To MSNAP or not to MSNAP? Testing a small regional memory clinic against the UK Memory Service National Accreditation Program (MSNAP).

AimTo investigate whether a small regional memory clinic would benefit from engaging with a structured external audit process such as the Royal College of Psychiatrists' Memory Service National Accreditation Program (MSNAP). BACKGROUND: The Psychiatry of Old Age service in Navan operates a public cognitive clinic. Despite the publication of the 2014 National Dementia Strategy, there are currently no national standards for memory clinics in Ireland. It may be beneficial to link in with an external quality control system as part of routine clinical governance. METHODS: Published data from the MSNAP group was reviewed and a set of audit materials extrapolated to replicate the MSNAP self-review process. The audit cycle involved (1) retrospective case review, (2) institution of a range of interventions and (3) a prospective audit, which included service user feedback. RESULTS: Overall the results demonstrated a high standard of service, especially in the areas of accessibility, assessment and communication of diagnosis. The clinic performed well against MSNAP key performance indicators. Patient and carer satisfaction with the service was very high. Clinic policies needed further development, particularly in the areas of referral, consent and data protection. CONCLUSIONS: The process was useful, providing clear pointers for action. It highlighted the need to formalise organisational and practice policies, patient support and education, audit and outreach. Although accreditation is a laborious process requiring financial investment, it provides a strong scaffold to maintain and improve standards and is likely to be a valuable learning experience, where national guidelines are lacking.

Interleukin 7 (IL-7) receptor-specific cell killing by DAB389 IL-7: a novel agent for the elimination of IL-7 receptor positive cells.

Interleukin 7 (IL-7) induces the proliferation of B cell progenitors in long-term bone marrow cultures, promotes the growth of resting fetal and adult thymocytes, and costimulates mature human T cell proliferation. IL-7 also induces cell growth in hematologic malignancies such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and Sezary syndrome. We have constructed a recombinant fusion protein, DAB389 IL-7, composed of the catalytic and transmembrane domains of diphtheria toxin (DT), fused to IL-7. We demonstrate that DAB389 IL-7 is selectively cytotoxic for only those cells bearing the IL-7 receptor and that entry into target cells is mediated through the receptor. The nontoxic mutant, DA(E149S)B389 IL-7, was constructed and used to demonstrate that the catalytic domain of DT is responsible for the ADP ribosylation of elongation factor 2 that results in cytotoxicity. Finally, we demonstrate that DA(E149S)B389 IL-7 induces the growth of IL-7-dependent cells, verifying the bioactivity of the IL-7 binding domain of DAB389 IL-7. We propose that DAB389 IL-7 may be an important reagent in studying the IL-7--IL-7 receptor complex and may possess potential as a therapeutic agent against IL-7 receptor-bearing hematologic malignancies.

Induction of apoptosis by cordycepin in ADA-inhibited TdT-positive leukemia cells.

The nucleoside analogue cordycepin (3'-deoxyadenosine), when protected against ADA deamination, is specifically cytotoxic for TdT-positive leukemia cells. Cordycepin-treated, ADA-inhibited, TdT-positive cells undergo the classic changes associated with drug-induced apoptosis: reduction in cell volume, chromatin clumping, membrane blebbing, and 180-bp multimer DNA laddering on agarose gels. In common with the apoptosis seen in normal TdT-positive thymocytes, following exposure to various agents, apoptosis induced by cordycepin in TdT-positive leukemia cells was associated with increased protein kinase A (PK-A) activity. Unlike thymocyte apoptosis however, no elevation in cAMP levels was seen preceding the rise in PK-A activity. Ex vivo we show that cordycepin monophosphate can activate PK-A as efficiently as cAMP. On this basis we speculate that cordycepin monophosphate in TdT-positive cells may be able to activate PK-A in place of cAMP, and that PK-A may phosphorylate TdT, augmenting its activity as an endonuclease. In cell-free experiments, the activity of recombinant TdT as an endonuclease digesting supercoiled plasmid DNA into linear fragments was dramatically increased following phosphorylation of TdT by PK-A. A role for TdT as an apoptotic endonuclease in TdT-positive leukemia cells following cordycepin exposure is now the subject of on-going work.

Diphtheria toxin-based receptor-specific chimaeric toxins as targeted therapies.

The results from the phase I/II studies of the intravenous administration of DAB486-IL-2 to patients with refractory haematological malignancies have now proven in principle the feasibility of fusion toxin therapy in man. Indeed, the cell-surface receptor-specific intoxication of neoplastic cells through the catalytic ADP-ribosylation of EF-2 is the prototype of a new class of biological response modifiers that may be generally applicable. In those circumstances where either the de novo expression or up-regulation of a cell-surface receptor can be associated with human disease [e.g. the up-regulation of the epidermal growth factor (EGF) receptor on breast cancer], it should be possible to construct genetically a DT-related/growth factor fusion protein to produce an experimental biological treatment of that malignancy. The EGF receptor-targeted fusion toxin DAB389-EGF has within the last year begun human phase I clinical trials. The pre-clinical development of DAB389-IL-7 has begun with the anticipation that this novel fusion toxin will be evaluated in the treatment of the acute leukaemias in which the IL-7R has been shown to be present.