A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Targeting improved resilience in Merino sheep - Correlations between immune competence and health and fitness traits.

Resilience can be defined as the ability of an animal to remain productive in the face of diverse environmental challenges. Several factors contribute to an animal's resilience including its ability to resist disease, cope with climatic extremes and respond to stressors. Immune competence, a proxy trait for general disease resistance, is expected to contribute to an animal's resilience. This research aimed to develop a practical method to assess immune competence in Merino sheep which would not restrict the future sale of tested animals, and to estimate genetic parameters associated with the novel trait. We also aimed to explore associations between immune competence and other industry-relevant disease resistance and fitness-related traits and to assess the ability of immune competence phenotypes to predict health outcomes. Here, the ability of Merino wethers (n = 1 339) to mount both an antibody-mediated and cell-mediated immune response was used to define their immune competence phenotype. For that purpose, antigens in a commercial vaccine were administered at the commencement of weaning and their responses were assessed. Univariate sire models were used to estimate variance components and heritabilities for immune competence and its component traits. Bivariate sire models were used to estimate genetic correlations between immune competence and a range of disease resistance and fitness-related traits. The heritability of immune competence and its component traits, antibody-mediated immune response and cell-mediated immune response were estimated at 0.49 ±â€¯0.14, 0.52 ±â€¯0.14 and 0.36 ±â€¯0.11, respectively. Immune competence was favourably genetically correlated with breech flystrike incidence (-0.44 ±â€¯0.39), worm egg count (-0.19 ±â€¯0.23), dag score (-0.26 ±â€¯0.31) and fitness compromise (-0.35 ±â€¯0.24) but not fleece rot (0.17 ±â€¯0.23). Results suggest that selection for immune competence has the potential to improve the resilience of Merino sheep; however, due to the large standard errors associated with correlation estimates reported here, further studies will be required in larger populations to validate associations between immune competence and disease resistance and fitness traits in Australian Merino sheep.

Paleomagnetic tests of pacific plate reconstructions and implications for motion between hotspots.

The plate-motion circuit through the South Pacific and Antarctica is shown to fail paleomagnetic tests of consistency. These failures imply that reconstructions of Pacific basin plates relative to surrounding plates inferred from this circuit are systematically in error and that estimates of motion between hotspots inferred from this circuit are probably too large. Therefore, the motions between hotspots remain poorly known and may be much smaller than previously estimated.

Purification to homogeneity and some properties of L-phenylalanine ammonia-lyase of irradiated mustard (Sinapis alba L.) cotyledons.

1. Lyase (L-Phenylalanine ammonia-lyase, EC 4.3.1.5) from far-red light-irradiated mustard cotyledons was purified to a single protein using ammonium sulphate fractionation, column chromatography on L-phenylalanyl-Sepharose 4B and on Sephadex G-200, isoelectric focusing and polyacryalmide gel electrophoresis. 2. The enzyme constituted 0.01% of total cellular protein, did not catalyse the deamination of L-tyrosine, had a pH optimum of pH 8.6 and an isoelectric point of pH 5.6. 3. The sedimentation coefficient was estimated as 11.3 S, the Stokes' radius 4.25 nm, and the molecular weight 240 000 +/- 9000 (S.E.). 4. Electrophoresis on denaturing polyacrylamide gels gave a single stained protein band corresponding to a subunit molecular weight of 55 000 indicating a tetrameric structure of equal (or near-equal) size subunits. 5. Maximum velocity (V) for the purified lyase at 25 degrees C was 3.83--4.10 nkat. 1(-1) enzyme and Km value 0.151--0.154 mM. Negative cooperativity (Hill coefficient, n = 1.08) was not detected over the substrate concentration range tested. 6. A putative non-diffusible inhibitor isolated from dark-grown gherkin hypocotyls inhibited the homogeneously purified mustard lyase.

Control over activation or synthesis of phenylalanine ammonia-lyase by phytochrome in mustard (Sinapis alba L.)? A contribution to eliminate some misconceptions.

1. Density labelling with 80 atom% of 2H2O has been used to examine the mode of action of phytochrome (continuous far-red light) in increasing levels of L-phenylalanine ammonia-lyase (EC 4.3.1.5) activity in cotyledons of developing mustard seedlings (Sinapis alba L.). 2. Bandwidths and density shifts of isopycnically banded enzyme show that in darkness the enzyme was synthesized de novo, continuously turning over (half-life approx. 3 h) and that maximum labelling achievable was reached at 12 h. 3. 2-fold (6h), 5-fold (12h) and 10-fold (24 h) light-mediated increases in enzyme activity were accompanied by a similar pattern of labelling as observed in darkness. 4. Experimental evidence and theoretical arguments are presented which make it unlikely that phytochrome increases enzyme activity by slowing down the rate of degradation or by activating preformed enzyme molecules. 5. The conclusion is drawn that the rate of turnover of phenylalanine ammonia-lyase in dark-grown mustard cotyledons is too rapid compared to the measured rise in enzyme activity for density labelling to reveal directly control over the rate of synthesis de novo by phytochrome. However, the elimination of other control mechanisms leads us to the conclusion that phytochrome most probably does control synthesis of this enzyme in mustard, which agrees with the previous findings for parsley cells.

