Emerging data from heart failure trials: clinical application.
Explore the source record for details and available documents.
Adrenergic beta-Antagonists↗
Biomedical subjects
G Francis
Publications and source records attributed to G Francis.
The effect of delayed reperfusion following infarction in the rat on structural changes in viable myocardium.
OBJECTIVE: Evidence indicates that patency of the infarct related artery following the completion of myocardial necrosis can attenuate ventricular remodeling. Data have also demonstrated that inhibition of infarct expansion contributes to the anti-remodeling effect of delayed reperfusion. However, the influence of a patent artery on components of the remodeling process in the viable myocardium is poorly understood. METHODS: Myocyte morphometrics (isolated cell technique) and collagen content (hydroxyproline analysis) were assessed 28 days following experimental myocardial infarction from rats with permanently ligated left coronary vessels (NRP; n = 10) compared with rats who underwent reperfusion 150 minutes after ligation (RP; n = 11) and a sham-operated group (n = 10). RESULTS: Analysis of infarct size (planimetry) in a separate group of rats demonstrated that reperfusion at this late time point did not reduce infarct size (NRP: 33 +/- 3 vs. RP: 35 +/- 5%). Myocyte length in RP rats was less than in NRP rats in viable, non-infarcted left ventricular tissue (155 +/- 3 vs. 167 +/- 4 microns, p = 0.02), in the right ventricle (154 +/- 4 vs. 167 +/- 3 microns, p = 0.02) and in the septum (158 +/- 4 vs. 169 +/- 4 microns, p = 0.05). Reperfusion also attenuated the expected increase in cell volume compared with NRP rats (left ventricle 39.4 +/- 1.7 x 10(3) vs. 44.1 +/- 1.6 x 10(3) micron 3, p = 0.06; right ventricle 36.7 +/- 1.6 x 10(3) vs. 42.7 +/- 2.0 x 10(3) micron 3, p = 0.02; septum 41.0 +/- 1.6 x 10(3) vs. 44.2 +/- 1.8 x 10(3) micron 3, p = 0.19). Hydroxyproline content increased in the viable left ventricular tissue in both the reperfused and non-reperfused groups. CONCLUSION: Reperfusion without myocardial salvage attenuates the increase in myocyte length and volume that occurs in remodeling myocardium following infarction in the rat, with no effect on the increase in collagen content. These data indicate that patency of the infarct vessel, which is known to have an inhibitory effect on infarct expansion, also has an anti-remodeling effect remote from the area perfused by this artery.
Animals↗
Cortical dynamics of lateral inhibition: metacontrast masking.
The dynamic properties of a neural network model of visual perception, called the boundary contour system, explain characteristics of metacontrast visual masking. Computer simulations of the model, with a single set of parameters, demonstrate that it accounts for 9 key properties of metacontrast masking: Metacontrast masking is strongest at positive stimulus onset asynchronies (SOAs); decreasing target luminance changes the shape of the masking curve; increasing target duration weakens masking; masking effects weaken with spatial separation; increasing mask duration leads to stronger masking at shorter SOAs; masking strength depends on the amount and distribution of contour in the mask; a second mask can disinhibit the masking of the target; such disinhibition depends on the SOA of the 2 masks; and such disinhibition depends on the spatial separation of the 2 masks. No other theory provides a unified explanation of these data sets. Additionally, the model suggests a new analysis of data related to the SOA law and makes several testable predictions.
Attention↗
Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators.
BACKGROUND: Elevated plasma neurohormonal levels are associated with increased mortality rates in patients with symptomatic heart failure. A previous Studies of Left Ventricular Dysfunction (SOLVD) trial suggested that neurohumoral activation precedes the development of symptoms as demonstrated by increased neurohormonal levels in patients with asymptomatic left ventricular dysfunction. However, the significance of this early neurohumoral activation is unclear. The goals of this study were to determine the prognostic significance of the plasma concentrations of plasma norepinephrine (PNE) and atrial natriuretic peptide (ANP) and the renin activity (PRA) in patients with asymptomatic left ventricular dysfunction. METHODS AND RESULTS: PNE and PRA were measured before randomization in 514 patients with left ventricular ejection fractions < or = 35% who did not require treatment for congestive heart failure and were enrolled in the SOLVD Prevention Trial. Plasma ANP levels were measured in a subset of 241 patients owing to study design. Using the Cox proportional hazards model that included left ventricular ejection fraction, New York Heart Association functional class, age, sex, treatment assignment to placebo or enalapril, and cause of heart failure, we examined whether these neurohormones predicted all-cause mortality, cardiovascular mortality, hospitalization for heart failure, development of heart failure, or development of ischemic events (myocardial infarction or unstable angina). PNE was the strongest predictor of clinical events in this patient population. PNE levels above the median of 393 pg/mL were associated with a relative risk of 2.59 (P = .002) for all-cause mortality, 2.55 (P = .003) for cardiovascular mortality, 2.55 (P = .005) for hospitalization for heart failure, 1.88 (P = .002) for development of heart failure, 1.92 (P = .001) for ischemic events, and 2.59 (P = .005) for myocardial infarction. PNE remained the most powerful predictor for all-cause mortality and ischemic events when the analysis included only the patients with histories of ischemic left ventricular dysfunction. The increases in other neurohormonal levels were not useful in predicting the subsequent development of clinical events. CONCLUSIONS: Increased PNE levels in patients with asymptomatic left ventricular dysfunction appear to predict all-cause and cardiovascular mortalities and development of clinical events related to the onset of heart failure or acute ischemic syndromes. Thus, measurement of PNE may be a possible early marker for assessment of disease progression in patients with left ventricular dysfunction, and modulating the release or effect of PNE may lead to improved prognosis and/or a reduction in morbidity.
