Cardiovascular and autonomic effects of omega-conotoxins MVIIA and CVID in conscious rabbits and isolated tissue assays

1. The effects of a novel N-type voltage-operated calcium channel antagonist, omega-conotoxin CVID, were compared with omega-conotoxin MVIIA on sympathetic-evoked activation of right atria (RA), small mesenteric arteries (MA) and vasa deferentia (VD) isolated from the rat. Their effects were also compared on blood pressure and cardiovascular reflexes in conscious rabbits. 2. The pIC(50) values for MVIIA and CVID, respectively, for inhibiting sympathetic-evoked responses were equivalent in RA (8.7 and 8.7) and VD (9.0 and 8.7); however, in MA the values were 8.4 and 7.7. The cardiac to vascular (RA/MA) potency ratios, antilog (plog RA - plog MA), for MVIIA and CVID were 2 and 10. The offset rates for CVID and MVIIA were rapid, and peptide reapplication caused rapid onset of blockade, suggesting limited desensitization. 3. In the conscious rabbit, CVID and MVIIA (100 microg kg(-1) i.v.) caused a similar fall in blood pressure and a tachycardia that rapidly reached maximum. Both peptides decreased the vagal- and sympathetic-mediated components of the baroreflex, but had no effect on the vagal nasopharyngeal reflex. The orthostatic reflex to 90 degrees tilt was blocked by MVIIA with sustained postural hypotension for > or = 90 min after administration. In contrast, CVID caused postural hypotension at 30 min which recovered rapidly. 4. Neither CVID nor MVIIA (3 microg kg(-1) i.t.) significantly altered cardiovascular variables or autonomic reflexes. 5. In conclusion, CVID appears to be relatively weak at inhibiting the reflex response to tilt consistent with its weaker inhibition of rat mesenteric artery constriction to perivascular nerve stimulation. This may point to subtype N-type calcium channel selectivity.     

High dose ifosfamide in combination with etoposide and epirubicin followed by autologous stem cell transplantation in the treatment of relapsed/refractory Hodgkin's disease: a report on toxicity and efficacy

Patients with Hodgkin's disease (HD) refractory to first line chemotherapy and those who have rapid or multiple relapses have a very poor prognosis. With the increasing use of hybrid chemotherapy these patients will have been exposed to many of the drugs active in HD so it is important to develop salvage regimens that are novel and demonstrate activity in this group of patients. We report the use of a continuous high dose infusion of ?fosfamide at a dose of 9g/m(2) over 3 days in combination with etoposide and epirubicin followed by autologous stem cell transplant with either BEAM or Melphalan/VP16 conditioning in this difficult group. Forty six patients (28M:18F) with a median age of 28 years (range 13-45) were treated. Overall 39 out of 46 (85%) patients responded to treatment, with 17 achieving complete remission and 11 a good partial remission; 28 proceeded to autologous bone marrow/stem cell transplantation. In total, 23 patients are alive and in continuous remission with a follow up of between 12 and 61 months. Median overall survival for the whole group is 36 months. Haematological toxicity, particularly neutropenia (WHO grade IV), was observed in all cases but improved over the 3 courses of treatment in all patients. Non-haematological toxicity was not a major problem; no significant cardiac, hepatic, renal, pulmonary or neuro toxicity was observed and there were no deaths on treatment. This regime shows promise in patients with difficult Hodgkin's disease and warrants further study.     

Learning needs analysis: the development of a tool to support the on-going professional development of multiple sclerosis specialist nurses

Continuous professional development (CPD) is essential in modern day nursing. Learning needs analysis (LNA) is an important element of CPD. This paper describes the development of a LNA tool for multiple sclerosis specialist nurses. The tool contains an empirically developed LNA schedule and uses a blend of both subjective and objective exercises to help the nurse formulate a comprehensive learning plan. The tool is organised into four phases: phase 1, focuses on the knowledge and skills necessary to the fulfillment of work-based objectives; phase 2, involves a more in-depth assessment of particular areas of professional knowledge; phase 3, examines learning strategies; and phase 4, involves the development of a learning plan. The tool has been implemented throughout the UK via local trainers. While the tool was developed for a specialist nurse population the principles upon which it is based are likely to be transferable to other nursing contexts.     

Designing clinical trials in acute lung injury/acute respiratory distress syndrome

PURPOSE OF REVIEW: To review the implications of recent literature for clinical trial design in acute lung injury/acute respiratory distress syndrome (ARDS). RECENT FINDINGS: Refinement of acute lung injury/acute respiratory distress syndrome diagnostic criteria and study enrollment criteria, greater efforts to define usual care appropriately, and balancing of efficacy and effectiveness design principles will be key components of future trials. SUMMARY: Clinical trial design in acute lung injury/acute respiratory distress syndrome faces many challenges. Although we have learned much from past trials, persistent design dilemmas must be addressed for future trials.     

Impaired allocentric spatial memory underlying topographical disorientation

The cognitive processes supporting spatial navigation are considered in the context of a patient (CF) with possible very early Alzheimer's disease who presents with topographical disorientation. Her verbal memory and her recognition memory for unknown buildings, landmarks and outdoor scenes was intact, although she showed an impairment in face processing. By contrast, her navigational ability, quantitatively assessed within a small virtual reality (VR) town, was significantly impaired. Interestingly, she showed a selective impairment in a VR object-location memory test whenever her viewpoint was shifted between presentation and test, but not when tested from the same viewpoint. We suggest that a specific impairment in locating objects relative to the environment rather than relative to the perceived viewpoint (i.e. allocentric rather than egocentric spatial memory) underlies her topographical disorientation. We discuss the likely neural bases of this deficit in the light of related studies in humans and animals, focusing on the hippocampus and related areas. The specificity of our test indicates a new way of assessing topographical disorientation, with possible application to the assessment of progressive dementias such as Alzheimer's disease.     

Cryopreserved dendritic cells for intratumoral immunotherapy do not require re-culture prior to human vaccination

Dendritic cell (DC) immunotherapy for cancer has shown great promise so far. The ability to deliver dendritic cells directly into tumours where they are capable of acquiring tumour antigens prior to stimulating specific T cell responses has been demonstrated both in animal models and human patients. Clinical grade DCs can be grown from peripheral blood monocytes in the absence of foetal calf serum (FCS) and cryopreserved to generate plentiful identical aliquots thus avoiding repeated venesection. However, the approach is still limited by the necessity to return thawed DCs to culture prior to injection. It would be more advantageous to directly inject the DCs whilst still in the freezing medium and thus prevent the need for further manipulation. Whilst several reports have shown that cryopreserved DCs can survive for over 72 h when returned to culture, there is no information regarding the longevity of cells maintained in the freezing medium after thawing. In this report we have shown that DCs may remain in freezing medium for up to 1 h without affecting their survival, phenotype or function. This period of time is sufficient to allow for any delays incurred between the preparation of the DCs and time taken to be administered within a standard clinical setting. This study demonstrates that clinical grade DCs can be cryopreserved and thawed whilst retaining the ability to acquire exogenous antigenic material required for intratumoural immunotherapy. The survival of these cells within the freezing medium without the requirement for re-culture expands their availability for administration directly to the tumours of patients in non-specialist centres that do not have the appropriate facilities for DC re-culture.