Comment: 6 pages, 2 figures

Introduction A growing number of adult patients are seeking orthodontic treatment. This research aimed to analyze the particulars of patients seeking retreatment and identify the causes of their original treatment failure. Methods An online questionnaire survey of adults seeking first-time orthodontic treatment (control) and retreatment (study) was conducted. Index of complexity, outcome, and need (ICON) scores were determined. Appraisal of treatment records was carried out to identify the causes of original treatment failure. Results No significant differences were found between retreatment adult patients and first-timers regarding reasons for seeking orthodontic treatment, malocclusion type, self-perception of malocclusion, level of self-motivation, willingness for surgery, expectations of treatment improvement and duration. The predominant reason for seeking treatment in both groups was for aesthetic concerns. Retreatment patients presented with lower ICON scores (39.4; standard error, 0.26) than the first-time patients (54.3; standard error, 0.23), P ≤0.001. The predominant reasons for original treatment failings were poor treatment, maturational changes, inadequate retention, shortcomings in diagnosis and treatment planning, and unfavorable growth. Other causes were related to transverse deficiency, secondary malocclusion (after periodontal breakdown), poor retention compliance, and temporomandibular joint degeneration. Conclusions Adult orthodontic retreatment and first-time seekers' profiles are remarkably similar. Aesthetic concerns were the leading reasons patients sought treatment. ICON was not a useful proxy of patient profiles. Poor treatment was the chief reason for the failure of the original treatment. In terms of clinical significance, clinicians should be mindful of the patient profiles of retreatment seekers and vigilant about the possible causes of failings of orthodontic treatment to avoid suboptimal outcomes.

The sexual citizenship of disabled persons is an ethically contentious issue with important and broad-reaching ramifications. Awareness of the issue has risen considerably due to the increasingly public responses from charitable organisations which have recently sought to respond to the needs of disabled persons—yet this important debate still struggles for traction in academia. In response, this paper continues the debate raised in this journal between Appel and Di Nucci, concurring with Appel’s proposals that sexual pleasure is a fundamental human right and that access to sexual citizenship for the severely disabled should be publicly funded. To that endeavour, this paper refutes Di Nucci’s criticism of Appel’s sex rights for the disabled and shows how Di Nucci’s alternative solution is iniquitous. To advance the debate, I argue that a welfare-funded ‘sex doula' programme would be uniquely positioned to respond to the sexual citizenship issues of disabled persons.

Sherpa Romeo green journal. Open access article. Creative Commons Attribution 4.0 International License (CC BY 4.0) applies.

To investigate differences in survival after diagnosis with colorectal cancer (CRC) by rurality, ethnicity and deprivation.In this retrospective cohort study, clinical records and National Collections data were merged for all patients diagnosed with CRC in New Zealand in 2007-2008. Prioritised ethnicity was classified using New Zealand Cancer Registry data; meshblock of residence at diagnosis was used to determine rurality and socioeconomic deprivation.Of the 4,950 patients included, 1,938 had died of CRC by May 2014. The five-year risks of death from CRC were: Māori 47%; Pacific 59%; non-Māori-non-Pacific (nMnP) 38%. After adjustment for demographic characteristics, comorbidity and disease stage at diagnosis, compared to nMnP the relative risk (RR) for Māori was 1.1 (95%CI: 0.8-1.3) and for Pacific 1.8 (95% CI: 1.4-2.5). We found no differences in risk of death from CRC by rurality, but some differences by deprivation.Disparity in outcome following diagnosis with CRC exists in New Zealand. Much of this disparity can be explained by stage of disease at diagnosis for Māori, but for Pacific peoples and those in deprived areas other factors may influence outcome. Further analyses of the PIPER data will explore the impact of any differences in management.

Given that a properly formed utilitarian response to healthcare distribution issues should evaluate cost effectiveness against the total utility increase, it follows that any utilitarian cost-effectiveness metric should be sensitive to increases in both individual and social utility afforded by a given intervention. Quality adjusted life year (QALY) based decisionmaking in healthcare cannot track increases in social utility, and as a result, the QALY cannot be considered a strict utilitarian response to issues of healthcare distribution. This article considers arguments against, and a possible defence of, the QALY as a utilitarian concept; in response, the article offers a similar — but properly formed — utilitarian metric called the (IALY). This article also advances a tool called the ‘glee factor’ (GF) on which the IALY may lean in a similar way to which the QALY leans on the Rosser Index.

