Systematic reviews as a tool for planning and interpreting trials

Background Systematic reviews followed by ameta-analysis are carried out in medical research to combine the results of two or more related studies. Stroke trials have struggled to show beneficial effects and meta-analysis should be used more widely throughout the research process to either speed up the development of useful interventions, or halt more quickly research with hazardous or ineffective interventions. Summary of review. This review summarises the clinical research process and illustrates how and when systematic reviews may be used throughout the development programme. Meta-analyses should be performed after observational studies, preclinical studies in experimental stroke, and after phase I, II, and III clinical trials and phase IV clinical surveillance studies. Although meta-analyses most commonly work with summary data, they may be performed to assess relationships between variables (meta-regression) and, ideally, should utilise individual patient data. Meta-analysis techniques may alsoworkwith ordered categorical outcome data (ordinal meta-analysis) and be used to perform indirect comparisons where original trial data do not exist. Conclusion Systematic review/meta-analyses are powerful tools in medical research and should be used throughout the development of all stroke and other intervention

Group 62 Section Leaders Meeting -- May 3, 1954

The IBM designed light gun has been installed and tested on Cape Cod. Evaluation of sources of prime power and the problem of power interruption is under way. Studies will be under taken concerning the use of transistors in various parts of Duplex Central

Group 62 Section Leaders Meeting--May 10, 1954

Memorandum on the Group 62 Section Leaders Meeting of April 26, 1954

Positional differences in reactive hyperemia provide insight into initial phase of exercise hyperemia.

Studies have reported a greater blood flow response to muscle contractions when the limb is below the heart compared with above the heart, and these results have been interpreted as evidence for a skeletal muscle pump contribution to exercise hyperemia. If limb position affects the blood flow response to other vascular challenges such as reactive hyperemia, this interpretation may not be correct. We hypothesized that the magnitude of reactive hyperemia would be greater with the limb below the heart. Brachial artery blood flow (Doppler ultrasound) and blood pressure (finger-cuff plethysmography) were measured in 10 healthy volunteers. Subjects lay supine with one arm supported in two different positions: above or below the heart. Reactive hyperemia was produced by occlusion of arterial inflow for varying durations: 0.5 min, 1 min, 2 min, or 5 min in randomized order. Peak increases in blood flow were 77 ± 11, 178 ± 24, 291 ± 25, and 398 ± 33 ml/min above the heart and 96 ± 19, 279 ± 62, 550 ± 60, and 711 ± 69 ml/min below the heart (P \u3c 0.05). Thus a standard stimulus (vascular occlusion) elicited different responses depending on limb position. To determine whether these differences were due to mechanisms intrinsic to the arterial wall, a second set of experiments was performed in which acute intraluminal pressure reduction for 0.5 min, 1 min, 2 min, or 5 min was performed in isolated rat soleus feed arteries (n = 12). The magnitude of dilation upon pressure restoration was greater when acute pressure reduction occurred from 85 mmHg (mimicking pressure in the arm below the heart; 28.3 ± 7.9, 37.5 ± 5.9, 55.1 ± 9.9, and 68.9 ± 8.6% dilation) than from 48 mmHg (mimicking pressure in the arm above the heart; 20.8 ± 4.8, 22.6 ± 4.4, 31.2 ± 5.8, and 49.2 ± 7.1% dilation). These data support the hypothesis that arm position differences in reactive hyperemia are at least partially mediated by mechanisms intrinsic to the arterial wall. Overall, these results suggest the need to reevaluate studies employing positional changes to examine muscle pump influences on exercise hyperemia

Extracellular heat shock proteins in cell signaling

AbstractExtracellular stress proteins including heat shock proteins (Hsp) and glucose regulated proteins (Grp) are emerging as important mediators of intercellular signaling and transport. Release of such proteins from cells is triggered by physical trauma and behavioral stress as well as exposure to immunological “danger signals”. Stress protein release occurs both through physiological secretion mechanisms and during cell death by necrosis. After release into the extracellular fluid, Hsp or Grp may then bind to the surfaces of adjacent cells and initiate signal transduction cascades as well as the transport of cargo molecules such as antigenic peptides. In addition Hsp60 and hsp70 are able to enter the bloodstream and may possess the ability to act at distant sites in the body. Many of the effects of extracellular stress proteins are mediated through cell surface receptors. Such receptors include Toll Like Receptors 2 and 4, CD40, CD91, CCR5 and members of the scavenger receptor family such as LOX-1 and SREC-1. The possession of a wide range of receptors for the Hsp and Grp family permits binding to a diverse range of cells and the performance of complex multicellular functions particularly in immune cells and neurones

Mechanisms of comorbidity, continuity, and discontinuity in anxiety-related disorders

We discuss comorbidity, continuity, and discontinuity of anxiety-related disorders from the perspective of a two-dimensional neuropsychology of fear (threat avoidance) and anxiety (threat approach). Pharmacological dissection of the "neurotic" disorders justifies both a categorical division between fear and anxiety and a subdivision of each mapped to a hierarchy of neural modules that process different immediacies of threat. It is critical that each module can generate normal responses, symptoms of another syndrome, or syndromal responses. We discuss the resultant possibilities for comorbid dysfunction of these modules both with each other and with some disorders not usually classified as anxiety related. The simplest case is symptomatic fear/anxiety comorbidity, where dysfunction in one module results in excess activity in a second, otherwise normal, module to generate symptoms and apparent comorbidity. More complex is syndromal fear/anxiety comorbidity, where more than one module is concurrently dysfunctional. Yet more complex are syndromal comorbidities of anxiety that go beyond the two dimensional fear/anxiety systems: depression, substance use disorder, and attention-deficit/hyperactivity disorder. Our account of attention-deficit/hyperactivity disorder-anxiety comorbidity entails discussion of the neuropsychology of externalizing disorders to account for the lack of anxiety comorbidity in some of these. Finally, we link the neuropsychology of disorder to personality variation, and to the development of a biomarker of variation in the anxiety system among individuals that, if extreme, may provide a means of unambiguously identifying the first of a range of anxiety syndromes

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 randomised (1:1), double blind, placebo-controlled trial. Subjects received dexamphetamine (5mg initially, then 10mg 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 minutes after, the first 2 doses. 33 subjects were recruited, age 33-88 (mean 71) years, males 52%, 4-30 (median 15) days post stroke to inclusion. 16 patients were randomised to placebo and 17 amphetamine. Amphetamine did not improve motor function at 90 days; mean (standard deviation) 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, were 11.2 mmHg (p=0.03), 9.5 mmHg (p=0.04) and 7 beats/minute (p=0.02) higher respectively with amphetamine, compared with control. A non-significant reduction in myocardial perfusion (Buckberg Index) 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 heart rate without altering cerebral haemodynamics