The relationship between patients' illness beliefs and recovery after stroke.

The Common Sense Model (CSM) is a useful framework for understanding mood and treatment adherence amongst survivors in the acute phase of stroke. CSM stroke studies have thus far focused on the single outcomes, mood and medication adherence, neglecting other aspects of post-stroke recovery (i.e., Health-Related Quality of Life (HRQL) and disability). The purpose of this study was to examine relationships between baseline illness beliefs and three-month post-stroke HRQL, mood and disability. A longitudinal observational design was adopted, involving 50 survivors (mean age = 66.9 years, 68% male). The primary outcome, HRQL, was measured using EQ-5D-5L. The secondary outcome, mood was measured using the Patient Health Questionnaire-9; and disability, using the Nottingham Extended Activities of Daily Living Scale. The Stroke Illness Perception Questionnaire-Revised measured illness beliefs. Spearman's correlations showed that beliefs about the fluctuating effects of stroke (ρ = 0.50, p < 0.001) and considerable distress at baseline were significantly associated with worse mood three-months post-stroke (ρ = 0.41, p < 0.001). Baseline illness beliefs were not significantly related to three-month post-stroke HRQL or disability. Despite being limited by a modest sample size, the findings reiterated the need for routine clinical assessment of mood immediately after stroke, and indicated that simultaneous measurement of illness beliefs may also be beneficial.

Can illness beliefs, from the common-sense model, prospectively predict adherence to self-management behaviours? A systematic review and meta-analysis.

OBJECTIVE: To determine whether people's beliefs about their illness, conceptualised by the common sense model (CSM), can prospectively predict adherence to self-management behaviours (including, attendance, medication, diet and exercise) in adults with acute and chronic physical illnesses. DESIGN AND MAIN OUTCOME MEASURES: Electronic databases were searched in September 2014, for papers specifying the use of the 'CSM' in relation to 'self-management', 'rehabilitation' and 'adherence' in the context of physical illness. Six hundred abstracts emerged. Data from 52 relevant studies were extracted. Twenty-one studies were meta-analysed, using correlation coefficients in random effects models. The remainder were descriptively synthesised. RESULTS: The effect sizes for individual illness belief domains and adherence to self-management behaviours ranged from .04 to .13, indicating very weak, predictive relationships. Further analysis revealed that predictive relationships did not differ by the: type of self-management behaviour; acute or chronic illness; or duration of follow-up. CONCLUSION: Individual illness belief domains, outlined by the CSM, did not predict adherence to self-management behaviours in adults with physical illnesses. Prospective relationships, controlling for past behaviour, also did not emerge. Other factors, including patients' treatment beliefs and inter-relationships between individual illness beliefs domains, may have influenced potential associations with adherence to self-management behaviours.

Occupational therapy predischarge home visits for patients with a stroke (HOVIS): results of a feasibility randomized controlled trial.

OBJECTIVE: To assess the feasibility of conducting a randomized controlled trial of occupational therapy predischarge home visits for people after stroke. DESIGN: Randomized controlled trial and cohort study. We randomized eligible patients for whom there was clinical uncertainty about the need to conduct a home visit to a randomized controlled trial; patients for whom a visit was judged 'essential' were enrolled into a cohort study. SETTING: Stroke rehabilitation unit of teaching hospital. PARTICIPANTS: One hundred and twenty-six participants hospitalized following recent stroke. INTERVENTIONS: Predischarge home visit or structured, hospital-based interview. MAIN OUTCOME MEASURES: The primary objective was to collect information on the feasibility of a randomized controlled trial, including eligibility, control intervention and outcome assessments. The primary outcome measure was the Nottingham Extended Activities of Daily Living Scale at one month after discharge from hospital. Secondary outcomes included mood, quality of life and costs at one week and one month following discharge. RESULTS: Ninety-three people were allocated to the randomized controlled trial; 47 were randomized to intervention and 46 to control. Thirty-three were enrolled into the cohort study. More people were allocated to the randomized controlled trial as the study progressed. One hundred and thirteen people (90%) received the proposed intervention, although there was a need for stricter protocol adherence. Follow-up was good: at one month 114 (90%) were assessed. There were no significant differences between the groups in the randomized controlled trial for the primary outcome measure at one month. The average cost of a home visit was £208. CONCLUSION: A trial is feasible and warranted given the resource implications of predischarge occupational therapy home visits.

The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34(+) stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin.