ObjectiveToe systolic pressure is a component of the standard vascular and diabetic foot assessment. Until now, clinicians have measured only first toe pressure given a lack of evidence for measurements of the other toes. In diabetic patients, first toe measurements are often not possible because of ulceration or amputation. It was hypothesized that the adjacent second toe systolic pressure measurements would be interchangeable with those of the first toe.MethodsA prospective study was performed on 100 participants with diabetes mellitus. Duplicate systolic toe pressures were measured in the first toe and adjacent second toe using the Systoe Automated Toe Pressure System, Systoe Photophlethysmograph Sensor Cuff, and occlusion cuffs measuring 120 × 25 mm for the first toe and 90 × 15 mm for the second toe. Correlation analysis was followed by Ordinary Least Products regression to detect and distinguish fixed and proportional bias between the two toe measurements. The acceptable limits of interchangeable results were defined as 5–10 mmHg.ResultsCorrelation coefficient r = 0.908; p

Setting Contact tracing using pediatric index cases has not been adequately investigated in high tuberculosis (TB) and human immunodeficiency virus (HIV) prevalence settings. Objective To determine the yield of contact tracing in household contacts of pediatric TB index cases in Botswana. Design Index cases included all pediatric (age ≤ 13 years) TB admissions from January 2009 to December 2011 to Botswana's largest referral hospital. A contact tracing team identified cases, conducted home visits, symptom-screened contacts and referred those with ≥ 1 TB symptoms. The primary outcome was newly diagnosed TB in a contact. Results From 163 pediatric index cases, 548 contacts were screened (median 3 contacts/case, interquartile range [IQR] 2-4). Of these, 49 (9%) were referred for positive symptoms on screening and 27/49 (55%) were evaluated for active TB. Twelve new TB cases were diagnosed (12/548, 2.2%); the median age was 31 years (IQR 23-38); 11 (92%) were smear-positive. Ten (83%) had known HIV status: 7 (70%) were HIV-positive. To find one new TB case, the number needed to contact trace (index cases/new cases) was 13.6, and the number needed to screen (contacts/new cases) was 46. Conclusion This yield of contact tracing using pediatric index cases is similar to the traditional adult index case approach. Improving the proportion of symptomatic contacts evaluated may increase yield.

Colorectal cancer is one of the most common cancers, and second-leading cause of cancer-related death, in New Zealand. The PIPER (Presentations, Investigations, Pathways, Evaluation, Rx [treatment]) project was undertaken to compare presentation, investigations, management and outcomes by rurality, ethnicity and deprivation. This paper reports the methods of the project, a comparison of PIPER patient diagnoses to the New Zealand Cancer Registry (NZCR) data, and the characteristics of the PIPER cohort.National, retrospective cohort review of secondary care medical records (public and private) of all cases of ICD-10-AM C18-C20 on the NZCR in the calendar years 2007 and 2008 (main cohort) and an extended sample of Māori and Pacific cases, and non-Māori non-Pacific controls in 2006 and 2009 (extended cohort).Of the 6,387 patients identified from the NZCR 5,610 (88%) were eligible for PIPER. Reasons for exclusion were non-adenocarcinoma histology (3%) and non-colorectal primary (2%). Data were collected on 3,695 patients with colon cancer, 1,385 with rectal cancer and 466 with cancer of the recto sigmoid junction.The PIPER Project has generated comprehensive population level data detailing the diagnosis and management of colorectal adenocarcinoma in New Zealand. This will be used to assess the care provided to patients, and the impact of variations in care occurring between patient groups.

As the number of Australians engaging in short-term international travel increases, so does the opportunity for importing overseas-acquired infectious diseases. This study aimed to determine knowledge of infectious disease risks and pre-travel health advice (PTHA) seeking behaviour among Western Australians travelling to Bali, Indonesia or Thailand. Passengers departing from Perth International Airport were invited to participate in a self-administered survey. The survey determined PTHA seeking behaviour, knowledge of specific disease risks, and expected disease-prevention behaviours abroad. Multivariate regression modelling was used to assess demographic and travel-related factors associated with seeking PTHA. Responses from 1334 travellers were analysed. The proportion correctly identifying specific overseas disease risks ranged from 27% to 98%. High levels of planned disease-preventive behaviours were reported; however only 32% of respondents sought PTHA for their trip, most commonly from friends/family (15%) or a GP (14%). Many travellers (87%) made online travel purchases, but few (8%) used the Internet to source PTHA. WA travellers to Bali and Thailand were unlikely to seek PTHA and knowledge varied regarding infectious disease risks associated with travel. High rates of internet use when planning travel may provide an opportunity for destination-specific health promotion messaging and should be explored.

