Effects of physical fitness training on the mental and physical health of stroke survivors.

After a stroke, physical activity can be key in enhancing the rehabilitation of patients and preventing a secondary stroke. In this commentary, we critically appraise a systematic review which investigated how different types of physical fitness training impact on the mental and physical conditions of stroke survivors. Cardiorespiratory, resistance and mixed training (especially when including walking) can improve key outcomes such as the balance and mobility of stroke survivors, but the most suitable type of training depends on the individual needs and aims of the rehabilitation process. More research is needed to understand how the effects of the different types of training vary by considering the time between stroke and intervention onset, stroke severity, and the dose of intervention.

Evaluating a systematic voiding programme for patients with urinary incontinence after stroke in secondary care using soft systems analysis and Normalisation Process Theory: findings from the ICONS case study phase.

BACKGROUND: Urinary incontinence (UI) affects between 40 and 60% of people in hospital after stroke, but is often poorly managed in stroke units. OBJECTIVES: To inform an exploratory trial by three methods: identifying the organisational context for embedding the SVP; exploring health professionals' views around embedding the SVP and measuring presence/absence of UI and frequency of UI episodes at baseline and six weeks post-stroke. DESIGN: A mixed methods single case study included analysis of organisational context using interviews with clinical leaders analysed with soft systems methodology, a process evaluation using interviews with staff delivering the intervention and analysed with Normalisation Process Theory, and outcome evaluation using data from patients receiving the SVP and analysed using descriptive statistics. SETTING: An 18 bed acute stroke unit in a large Foundation Trust (a 'not for profit' privately controlled entity not accountable to the UK Department of Health) serving a population of 370,000. PARTICIPANTS: Health professionals and clinical leaders with a role in either delivering the SVP or linking with it in any capacity were recruited following informed consent. Patients were recruited meeting the following inclusion criteria: aged 18 or over with a diagnosis of stroke; urinary incontinence (UI) as defined by the International Continence Society; conscious; medically stable as judged by the clinical team and with incontinence classified as stress, urge, mixed or 'functional'. All patients admitted to the unit during the intervention period were screened for eligibility; informed consent to collect baseline and outcome data was sought from all eligible patients. RESULTS: Organisational context: 18 health professionals took part in four group interviews. Findings suggest an environment not conducive to therapeutic continence management and a focus on containment of UI. Embedding the SVP into practice: 21 nursing staff took part in six group interviews. Initial confusion gave way to embedding of processes facilitated by new routines and procedures. Patient outcome: 43 patients were recruited; 28 of these commenced the SVP. Of these, 6/28 (21%) were continent at six weeks post-stroke or discharge. CONCLUSION: It was possible to embed the SVP into practice despite an organisational context not conducive to therapeutic continence care. Recommendations are made for introducing the SVP in a trial context.

The challenge of targeting EGFR: experience with gefitinib in nonsmall cell lung cancer.

As the first approved epidermal growth factor receptor (EGFR)-targeted therapy for nonsmall cell lung cancer (NSCLC), the clinical development of gefitinib was complex. Advances in scientific understanding of the target biology during its clinical development enabled the identification of a biomarker to define patients most likely to derive benefit from gefitinib. Initial phase II trials showed clinically meaningful anti-tumour activity in 12-18% of unselected pretreated patients with advanced NSCLC at the optimum biological dose (250 mg). Subgroup analyses of these and subsequent phase III trials in unselected patients suggested that EGFR mutation and some clinical characteristics associated with a higher incidence of EGFR mutation (Asian ethnicity, adenocarcinoma histology, never-smoking and female sex) were linked with increased response to gefitinib. Consequently, the IRESSA Pan-Asia Study (IPASS) was conducted in never-smokers or former light-smokers in East Asia who had adenocarcinoma of the lung. IPASS showed that EGFR mutation was the strongest predictor of improved progression-free survival (mutation-positive subgroup hazard ratio (HR) 0.48, 95% CI 0.36-0.64 (p<0.001, n = 261); mutation-negative subgroup HR 2.85, 95% CI 2.05-3.98 (p<0.001, n = 176); interaction test p<0.001) with gefitinib versus carboplatin/paclitaxel as first-line therapy for advanced NSCLC. Important lessons for the development of future personalised medicines are discussed.

