Selective brain entry of lipid nanoparticles in haemorrhagic stroke is linked to biphasic blood-brain barrier disruption.

Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. Methods: Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. Results: Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (Ktrans [min-1]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. Discussion: Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules.

Building on transformative learning and response shift theory to investigate health-related quality of life changes over time in individuals with chronic health conditions and disability.

A major goal of treatment for people living with chronic illness or disability is self-management leading to optimized health-related quality of life. This change process has been described in the adult education literature as transformative learning, while in health-related quality of life research, response shift has emerged as a key concept. Response shift and transformative learning literature were reviewed, and the theoretical frameworks of the 2 concepts were compared and contrasted. Response shift is described as a change in internal standards, values, or definition of a construct (eg, health-related quality of life) over time, commonly seen in individuals with chronic illness. In the context of chronic illness, transformative learning is described as a complex process of personal change including beliefs, feelings, knowledge, and values. Transformative learning is often triggered by the diagnosis of a chronic illness. This results in a critical reflection of taken-for-granted assumptions and leads to new ways of thinking, influencing personal changes in daily living. Comparing the models of response shift and transformative learning in chronic illness, the catalyst in response shift appears comparable with the trigger in transformational learning; mechanisms to process of changing; and perceived quality of life to outcomes. Both transformative learning and response shift have much to offer health care providers in understanding the learning process for the person living with chronic illness or disability to optimize their quality of life. Suggestions for future research in response shift and transformative learning in individuals with chronic health conditions and disability are proposed.

Developing a model of participation post-stroke: a mixed-methods approach.

PURPOSE: To develop and verify a model of participation post stroke, as a domain of health related quality of life. METHODS: An explanatory sequential mixed-methods design was selected. The quantitative phase developed a participation model with data from an observational study of 453 participants at 12 months post-stroke, using structural equation modeling. The qualitative phase followed to verify the model from the perspective of individuals post-stroke. Data was collected from two groups of eight stroke survivors involved in a multicentre trial about participation in the community. Individuals took photographs to describe participation; discussion of photographs was conducted over the course of three focus groups, and analysis identified emergent categories related to the model. RESULTS: The 12-month post stroke participation model consisted of latent variables: accomplishment, restricted roles, and health efficacy. The model fit was reasonable: normed χ(2) = 2.95, RMSEA = 0.066(0.052; 0.079). The qualitative data verified the model; participants initiated photo-taking and discussion of all aspects of the model. Concepts of social support, environment, and cognitive difficulties were also discussed in relation to participation. CONCLUSIONS: The participation model was developed and verified. Additions to future models are suggested. Theoretical, clinical, and research implications are discussed.

Health-related quality of life after stroke: does response shift occur in self-perceived physical function?

OBJECTIVE: To determine whether response shift (a change in the self-perceived meaning of health-related quality of life [HRQL]) was present in a model of physical function over time poststroke. DESIGN: Secondary data analysis of a longitudinal observational study. SETTING: Community. PARTICIPANTS: A consecutive sample of stroke survivors (N=677) at 1, 3, 6, and 12 months poststroke was included. Sixty-seven individuals were approached, but refused. Sixty-seven percent completed the study at 12 months. Mean age was 68 years; 45% of the participants were women. INTERVENTIONS: Not applicable. MAIN OUTCOMES MEASURES: The Medical Outcomes Study 36-Item Short-Form Health Survey, Euroqol, Stroke Impact Scale, Preference-Based Stroke Index, and the Health Utilities Index. RESULTS: Structural equation modeling was used to identify response shift. A chi-square difference test between constrained and unconstrained longitudinal models suggested the presence of response shift in the data. Reprioritization response shift, a change in relative importance of domains, was observed for physical activites. Recalibration response shift, a change in internal standards of measurement, was observed in physical activities, stairs, walking, and hand function. CONCLUSIONS: Response shift has implications for the measurement of change in physical function. Measures that focus on difficulty in task performance may be sensitive to response shift, resulting in a change in perceived HRQL over time. This has implications for choosing self-perceived or performance-based measures to detect change in physical function.

Mental practice for treating upper extremity deficits in individuals with hemiparesis after stroke.

