Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival

Better treatment is required for older patients with acute myeloid leukemia (AML) not considered fit for intensive chemotherapy. We report a randomized comparison of lowdose Ara-C (LDAC) vs the novel nucleoside, clofarabine, in untreated older patients with AML and high-risk myelodysplastic syndrome (MDS). A total of 406 patients with de novo (62%), secondary disease (24%), or high-risk MDS (>10% marrow blasts) (15%), median age 74 years, were randomized to LDAC 20 mg twice daily for 10 days every 6 weeks or clofarabine 20 mg/m2 on days 1 to 5, both for up to 4 courses. These patients had more adverse demographics than contemporaneous intensively treated patients. The overall remission rate was 28%, and 2-year survival was 13%. Clofarabine significantly improved complete remission (22% vs 12%; hazard ratio [HR] 5 0.47 [0.28-0.79]; P 5 .005) and overall response (38% vs 19%; HR 5 0.41 [0.26-0.62]; P < .0001), but there was no difference in overall survival, explained by poorer survival in the clofarabine patients who did not gain complete remission and also following relapse. Clofarabine was more myelosuppressive and required more supportive care. Although clofarabine doubled remission rates, overall survival was not improved overall or in any subgroup. The treatment of patients of the type treated here remains a major unmet need. This trial was registered at www.clinicaltrials.gov as #ISRCTN 11036523.

General Nurses’ Experiences of End-Of-Life Care in the Acute Hospital Setting

Approximately 90% of the UK population spend some time in hospital in their final year of life, and more than half of the population die in hospital. This review aims to explore the experiences of general nurses when providing end-of-life care to patients in the acute hospital setting. Nine studies were identified through a literature search, and each was then analysed and evaluated until themes emerged. Six themes were drawn from the literature: lack of education and knowledge, lack of time with patients, barriers arising in the culture of the health-care setting, communication barriers, symptom management, and nurses' personal issues. The themes cause concern about the quality of end-of-life care being provided in the acute care setting. The literature appears to be consistent in the view that terminally ill patients are best cared for in specialised care settings, such as palliative care units and hospices. However, increasing demands on health services will result in greater numbers of dying patients being admitted to the acute hospital setting. It is therefore paramount that general nurses' educational needs are met to ensure they develop clinical competence to provide high-quality holistic end-of-life care.

Antibodies to the structural polypeptides of measles virus following acute infection and in SSPE

A solid-phase radioimmunoassay was used to determine the specificity of IgG antibodies from normal sera, sera and CSF from patients with SSPE for the structural polypeptides of measles virus. The polypeptide specificity of antibodies from these sources were qualitatively similar; these results indicate antigenic cross-reactivity between SSPE-derived (Mantooth) and non-SSPE-derived strains of measles virus and stimulation of antibody formation by comparable antigens.

Low molecular weight measles immunoglobulin M in subacute sclerosing panencephalitis and acute measles

Thirty eight patients with subacute sclerosing panencephalitis (SSPE) were investigated. Five patients who previously had measles immunoglobulin M (IgM) detected in unfractionated serum and cerebrospinal fluid (CSF) had measles IgM exclusively in the low molecular weight (LMW) fractions of serum and CSF. Measles IgM had previously not been found in unfractionated serum from 33 patients but was detected exclusively in the LMW fractions of serum from 30 patients. Seven children with acute measles had the expected high molecular weight (HMW) measles IgM in serum but 5 also had LMW measles IgM. Four young adults who had had measles in childhood had neither HMW nor LMW measles IgM in their sera.

Testing a model for developing, implementing and evaluating a strategy to improve the quality of nursing and midwifery care in an acute hospital trust.

Abstract:
Background: Health care organisations
worldwide are faced with the need to develop
and implement strategic organisational plans
to meet the challenges of modern health care.
There is a need for models for developing, implementing and evaluating strategic plans that engage practitioners, and make a measurable difference to the patients that they serve. These presentations describe the development, implementation and evaluation of such a model by a team of senior nurses and practice developers, to underpin a strategy for nursing and midwifery in an acute hospital trust. Developing a Strategy The PARIHS (Promoting Action on Research Implementation in Health Services) conceptual framework (Kitson et al, 1998) proposes that successful implementation of change in practice is a function of the interplay of three core elements: the level of evidence supporting the proposed change; the context or environment in which the change takes place, and the way in which change is facilitated. We chose to draw on this framework to develop our strategy and implementation plan (O’Halloran, Martin and Connolly, 2005). At the centre of the plan are ward managers. These professionals provide leadership for the majority of staff in the trust and so were seen to be a key group in the implementation process.

Lung stereotactic body radiation therapy (SBRT) delivered over 4 or 11days: A comparison of acute toxicity and quality of life.

Abstract
PURPOSE:
The optimal duration over which lung SBRT should be delivered is unknown. We conducted a randomized pilot study in patients treated with four fractions of lung SBRT delivered over 4 or over 11days.
METHODS:
Patients with a peripheral solitary lung tumor (NSCLC or pulmonary metastasis) ?5cm were eligible. For NSCLC lung tumors ?3cm, a dose of 48Gy in 4 fractions was used, otherwise 52Gy in 4 fractions was delivered. Patients were randomized to receive treatment over 4 consecutive days or over 11days. The primary end-point was acute grade ?2 toxicity. Secondary end-points included quality of life (QOL) assessed using the EORTC QLQ-C30 and QLQ-LC13 questionnaires.
RESULTS:
Fifty four patients were enrolled. More patients in the 11day group had respiratory symptoms at baseline. 55.6% patients treated over 4days and 33.3% of patients treated over 11days experienced acute grade ?2 toxicity (p=0.085). Dyspnea, fatigue and coughing domains were worse in the 11day group at baseline. At 1 and 4months, more patients in the 4day group experienced a clinically meaningful worsening in the dyspnea QOL domain compared to the 11day group (44.5% vs 15.4%, p=0.02; 38.5% vs 12.0%, p=0.03, respectively). However, raw QOL scores were not different at these time-points between treatment groups.
CONCLUSIONS:
Grade 2 or higher acute toxicity was more common in the 4day group, approaching statistical significance. More patients treated on 4 consecutive days reported a clinically meaningful increase in dyspnea, although interpretation of these results is challenging due to baseline imbalance between treatment groups. Larger studies are required to validate these results.