Age is well-known to be a significant factor in both disease pathology and response to treatment, yet the molecular changes that occur with age in humans remain ill-defined. Here, using transcriptome profiling of healthy human male skin, we demonstrate that there is a period of significantly elevated, transcriptome-wide expression changes occurring predominantly in middle age. Both pre and post this period, the transcriptome appears to undergo much smaller, linear changes with increasing age. Functional analysis of the transient changes in middle age suggest a period of heightened metabolic activity and cellular damage associated with NF-kappa-B and TNF signaling pathways. Through meta-analysis we also show the presence of global, tissue independent linear transcriptome changes with age which appear to be regulated by NF-kappa-B. These results suggest that aging in human skin is associated with a critical mid-life period with widespread transcriptome changes, both preceded and proceeded by a relatively steady rate of linear change in the transcriptome. The data provides insight into molecular changes associated with normal aging and will help to better understand the increasingly important pathological changes associated with aging.

In his book Untersuchungen zur Neusumerischen Textilindustrie (UNT), Hartmut Waetzoldt 1 has written extensively on the interpretation of Ur III textile texts. His emphasis in that work was directed towards the difficult task of understanding the cryptic texts that served to log the administration of the work of the textile industry. The aim of this paper is to bring together the information from the administrative texts that describe the tasks of spinning and weaving wool and to interpret these in the practical terms of textile making in order to gain a better understanding of the nature of these textiles. This will use the knowledge base gained by the Danish National Research Foundation’s Centre for Textile Research in Copenhagen (CTR). In particular, it will use the results of spinning and weaving experiments that were designed by CTR. The interpretation of the texts used here will closely follow that given by Waetzoldt in UNT. 2 In a discussion on the manufacture of woolen textiles it is natural to start by considering wool quality before going on to consider the spinning of the yarn and the weaving of the textiles. The textile tablets list many different types of fabrics and garments. However, the intention here is to concentrate on four of the main types of textile, namely, tug guz-za, tug nig-lam, tug us-bar and tug bar-dul 5 (which, for convenience, will be written in this paper without the determinatives). It will be shown that the eventual type of fabric produced was determined by both the selection of the wool and the spinning of the yarn.

The process of switching on bistable spatial dissipative solitons in a VCSEL with frequency selective feedback is analyzed experimentally and theoretically. Two regimes of successful writing of spatial solitons with an external pulse are identified: for short durations of the writing beam pulse, the input amplitude has to increase, while for longer durations, the input amplitude can remain constant. Switch on spectrograms of the frequency spectrum show a transient dynamics over many modes of the external cavity with a drift of the central frequency from higher to lower frequency. Such a multi-mode regime is almost independent of the frequency of the writing beam. It is interpreted to be due to the existence of multiple unstable solitons with different frequencies which channel the transient dynamics. Good agreement between experimental results and numerical simulations in both the time and frequency domains is found.

Separation into spectral and nonlinear complex-eigenvalue problems is shown to be an effective and flexible approach to soliton laser models. The simplest such model, a complex Ginzburg-Landau model with cubic nonlinearity, has no stable solitonic solutions. We show that coupling it to a resonant linear system is a simple and general route to stabilization, which encompasses several previous instances in both space- and time-domains. Graphical solution in the complex eigenvalue plane provides valuable insight into the similarities and differences of such models, and into the interpretation of related experiments. It can also be used predictively, to guide analysis, numerics and experiment., This work was supported in part by the EU FET Open Project FunFACS. P.V. Paulau acknowledges financial support from MEC (Spain) and FEDER (EU) through project No. FIS2007- 60327 FISICOS. We gratefully acknowledge helpful discussions with many FunFACS partner collaborators and colleagues, in particular Andrew Scroggie, Gian-Luca Oppo and Thorsten Ackemann.

Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.