BACKGROUND: Activity limitations of the upper extremity are a common finding for individuals living with stroke. Mental practice (MP) is a training method that uses cognitive rehearsal of activities to improve performance of those activities. OBJECTIVES: To determine if MP improves the outcome of upper extremity rehabilitation for individuals living with the effects of stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (November 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, November 2009), PubMed (1965 to November 2009), EMBASE (1980 to November 2009), CINAHL (1982 to November 2009), PsycINFO (1872 to November 2009), Scopus (1996 to November 2009), Web of Science (1955 to November 2009), the Physiotherapy Evidence Database (PEDro), CIRRIE, REHABDATA, ongoing trials registers, and also handsearched relevant journals and searched reference lists. SELECTION CRITERIA: Randomised controlled trials involving adults with stroke who had deficits in upper extremity function. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion. We considered the primary outcome to be the ability of the arm to be used for appropriate tasks (i.e. arm function). MAIN RESULTS: We included six studies involving 119 participants. We combined studies that evaluated MP in addition to another treatment versus the other treatment alone. Mental practice in combination with other treatment appears more effective in improving upper extremity function than the other treatment alone (Z = 3.48, P = 0.0005; standardised mean difference (SMD) 1.37; 95% confidence interval (CI) 0.60 to 2.15). We attempted subgroup analyses, based on time since stroke and dosage of MP; however, numbers in each group were small. We evaluated the quality of the evidence with the PEDro scale, ranging from 6 to 9 out of 10; we determined the GRADE score to be moderate. AUTHORS' CONCLUSIONS: There is limited evidence to suggest that MP in combination with other rehabilitation treatment appears to be beneficial in improving upper extremity function after stroke, as compared with other rehabilitation treatment without MP. Evidence regarding improvement in motor recovery and quality of movement is less clear. There is no clear pattern regarding the ideal dosage of MP required to improve outcomes. Further studies are required to evaluate the effect of MP on time post stroke, volume of MP that is required to affect the outcomes and whether improvement is maintained long-term. Numerous large ongoing studies will soon improve the evidence base.

Estimating the Accuracy of the Chedoke-McMaster Stroke Assessment Predictive Equations for Stroke Rehabilitation.

PURPOSE: To estimate the predictive accuracy and clinical usefulness of the Chedoke-McMaster Stroke Assessment (CMSA) predictive equations. METHOD: A longitudinal prognostic study using historical data obtained from 104 patients admitted post cerebrovascular accident was undertaken. Data were abstracted for all patients undergoing rehabilitation post stroke who also had documented admission and discharge CMSA scores. Published predictive equations were used to determine predicted outcomes. To determine the accuracy and clinical usefulness of the predictive model, shrinkage coefficients and predictions with 95% confidence bands were calculated. RESULTS: Complete data were available for 74 patients with a mean age of 65.3±12.4 years. The shrinkage values for the six Impairment Inventory (II) dimensions varied from -0.05 to 0.09; the shrinkage value for the Activity Inventory (AI) was 0.21. The error associated with predictive values was greater than ±1.5 stages for the II dimensions and greater than ±24 points for the AI. CONCLUSIONS: This study shows that the large error associated with the predictions (as defined by the confidence band) for the CMSA II and AI limits their clinical usefulness as a predictive measure. Further research to establish predictive models using alternative statistical procedures is warranted.

Response shift was identified over multiple occasions with a structural equation modeling framework.

OBJECTIVE: To develop and apply a framework that uses structural equation modeling to identify response shift (RS) in data with more than two time points. STUDY DESIGN AND SETTING: The framework addresses key issues that arise when analyzing data with multiple time points using a model-based approach to test for RS: model validation, correction for multiple testing, and adoption of an exploratory or theory-driven approach to identify the type and timing of RS. Data from an observational study of 678 individuals at 1, 3, 6, and 12 months poststroke are used to demonstrate the application of the framework to a model for mental health. RESULTS: Uniform and nonuniform recalibration was identified at 6 and 12 months poststroke. CONCLUSION: Studies that identify the type and timing of RS in certain client populations are useful for planning the timing of treatment and the methods to measure RS clinically. Validation of the model and adjusting for the effects of multiple testing increases confidence in the mental health model and the resulting identification of RS.