Detection of acute coronary occlusion in patients with acute coronary syndromes presenting with isolated ST-segment depression

This study sought to determine whether 80-lead body surface potential mapping (BSPM) would improve detection of acute myocardial infarction (AMI) and occluded culprit artery in patients presenting with ST-segment depression (STD) only on 12-lead ECG.

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial

Background: Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.

Methods/Design: Patients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1: 1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.

Susceptibility of streptozotocin-induced diabetic rat retinal function and ocular blood flow to acute intraocular pressure challenge.

PURPOSE: To consider whether STZ-induced hyperglycemia renders rat retinal function and ocular blood flow more susceptible to acute intraocular pressure (IOP) challenge.

METHODS: Retinal function (electroretinogram, ERG) was measured during acute IOP challenge (10-100 mmHg, 5 mmHg increments, 3 min/step, vitreal cannulation) in adult Long-Evans rats (6-week old, citrate: n=6, STZ: n=10) 4 weeks after citrate buffer or streptozotocin (STZ, 65 mg/kg, blood glucose > 15 mmol/l) injection. At each IOP, dim and bright flash (-4.56, -1.72 log cd.s.m^-2) ERG responses were recorded to measure inner retinal and ON-bipolar cell function, respectively. Ocular blood flow (laser Doppler flowmetry, citrate; n=6, STZ; n=10) was also measured during acute IOP challenge. Retinae were isolated for qPCR analysis of nitric oxide synthase mRNA expression endothelial, eNos; inducible, iNos; neuronal, nNos).

RESULTS: STZ-induced diabetes increased the susceptibility of inner retinal (IOP at 50% response, 60.1, CI: 57.0-62.0 mmHg vs. citrate: 67.5, CI: 62.1-72.4 mmHg) and ON-bipolar cell function (STZ: 60.3, CI: 58.0-62.8 mmHg vs. citrate: 65.1, CI: 58.0-62.78 mmHg) and ocular blood flow (43.9, CI: 40.8-46.8 vs. citrate: 53.4, CI: 50.7-56.1 mmHg) to IOP challenge. Citrate eyes showed elevated eNos mRNA (+49.7%) after IOP stress, an effect not found in STZ-diabetic eyes (-5.7%, P<0.03). No difference was observed for iNos or nNos (P>0.05) following IOP elevation.

CONCLUSIONS: STZ-induced diabetes increased functional susceptibility during acute IOP challenge. This functional vulnerability is associated with a reduced capacity for diabetic eyes to upregulate eNOS expression and to autoregulate blood flow in response to stress.

Relationship between the magnitude of intraocular pressure during an episode of acute elevation and retinal damage four weeks later in rats

Purpose: To determine relationship between the magnitude of intraocular pressure (IOP) during a fixed-duration episode of acute elevation and the loss of retinal function and structure 4 weeks later in rats.

Methods: Unilateral elevation of IOP (105 minutes) was achieved manometrically in adult Brown Norway rats (9 groups; n = 4 to 8 each, 10–100 mm Hg and sham control). Full-field ERGs were recorded simultaneously from treated and control eyes 4 weeks after IOP elevation. Scotopic ERG stimuli were white flashes (26.04 to 2.72 log cd.s.m^-2). Photopic ERGs were recorded (1.22 to 2.72 log cd.s.m22) after 15 min of light adaptation (150 cd/m2). Relative amplitude (treated/control, %) of ERG components versus IOP was described with a cummulative normal function. Retinal ganglion cell (RGC) layer density was determined post mortem by histology.

Results: All ERG components failed to recover completely normal amplitudes by 4 weeks after the insult if IOP was 70 mmHg or greater during the episode. There was no ERG recovery at all if IOP was 100 mmHg. Outer retinal (photoreceptor) function demonstrated the least sensitivity to prior acute IOP elevation. ERG components reflecting inner retinal function were correlated with post mortem RGC layer density.

Conclusions: Retinal function recovers after IOP normalization, such that it requires a level of acute IOP elevation approximately 10 mmHg higher to cause a pattern of permanent dysfunction similar to that observed during the acute event. There is a ‘threshold’ for permanent retinal functional loss in the rat at an IOP between 60 and 70 mmHg if sustained for 105 minutes or more.

Simvastatin decreases the level of heparin-binding protein in patients with acute lung injury

Heparin-binding protein is released by neutrophils during inflammation and disrupts the integrity of the alveolar and capillary endothelial barrier implicated in the development of acute lung injury and systemic organ failure. We sought to investigate whether oral administration of simvastatin to patients with acute lung injury reduces plasma heparin-binding protein levels and improves intensive care unit outcome.

Keratinocyte growth factor in acute lung injury to reduce pulmonary dysfunction--a randomised placebo-controlled trial (KARE):study protocol

Acute lung injury is a common, devastating clinical syndrome associated with substantial mortality and morbidity with currently no proven therapeutic interventional strategy to improve patient outcomes. The objectives of this study are to test the potential therapeutic effects of keratinocyte growth factor for patients with acute lung injury on oxygenation and biological indicators of acute inflammation, lung epithelial and endothelial function, protease:antiprotease balance, and lung extracellular matrix degradation and turnover.