A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma.

BACKGROUND: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry. RESULTS: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation. CONCLUSIONS: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY NUMBER: ACTRN12609000294257.

The controllability beliefs scale used with carers of people with intellectual disabilities: psychometric properties.

BACKGROUND: Beliefs about the controllability of behaviour have been consistently shown to be important in understanding the responses of carers to the challenging behaviour of people with intellectual disabilities (IDs). This paper reports the reliability and validity of the controllability beliefs scale (CBS), a 15-item measure of beliefs regarding the controllability of challenging behaviour when used with carers of people with IDs. METHODS: Two hundred and sixty-four carers of people with IDs completed the CBS, 74 people also completed the modified attributional style questionnaire and the self-injury behavioural understanding questionnaire scale to determine concurrent and convergent validity and 34 people completed the scale twice within a 2- to 4-week period to determine test-retest reliability. RESULTS: The scale has a two-factor structure and has adequate internal reliable. The scale is significantly correlated with the controllability, internality and stability items from the Modified Attributional Style Questionnaire, showed expected associations with behavioural and internal emotional understanding items from the self-injury behavioural understanding questionnaire. The scale has good test-retest reliability. CONCLUSIONS: The data support use of the CBS in clinical practice and research to assess carers' beliefs regarding challenging behaviour of people with IDs.

Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma.

BACKGROUND: Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. OBJECTIVES: The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. ANIMALS: Client-owned dogs with measurable lymphoma. METHODS: Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. RESULTS: The MTD in dogs > 15 kg body weight was 22 mg/m(2) . Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. CONCLUSIONS AND CLINICAL IMPORTANCE: PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials.

Suspected serotonin syndrome in a patient being treated with methylene blue for ifosfamide encephalopathy.

Methylene blue has been used not only as a diagnostic agent, but also as an agent in the treatment of ifosfamide-induced encephalopathy (IIE) for several years. Recently, several cases of suspected serotonin syndrome have been reported in patients who received methylene blue in combination with serotonin active agents. Rodent models have revealed that methylene blue is a potent, reversible inhibitor of monoamine oxidase A. It is well known that serotonin active drugs, in combination with monoamine oxidase inhibitors can produce profound serotonin syndrome. To date, cases of serotonin syndrome, which resulted from concurrent methylene blue and serotonin active agents, have been published in the anesthesia literature. We report the first known case of serotonin syndrome in a patient receiving methylene blue for IIE.

A water quality monitoring network design methodology for the selection of critical sampling points: part II.

In order to resolve the spatial component of the design of a water quality monitoring network, a methodology has been developed to identify the critical sampling locations within a watershed. This methodology, called Critical Sampling Points (CSP), focuses on the contaminant total phosphorus (TP), and is applicable to small, predominantly agricultural-forested watersheds. The CSP methodology was translated into a model, called Water Quality Monitoring Station Analysis (WQMSA). It incorporates a geographic information system (GIS) for spatial analysis and data manipulation purposes, a hydrologic/water quality simulation model for estimating TP loads, and an artificial intelligence technology for improved input data representation. The model input data include a number of hydrologic, topographic, soils, vegetative, and land use factors. The model also includes an economic and logistics component. The validity of the CSP methodology was tested on a small experimental Pennsylvanian watershed, for which TP data from a number of single storm events were available for various sampling points within the watershed. A comparison of the ratios of observed to predicted TP loads between sampling points revealed that the model's results were promising.

A water quality monitoring network design methodology for the selection of critical sampling points: Part I.

The principal instrument to temporally and spatially manage water resources is a water quality monitoring network. However, to date in most cases, there is a clear absence of a concise strategy or methodology for designing monitoring networks, especially when deciding upon the placement of sampling stations. Since water quality monitoring networks can be quite costly, it is very important to properly design the monitoring network so that maximum information extraction can be accomplished, which in turn is vital when informing decision-makers. This paper presents the development of a methodology for identifying the critical sampling locations within a watershed. Hence, it embodies the spatial component in the design of a water quality monitoring network by designating the critical stream locations that should ideally be sampled. For illustration purposes, the methodology focuses on a single contaminant, namely total phosphorus, and is applicable to small, upland, predominantly agricultural-forested watersheds. It takes a number of hydrologic, topographic, soils, vegetative, and land use factors into account. In addition, it includes an economic as well as logistical component in order to approximate the number of sampling points required for a given budget and to only consider the logistically accessible stream reaches in the analysis, respectively. The methodology utilizes a geographic information system (GIS), hydrologic simulation model, and fuzzy logic.

Paircoil2: improved prediction of coiled coils from sequence.