A conceptual and psychometric framework for distinguishing categories and dimensions.

An important, sometimes controversial feature of all psychological phenomena is whether they are categorical or dimensional. A conceptual and psychometric framework is described for distinguishing whether the latent structure behind manifest categories (e.g., psychiatric diagnoses, attitude groups, or stages of development) is category-like or dimension-like. Being dimension-like requires (a) within-category heterogeneity and (b) between-category quantitative differences. Being category-like requires (a) within-category homogeneity and (b) between-category qualitative differences. The relation between this classification and abrupt versus smooth differences is discussed. Hybrid structures are possible. Being category-like is itself a matter of degree; the authors offer a formalized framework to determine this degree. Empirical applications to personality disorders, attitudes toward capital punishment, and stages of cognitive development illustrate the approach.

Effects of low-dose cimetidine on nocturnal acid secretion in healthy subjects.

The effects of 100 mg and 200 mg bedtime doses of cimetidine on nocturnal gastric acid secretion were examined in nine healthy subjects in a double blind, placebo controlled, randomised three way crossover study. Treatment was given at 23.00 hours and the gastric contents continually aspirated from midnight until 07.00 hours the following morning. Hourly aliquots were analysed for pH and acid output. Relative to placebo the 100 mg and 200 mg doses of cimetidine respectively increased mean pH by 2.22 and 2.63 units/h (P less than 0.001) with mean acid output decreasing by 0.95 and 0.98 mmol/h (P less than 0.001). Whilst mean pH was higher and mean acid output was lower for 200 mg cimetidine compared to 100 mg cimetidine the difference was not statistically significant. Mean hourly pH was consistently above pH 3 for 100% of the time for both doses of cimetidine whereas mean pH failed to reach this value at anytime on placebo. Low doses of cimetidine taken at bedtime effectively reduced nocturnal gastric acid secretion in healthy individuals.

Depression and stages of change for smoking in psychiatric outpatients.

This article reports on the relations between depression and stages of change for smoking cessation. A convenience sample of 205 psychiatric outpatients (68% female, mean age 41) completed measures of depression Primary Care Evaluation of Mental Disorders [PRIME-MD] and Beck Depression Inventory-II [BDI-II]), all transtheoretical model constructs related to smoking (stages and processes of change, pros and cons of smoking, and situational temptations), and thoughts about abstinence. As hypothesized, patients who had never smoked showed substantially lower rates of currently diagnosed major depressive disorder (MDD) than those who had ever smoked. Patients in early stages of change did not show more MDD or depressive symptoms but, as hypothesized, showed more negative thoughts about abstinence. Findings are consistent with the documented association between smoking and depression and suggest the appropriateness of building smoking cessation interventions based on the transtheoretical model of change for use with psychiatric populations.

Basic need status and health-promoting self-care behavior in adults.

Health-promoting self-care behavior emphasizing positive lifestyle practices may improve the health and quality of life of adults. One variable that may influence health-related decisions is the status of basic needs as described by Maslow. The purpose of this study was to investigate the relationships among basic need satisfaction, health-promoting self-care behavior, and selected demographic variables in a sample of community-dwelling adults. A convenience sample of 84 community-dwelling adults was recruited to complete the Basic Need Satisfaction Inventory, the Health-Promoting Lifestyle Profile II, and demographic information. Results of the study indicated that self-actualization, physical, and love/belonging need satisfaction accounted for 64% of the variance in health-promoting self-care behavior. The findings of this study are consistent with Maslow's theory of human motivation and suggest that persons who are more fulfilled and content with themselves and their lives, have physical need satisfaction, and have positive connections with others may be able to make better decisions regarding positive health-promoting self-care behaviors.

Theory-testing research: building the science.

Lack of emphasis on the empirical validation of nursing models has hindered the development of nursing science. This article explores issues concerning theory development in nursing and criteria for evaluating theory-testing research. From a comprehensive review of the literature on theory testing, 15 criteria are identified as essential for evaluating theory-testing studies. The criteria are applied to selected research reports, and recommendations for future use of criteria are suggested.

Explicating middle-range theory through methodological diversity.

Debates about methodological diversity and the most appropriate paradigm for scientific inquiry are still flourishing within the community of nurse scholars. Rather than continuing to debate these controversies, the authors of this article suggest that nurse researchers set aside methodological differences and move to discover the truths that will build the foundational base of nursing practice and, thus advance the discipline. This article discusses the multiple methodological perspectives used to explicate middle-range concepts from the theory and paradigm for nursing, Modeling and Role-Modeling. Each author will demonstrate how combining different approaches and methodologies can be helpful in exploring and validating middle-range concepts.

Communicating with individuals with dementia. The impaired person's perspective.