Dendritic cells (DCs) are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous population of cells that differ in their development, surface phenotype and function. The study of human blood and spleen has shown the presence of two subsets of conventional DC including the CD1b/c(+) and CD141(+)CLEC9A(+) conventional DC (cDC) and a plasmacytoid DC (pDC) that is CD304(+)CD123(+). Studies on these subpopulations have revealed phenotypic and functional differences that are similar to those described in the mouse. In this study, the three DC subsets have been generated in vitro from human CD34(+) precursors in the presence of fms-like tyrosine kinase 3 ligand (Flt3L) and thrombopoietin (TPO). The DC subsets so generated, including the CD1b/c(+) and CLEC9A(+) cDCs and CD123(+) pDCs, were largely similar to their blood and spleen counterparts with respect to surface phenotype, toll-like receptor and transcription factor expression, capacity to stimulate T cells, cytokine secretion and cross-presentation of antigens. This system may be utilized to study aspects of DC development and function not possible in vivo.

Advances in spontaneous intracerebral haemorrhage.

OBJECTIVES: To assess the evidence and available literature on the clinical, pathogenetic, prognostic and therapeutic aspects of intracerebral haemorrhage. METHODS: The most important manuscripts and reviews on the subject were considered. Information was collected from Medline, Embase & National Library of Medicine over the last 40 years up to Oct 2011. The bibliographies of relevant articles were searched for additional references. The most up to date and randomised trials were given preference. Clinical guidelines including AHA/ASA, Royal college of Physicians, NICE, Scottish Intercollegiate guidelines and several others were taken into consideration. FINDINGS: There are numerous advances in the understanding of the pathogenesis and management, but hardly any change in the overall mortality in the last few decades. There is a poor understanding of the results of surgical trials that has resulted in a large drop in surgical intervention since 2007. INTERPRETATIONS AND IMPLICATIONS: Advances in neuroimaging and neurophysiology have improved our understanding of the mechanisms of neuronal injury and existence of perihaematomal 'tissue at risk'. Numerous new therapeutic targets have been identified. There is a lot of misunderstanding of the results of the newer surgical trials which need to be clarified. The importance of cerebral amyloid angiopathy and microbleeds in older patients is increasingly recognised. Control of hypertension is the most important public health measure. Stroke units provide the best outcomes for the patients.

A systematic review of delays in seeking medical attention after transient ischaemic attack.

BACKGROUND: Prompt assessment and investigation of transient ischaemic attack (TIA) followed by early initiation of secondary prevention is effective in reducing recurrent stroke. Nevertheless, many patients are slow to seek medical advice after TIA. A systematic review was undertaken to examine potential factors associated with delay in seeking medical review after TIA. METHODS: The electronic databases MEDLINE, EMBASE, and Science Citation Index were searched for observational studies assessing patient delay in presentation after TIA. The search was restricted to studies published between December 1995 and September 2008. RESULTS: The electronic search yielded nine studies with data on presentation delay in patients with TIA; variations existed in study size, population and methodology. One study included patients with TIA only (n = 241), whereas the remaining eight studies recruited both stroke and TIA patients. Overall, TIA patients (n = 821) made up only a small proportion of the total number of patients in this analysis (n = 3,202). Length of delay varied greatly across all studies. In most studies, patients with TIA who attended an emergency department arrived there within hours. Where patients first presented to their general practitioner, 50% attended within 24 hours whereas 25% waited 2 days or more. Recognition of symptoms as stroke/TIA did not reduce the delay. CONCLUSIONS: The majority of delay in seeking assessment after TIA is due to a lack of response by the patient-many patients do not recognise the symptoms of stroke/TIA, and even when they do, many fail to seek emergency medical attention. The public needs educating on the importance of contacting the emergency medical services or attending an emergency department immediately after TIA.

Amphetamine increases blood pressure and heart rate but has no effect on motor recovery or cerebral haemodynamics in ischaemic stroke: a randomized controlled trial (ISRCTN 36285333).

Amphetamine enhances recovery after experimental ischaemia and has shown promise in small clinical trials when combined with motor or sensory stimulation. Amphetamine, a sympathomimetic, might have haemodynamic effects in stroke patients, although limited data have been published. Subjects were recruited 3-30 days post-ischaemic stroke into a phase II randomized (1:1), double-blind, placebo-controlled trial. Subjects received dexamphetamine (5 mg initially, then 10 mg for 10 subsequent doses with 3- or 4-day separations) or placebo in addition to inpatient physiotherapy. Recovery was assessed by motor scales (Fugl-Meyer (FM)), and functional scales (Barthel index (BI) and modified Rankin score (mRS)). Peripheral blood pressure (BP), central haemodynamics and middle cerebral artery blood flow velocity were assessed before, and 90 min after, the first two doses. Thirty-three subjects were recruited, aged 33-88 (mean 71) years, males 52%, 4-30 (median 15) days post stroke to inclusion. Sixteen patients were randomized to placebo and seventeen to amphetamine. Amphetamine did not improve motor function at 90 days; mean (s.d.) FM 37.6 (27.6) vs control 35.2 (27.8) (P=0.81). Functional outcome (BI, mRS) did not differ between treatment groups. Peripheral and central systolic BP, and heart rate (HR), were 11.2 mm Hg (P=0.03), 9.5 mm Hg (P=0.04) and 7 beats per minute (P=0.02) higher, respectively, with amphetamine, compared with control. A nonsignificant reduction in myocardial perfusion (BUI) was seen with amphetamine. Other cardiac and cerebral haemodynamics were unaffected. Amphetamine did not improve motor impairment or function after ischaemic stroke but did significantly increase BP and HR without altering cerebral haemodynamics.

Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke.

BACKGROUND: Colony stimulating factors (CSFs), also called haematopoietic growth factors, regulate bone marrow production of circulating red and white cells, and platelets. They have been shown to be neuroprotective in experimental stroke. Some CSFs also mobilise the release of bone marrow stem cells into the circulation. OBJECTIVES: To assess the effects of CSFs on functional outcome and haematology measures in patients with acute or subacute stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched November 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1985 to June 2006), EMBASE (1985 to June 2006), and Science Citation Index (1985 to June 2006). In an attempt to identify further published, unpublished and ongoing trials we contacted manufacturers and principal investigators of trials (last contacted 2006). We also searched reference lists of relevant articles and reviews. SELECTION CRITERIA: Unconfounded randomised controlled trials recruiting patients with acute or subacute ischaemic or haemorrhagic stroke were included. CSFs included stem cell factor (SCF), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF, CSF-1), and thrombopoietin (TPO), or analogues of these. The primary outcome was functional outcome (assessed as combined death or disability and dependency using scales such as the modified Rankin Scale or Barthel Index) at the end of the trial. Secondary outcomes included safety at the end of treatment (death, impairment, deterioration, extension or recurrence), death at the end of follow up, and haematology measures (blood counts at or around day seven after treatment commenced). DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. Study authors were contacted for additional information. MAIN RESULTS: No large trials were identified. EPO therapy was associated with a non-significant reduction in neurological impairment in one small trial (n = 40 participants) but had no significant effect on haematological measures. G-CSF was associated with a non-significant reduction in combined death and dependency in two small trials (n = 46 participants) although there was substantial heterogeneity in this result. G-CSF significantly elevated white cell count in three trials (n = 91). Further small trials of EPO and G-CSF are ongoing. AUTHORS' CONCLUSIONS: No large trials of EPO, G-CSF or other colony stimulating factors have been performed and it is too early to know whether CSFs improve functional outcome.

Colony stimulating factors (including erythropoietin, granulocyte colony stimulating factor and analogues) for stroke.

BACKGROUND: Colony stimulating factors (CSFs), also called haematopoietic growth factors, regulate bone marrow production of circulating red and white cells, and platelets. They have been shown to be neuroprotective in experimental stroke. Some CSFs also mobilise the release of bone marrow stem cells into the circulation. OBJECTIVES: We systematically assessed the effects of CSFs on functional outcome and haematology measures in patients with acute or subacute stroke enrolled into randomised controlled trials. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched February 2005), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), MEDLINE (1985 to March 2006), EMBASE (1985 to November 2005), and Science Citation Index (1985 to November 2005). In an attempt to identify further published, unpublished and ongoing trials we contacted manufacturers and principal investigators of trials (last contacted 2005). We also searched reference lists of relevant articles and reviews. SELECTION CRITERIA: Unconfounded randomised controlled trials recruiting patients with acute or subacute ischaemic or haemorrhagic stroke were included. CSFs included stem cell factor (SCF), erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF, CSF-1), and thrombopoietin (TPO), or analogues of these. The primary outcome was functional outcome (assessed as combined death or disability and dependency using scales such as the modified Rankin Scale or Barthel Index) at the end of the trial. Secondary outcomes included safety at the end of treatment (death, impairment, deterioration, extension or recurrence), death at the end of follow up, and haematology measures (blood counts at or around day seven after treatment commenced). DATA COLLECTION AND ANALYSIS: Data on measures by intention to treat (where available) were collected and analysed as dichotomous or continuous outcomes, as relevant, using random-effects models. Heterogeneity was assessed. MAIN RESULTS: No large trials were identified. EPO therapy was associated with a non-significant reduction in neurological impairment in one small trial (n = 40 participants) but had no significant effect on haematological measures. Further small trials of EPO and G-CSF are ongoing. AUTHORS' CONCLUSIONS: No large trials of EPO, G-CSF or other colony stimulating factors have been performed and it is too early to know whether CSFs improve functional outcome.