We introduce Paircoil2, a new version of the Paircoil program, which uses pairwise residue probabilities to detect coiled-coil motifs in protein sequence data. Paircoil2 achieves 98% sensitivity and 97% specificity on known coiled coils in leave-family-out cross-validation. It also shows superior performance compared with published methods in tests on proteins of known structure.

Acute pain teams and the management of postoperative pain: a systematic review and meta-analysis.

BACKGROUND: The introduction of acute pain teams (APTs) in every hospital performing surgery in the UK has been recommended in order to reduce postoperative pain. However, recent evidence suggests that many APTs are under-resourced. Purchasers may be more prepared to invest in these services if they are persuaded that they result in measurable improvements in patient outcomes. AIM: A systematic review of the literature and meta-analysis were performed to determine the effectiveness of APTs in improving the quality of analgesia and other postoperative outcomes of adult patients undergoing surgery. METHODS: A broad search strategy using the terms 'pain team' and 'pain service' was adapted for a variety of databases. Key journals were hand-searched and reference lists of selected reports were reviewed. Subject experts and study authors were contacted. Studies describing the impact of the APT/acute pain service (APS) on postoperative pain relief, other postoperative outcomes or the processes of postoperative pain were included. Study quality was assessed using a multidimensional instrument. A broad qualitative overview of the included studies was conducted. Continuous outcome data for pain in the first 24 hours postoperatively (in one case worst pain at 24-48 hours) were pooled. RESULTS: Fifteen studies were included in the review. There were considerable differences in study design and quality, the nature of the APT and the outcomes measured. Of the nine studies measuring pain, it was possible to present data as Standardized Mean Differences for only four studies. Quantitative synthesis indicates a statistically significant overall estimate of effect using a fixed effects model only. LIMITATIONS: Only published studies in English were included. Study inclusion decisions and data extraction were performed by one reviewer only. CONCLUSION: There is insufficient robust research to assess the impact of APTs on postoperative outcomes of adult patients or on the processes of postoperative pain relief.

Monitoring the care of lung cancer patients: linking audit and care pathways.

Clinical audit plays an important role in monitoring the provision of care for patients whatever their condition. Care pathways define the steps and expected course of events in the care of patients with a specific clinical problem over a set time scale. This paper describes a study undertaken in a multisite cancer unit to develop a tool for monitoring the progress of lung cancer patients through a care pathway and auditing key standards within the pathway. Important issues associated with the development of this tool are highlighted. The process of developing this tool involved the following steps: a review of the literature dealing with the management of lung cancer patients; interviews with key personnel in primary, secondary, tertiary and palliative care; development of a paper-based series of forms representing key steps in the patient's care pathway; 3-month trial of the paper-based tool; analysis of completion rates and interviews with form users to evaluate effectiveness; and recommendations for creating an electronic record using the experience and lessons learned from the paper version. The paper forms developed through this multistage process were found to be acceptable to users and have the potential to provide accurate information at key points for audit throughout the patient's time within the health-care system for their lung cancer condition. The flexibility of this methodology allows it to be adapted readily to a variety of clinical situations and conditions.

The Saccharomyces cerevisiae MUM2 gene interacts with the DNA replication machinery and is required for meiotic levels of double strand breaks.

The Saccharomyces cerevisiae MUM2 gene is essential for meiotic, but not mitotic, DNA replication and thus sporulation. Genetic interactions between MUM2 and a component of the origin recognition complex and polymerase alpha-primase suggest that MUM2 influences the function of the DNA replication machinery. Early meiotic gene expression is induced to a much greater extent in mum2 cells than in meiotic cells treated with the DNA synthesis inhibitor hydroxyurea. This result indicates that the mum2 meiotic arrest is downstream of the arrest induced by hydroxyurea and suggests that DNA synthesis is initiated in the mutant. Genetic analyses indicate that the recombination that occurs in mum2 mutants is dependent on the normal recombination machinery and on synaptonemal complex components and therefore is not a consequence of lesions created by incompletely replicated DNA. Both meiotic ectopic and allelic recombination are similarly reduced in the mum2 mutant, and the levels are consistent with the levels of meiosis-specific DSBs that are generated. Cytological analyses of mum2 mutants show that chromosome pairing and synapsis occur, although at reduced levels compared to wild type. Given the near-wild-type levels of meiotic gene expression, pairing, and synapsis, we suggest that the reduction in DNA replication is directly responsible for the reduced level of DSBs and meiotic recombination.

Do new roles contribute to job satisfaction and retention of staff in nursing and professions allied to medicine?