Trimethylbenzenes (TMBs) and C9 aromatic hydrocarbon solvents are structurally similar and have similar toxicity. Based on a review of the entire TMB and C9 aromatic hydrocarbon solvents toxicology database, oral and inhalation studies were identified to serve as the basis for a Reference dose (RfD) and Reference concentrations (RfC). The RfD and RfC were derived using standard USEPA methods and assumptions. The RfD was calculated to be 0.4 mg/kg/day using a 90-day oral study that resulted in a NOAEL of 600 mg/kg/day, based on a lack of adverse effects at the highest dose level (reversible effects such as increased serum phosphorus levels and liver and kidney weights), along with a total uncertainty factor of 1000. For the RfC, three studies were considered based on different study designs and toxicological endpoints, including neurotoxicity, systemic toxicity, and potential developmental and reproductive toxicity. For all three studies, as the calculated RfCs were consistent (3–4 mg/m3), the most conservative RfC, 3 mg/m3, was selected. The C9 aromatic hydrocarbon solvents referred to herein are based on chemistries assessed as part of the TSCA Section 4 Test Rule. These solvents contain primarily ethyl toluene and tri-methyl benzene isomers, but the specific compositions can vary based on feedstock and manufacturing process, thus, it is important to consider the composition of any specific solvent to assess similarity to that assessed in the TSCA Section 4 Test Rule program.

Despite high cure rates 25% of children with acute lymphoblastic leukaemia (ALL) relapse and have dismal outcome. Crucially, many are currently stratified as standard risk (SR) and additional markers to improve patient stratification are required. Here we have used diagnostic bone marrow specimens from 101 children with pre-B ALL to examine the use of gene expression profiles (GEP) as predictors of long-term clinical outcome. Patients were divided into two cohorts for model development and validation based on availability of specimen material. Initially, GEP from 55 patients with sufficient material were analysed using HG-U133A microarrays, identifying an 18-gene classifier (GC) that was more predictive of outcome than conventional prognostic parameters. After feature selection and validation of expression levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR), a three-gene qRT-PCR risk index [glutamine synthetase (GLUL), ornithine decarboxylase antizyme inhibitor (AZIN), immunoglobulin J chain (IGJ)] was developed that predicted outcome with an accuracy of 89% in the array cohort and 87% in the independent validation cohort. The data demonstrate the feasibility of using GEP to improve risk stratification in childhood ALL. This is particularly important for the identification of patients destined to relapse despite their current stratification as SR, as more intensive front-line treatment options for these individuals are already available.

Summary In recent years microarrays have been used extensively to characterize gene expression in acute lymphoblastic leukaemia (ALL). Few studies, however, have analysed normal haematopoietic cell populations to identify altered gene expression in ALL. We used oligonucleotide microarrays to compare the gene expression profile of paediatric precursor-B (pre-B) ALL specimens with two control cell populations, normal CD34+ and CD19+IgM− cells, to focus on genes linked to leukemogenesis. A set of eight genes was identified with a ninefold higher average expression in ALL specimens compared with control cells. All of these genes were significantly deregulated in an independent cohort of 101 ALL specimens. One gene, connective tissue growth factor (CTGF, also known as CCN2), had exceptionally high expression, which was confirmed in three independent leukaemia studies. Further analysis of CTGF expression in ALL revealed exclusive expression in B-lineage, not T-lineage, ALL. Within B-lineage ALL approximately 75% of specimens were consistently positive for CTGF expression, however, specimens containing the E2A-PBX1 translocation showed low or no expression. Protein studies using Western blot analysis demonstrated the presence of CTGF in ALL cell-conditioned media. These findings indicate that CTGF is secreted by pre-B ALL cells and may play a role in the pathophysiology of this disease.

In the last four decades the survival of patients with newly diagnosed childhood T-cell acute lymphoblastic leukaemia (T-ALL) has improved dramatically. In sharp contrast, relapsed T-ALL continues to confer a dismal prognosis. We sought to determine if gene expression profiling could uncover a signature of outcome for children with T-ALL. Using 12 patient specimens obtained before therapy started, we examined the gene expression profile by oligonucleotide microarrays. We identified three genes, CFLAR, NOTCH2 and BTG3, whose expression at the time of diagnosis accurately distinguished the patients according to disease outcome. These genes are involved in the regulation of apoptosis and cellular proliferation. The prognostic value of the three predictive genes was assessed in an independent cohort of 25 paediatric T-ALL patients using quantitative real-time reverse transcription polymerase chain reaction. Patients assigned to the adverse outcome group had a significantly higher cumulative incidence of relapse compared with patients assigned to the favourable outcome group (46% vs. 8%, P = 0.029). Five-year overall survival was also significantly worse in the patients assigned to the adverse outcome group (P = 0.0039). The independent influence of the 3-gene predictor was confirmed by multivariate analysis. Our study provides proof of principle that genome-wide expression profiling can detect novel molecular prognostic markers in paediatric T-ALL.

