Efficient discovery of inhibitory ligands for diverse targets from a small combinatorial chemical library of chimeric molecules.

Living systems are mainly composed and regulated by compounds in four biochemical classes and their polymers-nucleotides, carbohydrates, lipids, and amino acids. Early combinatorial chemistry libraries consisted of peptides. The present report describes the general bioactivity and biophysical properties of a combinatorial chemical library that used glyco, nucleotidyl, and lipid building blocks. The resulting chimeric combinatorial library of 361 compounds had a confirmed cumulative hit rate of 0.16%, which is 8-fold higher than a commonly claimed industrial benchmark of 0. 02%. It produced 7 structurally confirmed hits for a third of 12 proprietary drug discovery projects, and these comprised a variety of molecular targets. Diversity analyses demonstrated that despite the small number of compounds, a wider range of diversity space was covered by this library of biochemical chimeras than by a branched tripeptide library of the same size and similar generic formula.

Gamma-irradiation directly affects the formation of coding joints in SCID cell lines.

SCID mice have a defect in the catalytic subunit of the DNA-dependent protein kinase, causing increased sensitivity to ionizing radiation in all tissues and severely limiting the development of B and T cell lineages. SCID T and B cell precursors are unable to undergo normal V(D)J recombination: coding joint and signal joint products are less frequently formed and often will exhibit abnormal structural features. Paradoxically, irradiation of newborn SCID mice effects a limited rescue of T cell development. It is not known whether irradiation has a direct impact on the process of V(D)J joining, or whether irradiation of the thymus allows the outgrowth of rare recombinants. To investigate this issue, we sought to demonstrate an irradiation effect ex vivo. Here we have been able to reproducibly detect low-frequency coding joint products with V(D)J recombination reporter plasmids introduced into SCID cell lines. Exposure of B and T lineage cells to 100 cGy of gamma irradiation made no significant difference with respect to the number of coding joint and signal joint recombination products. However, in the absence of irradiation, the coding joints produced in SCID cells had high levels of P nucleotide insertion. With irradiation, markedly fewer P insertions were seen. The effect on coding joint structure is evident in a transient assay, in cultured cells, establishing that irradiation has an immediate impact on the process of V(D)J recombination. A specific proposal for how the DNA-dependent protein kinase catalytic subunit influences the opening of hairpin DNA intermediates during coding joint formation in V(D)J recombination is presented.

Exercise and nursing therapy for patients with intermittent claudication.

Intermittent claudication is a common manifestation of arterial disease in the second half of life. Invasive treatments may be inappropriate or unsuccessful, leaving patients with a significant handicap. Nursing intervention can improve the functional ability and the general well-being of many patients. This paper provides an account of the development of an out-patient nursing service for patients with intermittent claudication. It focuses on the exercise training and the psychological support given to patients. A review of the first 102 claudicants referred to the programme shows the outcome for the patients in terms of improved walking ability. The details of the nursing intervention reported in the paper should help the growing number of nurses starting similar programmes for vascular patients. They may also be of interest to nurses caring for patients with other chronic health problems.

The art of clinical supervision.

Helping nurses to become effective and confident as primary nurses involves developing their interpersonal skills, sharpening their decision-making and nurturing their creativity. In our action research study, we found that traditional methods of ward teaching did not help to promote this kind of professional growth. We therefore developed, tested and refined three distinct strategies for clinical supervision which specifically aimed to foster more thoughtful and more sensitive nursing practice. Very importantly, we found that these approaches to supervision were feasible and practical to use in a busy hospital ward. In this paper, we describe the three supervision strategies, using a clinical story to illustrate what each demands from the supervisor and what it offers the nurse under supervision. We also suggest ways in which expert nurses can be helped to become effective clinical supervisors.

Action research: a strategy for theory generation and testing.

We define action research and relate it conceptually to other research strategies. The inadequacy of some action research methodologies for theory generation and testing is discussed. We describe the way we re-dressed this deficiency in our study of the journey from traditional nursing to patient-centered nursing. The differences and tensions between "research-thinking" and "practice-thinking" are explored and we show how our research partnership balances the two ways of thinking. We suggest that operating within the research criteria, presented here, may help action researchers to conduct rigorous research, as well as to improve practice.

What am I meant to be doing? Putting practice into theory and back again in new nursing roles.

This two-part paper is based on some of the findings from an action research study of the development of patient-centred nursing in an acute medical unit. In the first part, Angie Titchen presents findings from a case study of a ward undergoing the initial changes from traditional nursing to primary nursing. She documents and reflects upon the complexity of establishing new nursing roles, the devolution of authority and the shift in power relationships within the ward team, and the confusion and pain caused by role ambiguity. In the second part, we show how we addressed these problems through the action research.

Research partnerships: collaborative action research in nursing.

This methodological paper discusses and critiques the 'insider' and 'outsider' models of action research described in the nursing literature. It highlights tensions and problems with these models and demonstrates how the models developed by the authors--the 'double-act' and 'collaborative group' partnerships--overcome these difficulties. The success of this approach suggests that such partnerships of nurse practitioners and a researcher should be considered when practitioners want to introduce innovation and facilitate change in practice and generate and test theory which is relevant to practice. The paper is presented in the form of a commentary, interspersed with reflective conversations in which the authors illustrate and reflect upon their attempts to make the methodology described a reality.