Repetitive task training for improving functional ability after stroke.

BACKGROUND: The active practice of task-specific motor activities is a component of current approaches to stroke rehabilitation. OBJECTIVES: To determine if repetitive task training after stroke improves global, upper or lower limb function, and if treatment effects are dependent on the amount, type or timing of practice. SEARCH STRATEGY: We searched the Cochrane Stroke Trials Register (October 2006), The Cochrane Library, MEDLINE, EMBASE, CINAHL, AMED, SportDiscus, Science Citation Index, Index to Theses, ZETOC, PEDro, and OT Seeker (to September 2006), and OT search (to March 2006). We also searched for unpublished/non-English language trials, conference proceedings, combed reference lists, requested information on bulletin boards, and contacted trial authors. SELECTION CRITERIA: Randomised/quasi-randomised trials in adults after stroke, where the intervention was an active motor sequence performed repetitively within a single training session, aimed towards a clear functional goal, and where the amount of practice could be quantified. DATA COLLECTION AND ANALYSIS: Two authors independently screened abstracts, extracted data and appraised trials. Assessment of methodological quality was undertaken for allocation concealment, blinding, loss to follow up and equivalence of treatment. We contacted trial authors for additional information. MAIN RESULTS: Fourteen trials with 17 intervention-control pairs and 659 participants were included. PRIMARY OUTCOMES: results were statistically significant for walking distance (mean difference (MD) 54.6, 95% CI 17.5 to 91.7); walking speed (standardised mean difference (SMD) 0.29, 95% CI 0.04 to 0.53); sit-to-stand (standard effect estimate 0.35, 95% CI 0.13 to 0.56); and of borderline statistical significance for functional ambulation (SMD 0.25, 95% CI 0.00 to 0.51), and global motor function (SMD 0.32, 95% CI -0.01 to 0.66). There were no statistically significant differences for hand/arm function, or sitting balance/reach. SECONDARY OUTCOMES: results were statistically significant for activities of daily living (SMD 0.29, 95% CI 0.07 to 0.51), but not for quality of life or impairment measures. There was no evidence of adverse effects. Follow-up measures were not significant for any outcome at six or twelve months. Treatment effects were not modified by intervention amount or timing, but were modified by intervention type for lower limbs. AUTHORS' CONCLUSIONS: Repetitive task training resulted in modest improvement in lower limb function, but not upper limb function. Training may be sufficient to impact on daily living function. However, there is no evidence that improvements are sustained once training has ended. The review potentially investigates task specificity rather more than repetition. Further research should focus on the type and amount of training, and how to maintain functional gain.

Predicting spasticity after stroke in those surviving to 12 months.

OBJECTIVE: To measure muscle tone in a cohort of patients 12 months after stroke and develop a preliminary model, using data recorded routinely after stroke, to predict who will develop spasticity. DESIGN: A cohort study. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, United Kingdom. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Spasticity measured at a range of joints using the Tone Assessment Scale. RESULTS: The Tone Assessment Scale revealed spasticity in 38 (36%) patients and more severe spasticity in 21 (20%) of the 106 patients. Logistic regression analysis revealed that lower day 7 Barthel Index score and early arm or leg weakness were significant predictors of abnormal muscle tone; and lower day 7 Barthel Index score, left-sided weakness and ever smoked to be significant predictors of more severe muscle tone. CONCLUSIONS: Using the models, it may be possible to predict whether or not spasticity will develop in patients 12 months after stroke. The utility of the models is aided by their use of predictor variables that are routinely collected as part of stroke care in hospital and which are easy to measure. The models need testing prospectively in a new cohort of patients in order to test their validity, reliability and utility and to determine if other data could improve their efficiency.

An investigation of components of variance and tachyphylaxis in a placebo-controlled intravenous tyramine study.