The in vitro efficacies of three new drugs--clofarabine (CLOF), nelarabine (NEL) and flavopiridol (FP) - were assessed in a panel of acute lymphoblastic leukaemia (ALL) cell lines. The 50% inhibitory concentration (IC50) for CLOF across all lines was 188-fold lower than that of NEL. B-lineage, but not T-lineage lines, were >7-fold more sensitive to CLOF than cytosine arabinoside (ARAC). NEL IC50 was 25-fold and 113-fold higher than ARAC in T- and B-lineage, respectively. T-ALL cells were eightfold more sensitive to NEL than B-lineage but there was considerable overlap. FP was more potent in vitro than glucocorticoids and thiopurines and at doses that recent phase I experience predicts will translate into clinical efficacy. Potential cross-resistance of CLOF, NEL and FP was observed with many front-line ALL therapeutics but not methotrexate or thiopurines. Methotrexate sensitivity was inversely related to that of NEL and FP. Whilst NEL was particularly effective in T-ALL, a subset of patients with B-lineage ALL might also be sensitive. CLOF appeared to be marginally more effective in B-lineage than T-ALL and has a distinct resistance profile that may prove useful in combination with other compounds. FP should be widely effective in ALL if sufficient plasma levels can be achieved clinically.

In this paper we analyze in detail the structure of the phase space of a reversible dynamical system describing the stationary solutions of a model for a nonlinear optical cavity. We compare our results with the general picture described in [P.D. Woods, A.R. Champneys, Physica D 129 (1999) 147; P. Coullet, C. Riera, C. Tresser, Phys. Rev. Lett. 84 (2000) 3069] and find that the stable and unstable manifolds of homogeneous and patterned solutions present a much higher level of complexity than predicted, including the existence of additional localized solutions and fronts. This extra complexity arises due to homoclinic and heteroclinic intersections of the invariant manifolds of low-amplitude periodic solutions, and to the fact that these periodic solutions together with the high-amplitude ones constitute a one-parameter family generating a closed line on the symmetry plane.

We present an experimental and theoretical investigation of spontaneous pattern formation in the transverse section of a single retroreflected laser beam passing through a cloud of cold rubidium atoms. In contrast to previously investigated systems, the nonlinearity at work here is that of a two-level atom, which realizes the paradigmatic situation considered in many theoretical studies of optical pattern formation. In particular, we are able to observe the disappearance of the patterns at high intensity due to the intrinsic saturable character of two-level atomic transitions.

Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53–442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC50 >8000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL.

A systematic study of mould fouling during elastomer injection moulding is presented. Moulding was undertaken principally using nitrile rubber compound and purpose built tooling with interchangeable mould inserts. Rubber metal interactions between treated and untreated Stavax steel surfaces were characterised by a variety of analytical techniques to study factors influencing the onset of mould fouling and its origins. Preliminary simulation and supporting experimental investigation suggested that the design and location of the gate influenced both mould filling pattern and the position of rubber deposition within the cavity.

Misaligned cavities can be described by a 3 x 3 extension of the well-known ABCD matrix approach to aligned cavities. There is a corresponding Huygens integral (HI) formulation for the evolution of the field within such a cavity. We derive a differential 'master' equation (ME) formulation which yields identical eigenmodes and eigenvalues to this HI. This ME is fully equivalent to the HI for linear problems, while providing a more convenient route to the analysis of nonlinear behaviour in such cavities.

Atopic diseases are associated with hyperexpression of Th2 cytokines by allergen-specific T memory cells. However, clinical trials with recently developed Th2 inhibitors in atopics have proven disappointing, suggesting underlying complexities in atopy pathogenesis which are not satisfactorily explained via the classical Th1/Th2 paradigm. One likely possibility is that additional Th2-associated genes which are central to disease pathogenesis remain unidentified. The aim of the present study was to identify such novel Th2-associated genes in recall responses to the inhalant allergen house dust mite. In contrast to earlier human microarray studies in atopy which focused on mitogen-activated T cell lines and clones, we concentrated on PBMC-derived primary T cells stimulated under more physiological conditions of low dose allergen exposure. We screened initially for allergen-induced gene activation by microarray, and validated novel genes in independent panels of subjects by quantitative RT-PCR. Kinetic analysis of allergen responses in PBMC revealed an early wave of novel atopy-associated genes involved in signaling which were coexpressed with IL-4 and IL-4R, followed by a later wave of genes encoding the classical Th2 effector cytokines. We further demonstrate that these novel activation-associated Th2 genes up-regulate in response to another atopy-associated physiological stimulus bacterial superantigen, but remain quiescent in nonphysiological responses in primary T cells or cell lines driven by potent mitogens, which may account for their failure to be detected in earlier microarray studies.