BACKGROUND: Studies have suggested that job dissatisfaction is a major factor influencing nurses' and occupational therapists' intention to leave their profession. It has also been related to turnover of qualified nurses. However, literature relating to these factors among nurses and professions allied to medicine in innovative roles is scarce. AIMS: This paper considers the views of 452 nurses and 162 professionals allied to medicine (PAMs) in innovative roles, on job satisfaction, career development, intention to leave the profession and factors seen as hindering and enhancing effective working. METHODS: A self-completion questionnaire was developed as part of a larger study exploring new roles in practice (The ENRiP Study). FINDINGS: Overall there was a high level of job satisfaction in both groups (nurses and PAMs). Job satisfaction was significantly related to feeling integrated within the post-holder's own professional group and with immediate colleagues, feeling that the role had improved their career prospects, feeling adequately prepared and trained for the role, and working to protocol. Sixty-eight percent (n = 415) of respondents felt the role had enhanced their career prospects but over a quarter of respondents (n = 163; 27%) said they would leave their profession if they could. Low job satisfaction was significantly related to intention to leave the profession. CONCLUSIONS: The vast majority of post-holders in innovative roles felt that the role provided them with a sense of job satisfaction. However, it is essential that the post-holders feel adequately prepared to carry out the role and that the boundaries of their practice are well defined. Career progression and professional integration both being associated with job satisfaction.

Practical considerations in case study research: the relationship between methodology and process.

This paper explores the extent to which the design of a research study is influenced by pragmatic as well as theoretical considerations by describing the authors' experience of conducting multiple case studies in the context of a policy-orientated research project. The case studies in question formed part of a collaborative project exploring the development of innovative roles in nursing and the professions allied to medicine. The researchers adopted Yin's approach to the conduct of multiple case studies to explore issues relating to the effectiveness of new roles, their resource implications and educational issues surrounding their development. They address the fact that methodological decisions have practical implications and also explore the effects of practical and ethical issues on research design. Three purposively selected acute National Health Service Trust hospitals in England formed the case study sites for the work recorded in this paper. In each Trust, three nursing roles were selected, making nine cases for study. A variety of data collection strategies were used including semi-structured interviews with post-holders and other stakeholders (n = 51), non-participant observation of meetings, collection of audit, financial and statistical data and review of relevant documentation. This paper describes some of the dilemmas which arose during the course of the study, the rationale for methodological decisions taken to resolve these dilemmas and the steps taken to enhance rigour. In particular, the authors discuss the problems associated with obtaining informed consent in the context of qualitative research and with member validation of transcripts in a context where confidentiality was crucial. The decision to present findings thematically rather than as individual cases is justified both in terms of the nature and purpose of the research and in relation to the particular importance of anonymity and confidentiality in this study. Finally, the degree of reciprocity between researcher and researched is discussed.

Analysis of genes expressed at the infective larval stage validates utility of Litomosoides sigmodontis as a murine model for filarial vaccine development.

We used an expressed sequence tag approach to analyze genes expressed by the infective larvae of the rodent filarial parasite Litomosoides sigmodontis. One hundred fifty two new genes were identified, including several proposed as vaccine candidates in studies with human filarial parasites. Our findings have important implications for the use of L. sigmodontis as a model for filarial infection.

Phylogenetic analysis of partial mitochondrial cytochrome oxidase c subunit I and large ribosomal RNA sequences and nuclear internal transcribed spacer I sequences from species of Cyathostominae and Strongylinae (Nematoda, Order Strongylida), parasites of the horse.

Three nucleotide data sets, one nuclear (ITS-2) and two mitochondrial (COI and l-rRNA), have been investigated in order to determine relationships among species of Strongylinae and Cyathostominae, intestinal parasites of the horse. The data exhibited a strong mutational bias towards A and T and in the COI gene, silent sites appeared to saturate rapidly partly due to this substitution bias. Thus, the COI gene was found to be less phylogenetically informative than the l-rRNA and ITS-2 genes. Combined analysis of the l-rRNA and ITS-2 genes supported a monophyletic clade of the cyathostomes with Tridentoinfundibulum gobi, which had previously been classified as a nematode of' uncertain origin'. The Strongylinae grouped consistently outside the clade containing the cyathostomes and T. gobi. Molecular analysis failed to provide strong evidence for the separation of cyathostomes into classical genera, as previously defined by morphological classification.

Molecular delineation of Cylicocyclus nassatus and C. ashworthi (Nematoda:Strongylidae).