AIMS: To explore inter- and intra-volunteer variability for the dose of intravenous tyramine eliciting a 20 mmHg increase in systolic blood pressure from baseline (TYR20) and to evaluate potential tachyphylaxis. METHODS: Twelve healthy volunteers received blinded placebo-controlled ascending and descending sequences of intravenous tyramine injections on two separate occasions. The TYR20 was derived by linear interpolation, using three interventions to deal with missing data. RESULTS: Analysis of covariance (ancova) demonstrated no significant difference in TYR20 between sequences, regardless of the missing data methodology applied. Inter-volunteer variability was 2.4-3.4 times larger than within-volunteer variability. No evidence of tachyphylaxis was seen using either the sign test or generalized additive models. CONCLUSIONS: Since inter-volunteer variability was greater than intra-volunteer variability, a crossover study design would be a more efficient study design, and the descending sequence of injections could be omitted since tachyphylaxis was not demonstrated.

Prevalence of spasticity post stroke.

OBJECTIVES: To establish the prevalence of spasticity 12 months after stroke and examine its relationship with functional ability. DESIGN: A cohort study of prevalence of spasticity at 12 months post stroke. SETTING: Initially hospitalized but subsequently community-dwelling stroke survivors in Liverpool, UK. SUBJECTS: One hundred and six consecutively presenting stroke patients surviving to 12 months. MAIN OUTCOME MEASURES: Muscle tone measured at the elbow using the Modified Ashworth Scale and at several joints, in the arms and legs, using the Tone Assessment Scale; functional ability using the modified Barthel Index. RESULTS: Increased muscle tone (spasticity) was present in 29 (27%) and 38 (36%) of the 106 patients when measured using the Modified Ashworth Scale and Tone Assessment Scale respectively. Combining the results from both scales produced a prevalence of 40 (38%). Those with spasticity had significantly lower Barthel scores at 12 months (p < 0.0001). CONCLUSION: When estimating the prevalence of spasticity it is essential to assess both arms and legs, using both scales. Despite measuring tone at several joints, spasticity was demonstrated in only 40 (38%) patients, lower than previous estimates.

Reliability of measurements of muscle tone and muscle power in stroke patients.

OBJECTIVES: to establish the reliability of the modified Ashworth scale for measuring muscle tone in a range of muscle groups (elbow, wrist, knee and ankle; flexors and extensors) and of the Medical Research Council scale for measuring muscle power in the same muscle groups and their direct antagonists. DESIGN: a cross-sectional study involving repeated measures by two raters. We estimated reliability using the kappa statistic with quadratic weights (Kw). SETTING: an acute stroke ward, a stroke rehabilitation unit and a continuing care facility. SUBJECTS: people admitted to hospital with an acute stroke-35 patients, median age 73 (interquartile range 65-80), 20 men and 15 women. RESULTS: inter- and intra-rater agreement for the measurement of power was good to very good for all tested muscle groups (Kw = 0.84-0.96, Kw = 0.70-0.96). Inter- and intra-rater agreement for the measurement of tone in the elbow, wrist and knee flexors was good to very good (Kw = 0.73-0.96, Kw = 0.77-0.94). Inter- and intra-rater agreement for the measurement of tone in the ankle plantarflexors was moderate to good (Kw = 0.45-0.51, Kw = 0.59-0.64). CONCLUSIONS: the Medical Research Council scale was reliable in the tested muscle groups. The modified Ashworth scale demonstrated reliability in all tested muscle groups except the ankle plantarflexors. If reliable measurement of tone at the ankle is required for a specific purpose (e.g. to measure the effect of therapeutic intervention), further work will be necessary.

Reliability of the Tone Assessment Scale and the modified Ashworth scale as clinical tools for assessing poststroke spasticity.

OBJECTIVES: To establish reliability of the Tone Assessment Scale and modified Ashworth scale in acute stroke patients. SETTING: A North Liverpool university hospital. PATIENTS: Eighteen men and 14 women admitted with acute stroke and still in hospital at the study start date (median age, 74 yrs; median Barthel score, 8). MAIN OUTCOME MEASURES: The modified Ashworth scale and the Tone Assessment Scale. STUDY DESIGN: The 32 patients were examined with both scales on the same occasion by two raters (interrater comparison) and on two occasions by one rater (intrarater comparison). RESULTS: The reliability of the modified Ashworth scale was very good (kappa = .84 for interrater and .83 for intrarater comparisons). The reliability of the Tone Assessment Scale was not as strong as the modified Ashworth scale, with marked variability in the assessment of posture (kappa = .22 to .50 for interrater and .29 to .55 for intrarater comparisons) and associated reaction (kappa/kappaW = -.05 to .79 for interrater and .19 to .83 for intrarater comparisons). However, those aspects of the Tone Assessment Scale that addressed response to passive movement and that are scored similarly to the modified Ashworth scale showed good to very good interrater reliability (kappaW = .79 to .92) and good to very good intrarater reliability (kappaW = .72 to .86), except for the question related to movement at the ankle where agreement was only moderate (kappaW = .59). CONCLUSIONS: The modified Ashworth scale is reliable. The section of the Tone Assessment Scale relating to response to passive movement is reliable at various joints, except the ankle. It may assist in studies on the prevalence of spasticity after stroke and the relationship between tone and function. Further development of a measure of spasticity at the ankle is required. The Tone Assessment Scale is not reliable for measuring posture and associated reactions.