Significant variation in mortality and functional outcome after acute ischaemic stroke between Western countries: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. OBJECTIVE: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. METHODS: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. RESULTS: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles; similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. CONCLUSIONS: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.

Genetic deletion of murine SPRY domain-containing SOCS box protein 2 (SSB-2) results in very mild thrombocytopenia.

The SSB family is comprised of four highly homologous proteins containing a C-terminal SOCS box motif and a central SPRY domain. No function has yet been ascribed to any member of this family in mammalian species despite a clear role for other SOCS proteins in negative regulation of cytokine signaling. To investigate its physiological role, the murine Ssb-2 gene was deleted by homologous recombination. SSB-2-deficient mice were shown to have a reduced rate of platelet production, resulting in very mild thrombocytopenia (25% decrease in circulating platelets). Tissue histology and other hematological parameters were normal, as was the majority of serum biochemistry, with the exception that blood urea nitrogen (BUN) levels were decreased in mice lacking SSB-2. Quantitative analysis of SSB mRNA levels indicated that SSB-1, -2, and -3 were ubiquitously expressed; however, SSB-4 was only expressed at very low levels. SSB-2 expression was observed in the kidney and in megakaryocytes, a finding consistent with the phenotype of mice lacking this gene. Deletion of SSB-2 thus perturbs the steady-state level of two tightly controlled homeostatic parameters and identifies a critical role for SSB-2 in regulating platelet production and BUN levels.

Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction.

SOCS-1 was originally identified as an inhibitor of interleukin-6 signal transduction and is a member of a family of proteins (SOCS-1 to SOCS-7 and CIS) that contain an SH2 domain and a conserved carboxyl-terminal SOCS box motif. Mutation studies have established that critical contributions from both the amino-terminal and SH2 domains are essential for SOCS-1 and SOCS-3 to inhibit cytokine signaling. Inhibition of cytokine-dependent activation of STAT3 occurred in cells expressing either SOCS-1 or SOCS-3, but unlike SOCS-1, SOCS-3 did not directly interact with or inhibit the activity of JAK kinases. Although the conserved SOCS box motif appeared to be dispensable for SOCS-1 and SOCS-3 action when overexpressed, this domain interacts with elongin proteins and may be important in regulating protein turnover. In gene knockout studies, SOCS-1(-/-) mice were born but failed to thrive and died within 3 weeks of age with fatty degeneration of the liver and hemopoietic infiltration of several organs. The thymus in SOCS-1(-/-) mice was small, the animals were lymphopenic, and deficiencies in B lymphocytes were evident within hemopoietic organs. We propose that the absence of SOCS-1 in these mice prevents lymphocytes and liver cells from appropriately controlling signals from cytokines with cytotoxic side effects.

SOCS1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal actions of this cytokine.

Mice lacking suppressor of cytokine signaling-1 (SOCS1) develop a complex fatal neonatal disease. In this study, SOCS1-/- mice were shown to exhibit excessive responses typical of those induced by interferon gamma (IFNgamma), were hyperresponsive to viral infection, and yielded macrophages with an enhanced IFNgamma-dependent capacity to kill L. major parasites. The complex disease in SOCS1-/- mice was prevented by administration of anti-IFNgamma antibodies and did not occur in SOCS1-/- mice also lacking the IFNgamma gene. Although IFNgamma is essential for resistance to a variety of infections, the potential toxic action of IFNgamma, particularly in neonatal mice, appears to require regulation. Our data indicate that SOCS1 is a key modulator of IFNgamma action, allowing the protective effects of this cytokine to occur without the risk of associated pathological responses.

Twenty proteins containing a C-terminal SOCS box form five structural classes.

The four members of the recently identified suppressor of cytokines signaling family (SOCS-1, SOCS-2, SOCS-3, and CIS, where CIS is cytokine-inducible SH2-containing protein) appear, by various means, to negatively regulate cytokine signal transduction. Structurally, the SOCS proteins are composed of an N-terminal region of variable length and amino acid composition, a central SH2 domain, and a previously unrecognized C-terminal motif that we have called the SOCS box. By using the SOCS box amino acid sequence consensus, we have searched DNA databases and have identified a further 16 proteins that contain this motif. These proteins fall into five classes based on the protein motifs found N-terminal of the SOCS box. In addition to four new SOCS proteins (SOCS-4 to SOCS-7) containing an SH2 domain and a SOCS box, we describe three new families of proteins that contain either WD-40 repeats (WSB-1 and -2), SPRY domains (SSB-1 to -3) or ankyrin repeats (ASB-1 to -3) N-terminal of the SOCS box. In addition, we show that a class of small GTPases also contains a SOCS box. The expression of representative members of each class of proteins differs markedly, as does the regulation of expression by cytokines. The function of the WSB, SSB, and ASB protein families remains to be determined.