The nucleotide sequences of the first internal transcribed spacer (ITS-1), 5.8S gene and second internal transcribed spacer (ITS-2) of ribosomal DNA have been determined for Cylicocyclus nassatus, C. ashworthi and C. insignis. Pairwise comparisons revealed sequence differences between the taxa ranging from 3.8 to 6.2% for the ITS-2 and 2.2-2.7% for the ITS-1. For the ITS-1, the level of the sequence difference between C. ashworthi and C. nassatus (2.2%) was equivalent to that between C. nassatus and C. insignis (2.2%), indicating that C. ashworthi and C. nassatus represent separate species. Theoretical restriction maps were constructed from the sequence data, and a polymerase chain reaction-linked restriction fragment length polymorphism (PCR-linked RFLP) technique was established to unequivocally distinguish C. ashworthi from C. nassatus.

Further evidence that inhibitor-2 acts like a chaperone to fold PP1 into its native conformation.

The gamma1-isoform of protein phosphatase-1 expressed in Escherichia coli (PP1gamma) and the native PP1 catalytic subunit (PP1C) isolated from skeletal muscle dephosphorylated Ser-14 of glycogen phosphorylase at comparable rates. In contrast, PP1gamma dephosphorylated several tyrosine-phosphorylated proteins at similar rates to authentic protein tyrosine phosphatases (PTPases), but native PP1C was almost inactive towards these substrates. The phosphorylase phosphatase (PhP) and PTPase activities of PP1gamma were inhibited by vanadate with IC50 values (30-100 microM) comparable to authentic PTPases, whereas the PhP activity of native PP1C was insensitive to vanadate. PP1gamma lost its PTPase activity, and its PhP activity became insensitive to vanadate, after interaction with inhibitor-2, followed by the reversible phosphorylation of inhibitor-2 at Thr-72. These findings support and extend the hypothesis that inhibitor-2 functions like a chaperone to fold PP1 into its native conformation, and suggest that the correct folding of PP1 may be critical to prevent the uncontrolled dephosphorylation of cellular phosphotyrosine residues.

Phasing out seclusion through staff training and support.

Seclusion raises considerable ethical issues. While many services aim to phase out this practice, little research has been conducted into how this can be achieved. This article describes the phasing out of seclusion from a locked ward in a hospital for people with learning disabilities. The implications of these findings for other services are discussed.

Measurement by ELISA of equine alpha-1-proteinase inhibitor in uterine flushings from mares.

An enzyme linked immunosorbent assay (ELISA) was developed and used to estimate the concentrations of the serine proteinase inhibitor, alpha-1 proteinase inhibitor (API), in uterine flushings recovered from mares at different stages of the oestrous cycle and before and after the induction of experimental endometritis. There was a significant increase in the concentrations of API and albumin relative to total protein in flushings recovered during oestrus compared with dioestrus but no difference was observed in the concentrations of these proteins relative to total protein before and after the induction of endometritis. A regression analysis revealed a significant correlation between the concentrations of albumin and API in the flushings examined, suggesting that the API was derived entirely from serum and was not produced locally in the uterus.

Characteristics of cyclicity in maiden thoroughbred mares in the United Kingdom.

The characteristics of the cyclicity of 12 maiden thoroughbred mares kept in two groups were studied over a total of 58 cycles. On average, oestrus lasted 5.3 days and in 60 per cent of the cycles ovulation occurred in the last two days of oestrus. Oestrus and ovulation tended to be synchronised in each group of mares. The mean diameter of single-ovulating preovulatory follicles on the day before ovulation was 41.5 mm and during the seven days before ovulation they grew 2.5 mm/day. More than one follicle ovulated in 19 (33 per cent) of the cycles (seven double ovulations and 12 dioestrous ovulations). All the oestrous mares and 25 per cent of the mares with dioestrous ovulations had uterine oedema on the day before ovulation.

The effect of transcervical uterine manipulations on establishment of uterine infection in mares under the influence of progesterone.

Four pony mares were used in a cross-over study to investigate the effect of different treatments on experimentally-induced endometritis. The mares were treated with progesterone to facilitate establishment of uterine infections. They received an intrauterine infusion of Streptococcus zooepidemicus 5 days after the start of progesterone therapy. Five days later, they were treated by intrauterine infusions of 2 g ampicillin in 50 ml sterile water or by sterile water without antibiotic for 3 consecutive days. Prior to infusion of Strep. zooepidemicus, no bacteria were cultured from the uteri of the mares. However, 5 days after infusion of Strep. zooepidemicus and prior to antibiotic therapy, mixed bacterial growths were cultured from endometrial swabbings. After antibiotic therapy, ampicillin-resistant organisms were cultured from endometrial swabbings. Two other progesterone-treated mares received an intrauterine infusion of sterile phosphate buffered saline instead of bacteria. Mixed bacterial cultures were recovered 5 days later from the endometrial swabbings of these mares. It was concluded that the high circulating concentrations of progesterone were probably responsible for the treatment failure and that in clinical situations, therapy involving transcervical manipulations should not be administered when mares are in diestrus.