Risk-factor assessment for falls: from a written checklist to the penless clinic.

OBJECTIVE: to audit risk-factor identification of fallers before and after an education programme and the insertion of a written checklist in medical notes. Risk-factor identification in a dedicated, computerized falls clinic was then examined. METHODS: documentation of risk factors for falls was studied on wards and a self-auditing 'penless' clinic for fallers subsequently set up to generate reports for medical notes and letters for general practitioners. RESULTS: risk-factor identification improved after the insertion of the checklist but remained relatively poor. A dedicated clinic allowed almost complete identification of risk factors. Of the first 112 patients (median age 82) seen in the clinic, 75 (67%) were housebound. Remediable risk factors--e.g. inappropriate medication (67%), unsatisfactory footwear (59%) and postural hypotension (17%)--were found in most. Thirty-three patients (29%) had difficulty with alarm raising. CONCLUSION: ward-based intervention showed limited capacity to identify risk factors for falls: a dedicated clinic was more successful. The use of a portable computer with a programme to screen fallers for risk factors is worthy of consideration.

The effect of plasma solutes on total-body-water measurements via NMR.

Nuclear magnetic resonance (NMR) spectroscopy has been reported as an alternative method for quantitating deuterium oxide concentrations in the evaluation of total-body-water in humans. However, the presence of dissolved plasma proteins results in an underestimation of deuterium NMR (2H-NMR) intensity ratios, thereby causing an overestimation (5-6%) of total-body-water (TBW) values determined from nonsublimed patient plasma samples. We demonstrate that plasma samples must be corrected for the volume percentage of water in plasma. Correction of initial 2H-NMR intensity ratios with a factor of 0.93 results in intensity ratios comparable to those determined from plasma samples subjected to vacuum sublimation to remove all plasma solutes.

Stereoselective formation of bis(alpha-aminoacyl) esters of 5'-AMP suggests a primitive peptide synthesizing system with a preference for L-amino acids.

In the biosynthesis of proteins, each amino acid passes from the aminoacyl adenylate to become an amino acid ester and finally a 2' (3') peptidyl ester of the AMP residue at the end of a tRNA. Consequently, the chemistry of protein synthesis is the chemistry of aminoacyl and peptidyl AMP. Our data has revealed properties of 5'-AMP and its esters which should allow the preferential catalytic synthesis of L-amino acid peptides via a bis(2', 3'-aminoacyl) ester intermediate. Results in this paper concern one step in the proposed process and show that preexisting Ac-L-Phe monoester reacts about 2.5-times faster to form diester than preexisting Ac-D-Phe monoester.

Chemical esterification of 5'-AMP occurs predominantly at the 2' position.

We describe experiments here which show that chemical esterification of 5'-adenylic acid (5'-AMP) with N-acetyl D- or L-phenylalanine (Ac-D- or Ac-L-Phe) imidazolide occurs principally, if not exclusively, at the 2' position. Furthermore, in experiments with the formation of the 2'-3' diester with butyric acid and N-acetyl glycine (Ac-Gly), we found the second esterification was also predominantly at the 2' position. This means that mixed diesters can be predictably prepared with the positions of the substituents known. The results are consistent with a model for the preferential catalytic synthesis of L-based peptides via a 2'-3' diester intermediate of purine monoribonucleotides.

Teaching intraverbal behavior to severely retarded children.