1 To better meet needs of individuals with dementia, caregivers should focus on receiving and interpreting verbal and nonverbal messages conveyed by the afflicted individuals. 2 Prior research has focused on enhancing communication from caregivers to individuals with dementia; however, the content and meaning of communication received from individuals with dementia remains largely unexplored. 3 This study demonstrates that individuals with dementia are able to transmit meaningful communication and this communication can be interpreted by others, making client-centered interventions possible with this population. 4 If care models based on communication interpretation techniques can be built, perhaps the needs of individuals with dementia can be better met, tensions reduced, problematic behaviors decreased, and quality of life enhanced.

Affiliated-individuation as a mediator of stress and burden in caregivers of adults with dementia.

The purpose of this study was to test a midrange model based on Modeling and Role-Modeling Theory. The self-care resource of affiliated-individuation was tested to determine its mediational qualities between the stress and burden of caregiving and caregiver life satisfaction. The sample of 107 family caregivers of adults with dementia completed measures of stress, burden, affiliation, individuation, and life satisfaction. All variables were correlated in the expected direction. Affiliated-individuation decreased the effects of stress and burden on caregiver life satisfaction, lending support for the theory-based model.

Self-transcendence and family caregivers of adults with dementia.

Research has documented that caring for a family member with dementia is stressful and burdensome. However, difficult life experiences such as fear, loss, and grief may help persons move beyond a concern for self toward a larger perspective and concern for others. Both positive and negative experiences can promote positive movement toward growth and development. This movement has been described as self-transcendence, or the ability to look beyond the self and present difficulties, to extend concern to others, and to find personal meaning and wholeness in the context of life-changing events. The family caregiving experience with its inherent difficulties might provide the impetus for such a movement toward self-transcendence. The purpose of this article is to examine the concept of self-transcendence, explore its linkages to the caregiving experience, and suggest potential strategies to assist family caregivers to achieve self-transcendence.

Differential item functioning of the English and Chinese versions of the Fagerstrom Test for Nicotine Dependence.

Different language versions of the Fagerstrom Test for Nicotine Dependence (FTND) have been developed, but no studies have evaluated measurement equivalence between the respective non-English and English versions. We investigated differential item functioning (DIF) of the English and Chinese versions using a multidimensional item response theory approach. A community sample of 409 American smokers completed the English version (n=241) and the Chinese version (n=168). Results indicated two correlated dimensions (morning and daytime nicotine dependence) of the FTND and one item (difficult to refrain) showing significant large DIF, suggesting respondents using the Chinese version were more likely to endorse this item and report more difficulty to refrain from smoking at various public places even after controlling for the nicotine dependence level. However, the impact of this DIF item was found negligible on the scale level, suggesting the acceptability of conducting scale-level analysis using both language versions. Further analysis revealed that the reliabilities of two dimensions did not meet the commonly accepted standard. Suggestions were made to improve scale reliabilities of the FTND.

The construct of internalization: conceptualization, measurement, and prediction of smoking treatment outcome.

BACKGROUND: Depression symptoms and diagnoses are associated with failure to quit smoking in most studies, but not all. METHOD: A new measure of internalization (i.e. symptoms of depression or anxiety, or poor mood) was created to investigate whether internalization would predict smoking cessation in 549 smokers from three randomized clinical trials with inconsistent findings. RESULTS: Predicted item locations based on a map of the construct of internalization agreed with empirical locations based on item response theory. Internalization was highly correlated with neuroticism. Logistic regressions showed that internalization improved upon the predictions of other affect-related measures. High baseline internalization decreased abstinence from smoking at end of treatment and 3 months thereafter. History of major depression (single-episode or recurrent) failed to predict abstinence. CONCLUSIONS: The broad, dimensional construct of internalization as conceptualized herein appears to be an important predictor of smoking cessation.

Effects of D-5-hydroxytryptophan and D-DOPA on binding at serotonin and dopamine receptors.

Binding of the D-amino acids D-5-hydroxytryptophan (D-5-HTP) and D-dihydroxyphenylalanine (D-DOPA) to high affinity sites for serotonin (5-HT) and dopamine (DA) was studied in bovine striatum. D-5-HT bound to the 5-HT site with affinity in the micromolar range, but showed no appreciable binding at the DA site. D-DOPA showed little binding to either 5-HT or DA receptors.

Measurement of impulsivity in a hierarchical model of personality traits: implications for substance use.

This review describes how measures of a prominent three-dimensional hierarchical model of personality traits relate to substance use. H. J. Eysenck proposed a biologically based model of personality that gave rise to related models such as those of J. A. Gray, C. R. Cloninger, and M. Zuckerman. The varying role of impulsivity--a trait related to disinhibition, approach motivation, novelty seeking, and sensation seeking--in successive self-report measures of this model, including the Eysenck Personality Inventory (EPI) and Eysenck Personality Questionnaire (EPQ), is described. It is argued that certain findings in experimental, cross-sectional, and longitudinal research using these measures point to the importance of impulsivity as a temperamental vulnerability factor for substance use.