Response shift: a brief overview and proposed research priorities.

AIM: The objective of this overview is to review current methodologies of response shift research in patient-reported outcomes to facilitate and stimulate further research in this area. METHODS: This paper is a narrative overview of research in response shift. RESULTS: The following research priorities emerged: (1) obtain a consensus on terminology and theoretical models used, to ensure that all researchers and clinicians are at the same starting point; (2) determine the clinical importance of response shift; (3) determine the best way to measure and adjust for response shift as a clinically important confounder; (4) ascertain how response shift can best be identified when response shift is the focus of clinical treatment; and (5) establish what methods can be used to translate response shift knowledge into real-world settings. CONCLUSIONS: With the adoption of these research priorities, we anticipate that the theories and processes of response shift will be better understood, current methods to analyze this phenomenon will be improved while new ones may also be developed, and the clinical importance and impact of response shift in measuring changes in health-related quality of life (HRQL) will be determined.

Temperature dependence of Na+-H+ exchange, Na+-HCO3- co-transport, intracellular buffering and intracellular pH in guinea-pig ventricular myocytes.

Almost all aspects of cardiac function are sensitive to modest changes of temperature. We have examined the thermal sensitivity of intracellular pH regulation in the heart. To do this we determined the temperature sensitivity of pHi, intracellular buffering capacity, and the activity of sarcolemmal acid-extrusion proteins, Na+-H+ exchange (NHE) and Na+-HCO3- co-transport (NBC) in guinea-pig isolated ventricular myocytes. pHi was recorded fluorimetrically with acetoxymethyl (AM)-loaded carboxy-SNARF-1 at either 27 or 37 degrees C. At 27 degrees C, intrinsic (non-CO2-dependent) buffering power (betai) was approximately 60% of that at 37 degrees C. Acid-extrusion (Je) through NHE was approximately 50% slower than at 37 degrees C, consistent with a Q10 of approximately 2. In 5% CO2/HCO3--buffered conditions, in the presence of 30 microM cariporide to inhibit NHE, acid extrusion via NBC was also slowed at 27 degrees C, suggestive of a comparable Q10. Resting pHi at 27 degrees C was similar in Hepes- or 5% CO2/HCO3--buffered superfusates but, in both cases, was approximately 0.1 pH units lower at 37 degrees C. The higher the starting pHi, the larger was the thermally induced fall of pHi, consistent with a mathematical model where intrinsic buffers with a low principal pKa (e.g. close to 6.0) are less temperature-sensitive than those with a higher pKa. The high temperature sensitivity of pHi regulation in mammalian cardiac cells has implications for experimental work conducted at room temperature. It also has implications for the ability of intracellular acidosis to generate intracellular Na+ and Ca2+ overload, cardiac injury and arrhythmia in the heart.

A study of the proteins responsible for stimulating B-CLL-specific T-cell responses by autologous dendritic cells pulsed with tumour cell lysate.

We have previously shown that autologous dendritic cells (DCs) pulsed with tumour cell lysate and cultured with autologous T cells from patients with B-cell chronic lymphocytic leukaemia (B-CLL) stimulate significant increases in proliferation, IFN-gamma secretion and specific HLA class II-restricted cytotoxicity to B-CLL targets. In this study, normal and tumour cell lysates were analysed by reducing SDS-PAGE, and protein bands of interest eluted from the polyacrylamide gel by electroelution. The eluted protein fractions and whole-cell lysate were then pulsed onto autologous DCs and cocultured with autologous T cells. Finally, the stimulatory fractions were sequenced. B-CLL cell lysates revealed protein bands at 65, 42, 35 and 25 kDa, while normal B-cell lysates only showed a single protein band at 65 kDa. Both the 65 kDa band and 42 kDa bands were capable of stimulating comparable amounts of IFN-gamma secretion and specific cytotoxicity as whole lysate, while the other protein bands were not. Sequencing of the 65 kDa fraction showed a dominant peptide that matched human serum albumin, while sequencing the 42 kDa fraction showed three dominant peptides which matched human actin and another unidentified protein. The significance of these findings remains unclear.