The present study evaluated procedures to teach single and multiple intraverbal responses, and assessed whether intraverbals and tacts are functionally independent. A delayed echoic prompting procedure was used to assess transfer of stimulus control. Probes were interspersed among intraverbal training trials to measure the emergence of intraverbals that were not directly trained. Following intraverbal training, visual stimuli were presented to determine whether response topographies transferred to tact conditions. The results suggest that special training is necessary for the acquisition of intraverbal responding in retarded individuals, and provide some support for the functional independence of intraverbals and tacts at the time of acquisition.

High-dose combination alkylating agent therapy with autologous bone marrow rescue for refractory solid tumors.

Twenty-six adults, ages 27 to 60, with refractory metastatic solid tumors were treated with high-dose cyclophosphamide (Cy) + carmustine (BCNU) at one of three escalating dose schedules followed by autologous bone marrow transplantation (ABMT). Toxicity was severe and dose-related, with the maximum tolerated dose for the combination determined to be Cy 160 mg/kg and BCNU 900 mg/m2. Median time to WBC recovery (greater than or equal to 1,000/microL) was 13 days post-ABMT (range, nine to 22 days) and to a platelet count of greater than or equal to 50,000/microL, 22 days (range, 13 to 83 days). Sixteen of 20 evaluable patients (80%) responded to therapy with at least 50% reduction in measurable tumor, and three patients achieved complete remission (CR). Responders included eight of nine evaluable patients with breast carcinoma, two of five with melanoma, two of two with sarcoma, and four of four with colon carcinoma. Response durations were short (median, 4 months), even for complete responders, and relapses generally occurred at sites of previous metastases. In order for this approach to have a more significant impact on overall survival, it may need to be applied earlier in the natural history of the malignancy.

Differential distribution of D and L amino acids between the 2' and 3' positions of the AMP residue at the 3' terminus of transfer ribonucleic acid.

Amino acids esterified to the ribose group of 5'-adenylic acid (AMP) constantly migrate between the 2' and 3' positions of the ribose at a rate of several times per second, which is slower than the rate of peptide-bond synthesis (15-20 per sec). Because the contemporary protein-synthesizing system only incorporates amino acids into protein when they are at the 3' position of the AMP at the terminus of tRNA, the value of the equilibrium constant relative to the 2' and 3' positions is of considerable interest. Differences between D and L isomers in this regard might be especially revealing. We have used N-acetylaminoacyl esters of AMP as models for the 3' terminus of tRNA and find that glycine and the L amino acids consistently distribute predominantly to the 3' position (approximately equal to 67% 3', approximately equal to 33% 2'), but D amino acids distribute to that position generally to a lesser extent and in a manner inversely related to the hydrophobicity of the amino acid side chain. This consistency of the L amino acid preference for the 3' position, combined with the inconsistency of the D amino acid preference, may be one reason for the origin of our contemporary protein-synthesizing system, which forms the peptide bond preferentially with L amino acids and only when they are in the 3' position of the ribose moiety of the AMP residue at the 3' terminus of every tRNA.

Determination of total body water by deuterium NMR.

A new deuterium nuclear magnetic resonance (2H NMR) method is described for determining total body water in humans. The method has been validated against a standard infrared absorption (IR) procedure using a tracer dose of deuterium oxide (2H2O) of approximately 10 g for each human subject. The precision and accuracy for the methods have been compared and found to be very similar. The advantages of the 2H NMR method over other presently available techniques that are based on 2H2O dilution are as follows: it is fast, accurate, needs only a small dose of 2H2O, can be done using any body fluid, and, most importantly, does not require any sample preparation.

Aliphatic amino acid side chains associate with the "face" of the adenine ring.

We have synthesized the free amino acid adenylate anhydrides of phenylalanine, leucine, isoleucine and valine. These activated compounds are very labile at high pH, but at low pH they become more stable. Proton NMR spectra of these adenylates show that in every case, the hydrophobic side chains, even in these small molecules at low pH and low concentration, are associated with the "face" of the adenine ring. Although aromatic rings are known to associate with adenine in this fashion, to our knowledge this is the first report of an intercalative-type interaction of aliphatic side chains with nucleic acid bases. Since adenine is the most hydrophobic base, these interactions are of a hydrophobic character, and occur in spite of the fact that the adenine ring is protonated. These results may have implications regarding recognition processes in DNA-protein and RNA-protein interactions.