Angina, Unstable↗
Evolution of resistance in Staphylococcus aureus in Australian teaching hospitals. Australian Group on Antimicrobial Resistance (AGAR).
OBJECTIVE: To assess the changes in antibiotic resistances in Staphylococcus aureus, both methicillin-susceptible and methicillin-resistant strains, in Australia. DESIGN: Retrospective review of data collected annually. SETTING: Twenty metropolitan teaching hospitals in the six States of Australia and the Australian Capital Territory from 1988 to 1994. OUTCOME MEASURES: Changes in prevalence and resistance rates of methicillin-resistant S. aureus (MRSA) and methicillin-susceptible strains, based on antibiotic susceptibility testing of clinical isolates of S. aureus. RESULTS: Prevalence of MRSA has remained constant on the eastern seaboard of Australia. A distinctive strain of MRSA emerged in Western Australia which had different antimicrobial susceptibilities. Resistances emerged in MRSA strains from eastern Australia, principally to ciprofloxacin and rifampicin, while resistance to fusidic acid remained stable and resistance to chloramphenicol significantly declined. Resistances in methicillin-susceptible strains remained fairly stable, except for a decline in resistance levels for tetracycline. High levels of resistance were seen to penicillin, moderate levels to erythromycin and low levels to trimethoprim and fusidic acid in methicillin-susceptible strains. CONCLUSIONS: The continued high prevalence of and increasing resistance in MRSA in some Australian hospitals have meant that some strains are now untreatable with oral antibiotics.
Australia↗
Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis. US National MS Society Task Force.
Because of the major difficulties in measuring clinical end points in multiple sclerosis (MS) treatment trials, there has been much enthusiasm for using magnetic resonance imaging (MRI) findings as an alternative outcome. To provide international consensus guidelines for the use of MRI in MS clinical trials, a task force of the US National MS Society was convened. The recommendations of the task force are presented in this review. Given the high sensitivity for detecting pathological activity in relapsing-remitting and secondary progressive MS, monthly T2-weighted and gadolinium-enhanced brain MRI is an excellent tool for short-term exploratory trials of new agents where it serves as the primary end point; in particular, failure to demonstrate a reduction in lesion activity avoids the time, cost, and risks of a larger clinical end point study. However, conventional MRI findings have a limited correlation with disability in established MS. The primary end point of a definitive trial should therefore be clinical, although serial MRI at 6- to 12-month intervals is a useful secondary end point in providing an index of pathological progression. In trials of patients presenting with clinically isolated syndromes suggestive of MS, MRI findings can be used in the entry criteria, and as a secondary outcome measure, but conversion to clinically definite MS should be the primary outcome. The pathological substrates of irreversible disability are demyelination and axonal loss. Putative magnetic resonance markers for these processes include decreased N-acetylaspartate on proton magnetic resonance spectroscopy, decreased magnetization transfer ratios, hypointensity on T1-weighted images, and loss of short T2 water fractions, some of which relate more closely to disability than conventional MRI findings. Further technical developments should lead to more accurate quantitation, greater pathological specificity, and stronger clinical correlations.
Clinical Trials as Topic↗
Cortical dynamics of form and motion integration: persistence, apparent motion, and illusory contours.
How does the visual system generate percepts of moving forms? How does this happen when the forms are emergent percepts, such as illusory contours or segregated textures, and the motion percept is apparent motion between the emergent forms? We develop a neural model of form-motion interactions to explain and simulate parametric properties of psychophysical motion data and to make predictions about how the parallel cortical processing streams V1-->MT and V1-->V2-->MT control form-motion interactions. The model explains how an illusory contour can move in apparent motion to another illusory contour or to a luminance-derived contour; how illusory contour persistence relates to the upper interstimulus interval (ISI) threshold for apparent motion; and how upper and lower ISI thresholds for seeing apparent motion between two flashes decrease with stimulus duration and narrow with spatial separation (Korte's laws). The model accounts for these data by suggesting how the persistence of a boundary segmentation in the V1-->V2 processing stream influences the quality of apparent motion in the V1-->MT stream through V2-->MT interactions. These data may all be explained by an analysis of how orientationally tuned form perception mechanisms and directionally tuned motion perception mechanisms interact.
Contrast Sensitivity↗
A full genome search in multiple sclerosis.
The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.
Chromosome Mapping↗
Cortical dynamics of boundary segmentation and reset: persistence, afterimages, and residual traces.
In previous work with a neural-network model of boundary segmentation and reset, the percept of persistence was linked to the duration of a boundary segmentation after stimulus offset. In particular, the model simulated the decrease of persistence duration with an increase in stimulus duration and luminance. Further evidence is revealed for the neural mechanisms involved in the theory. Simulations show that the model reset signals generate orientational afterimages, such as the MacKay effect, when the reset signals can be grouped by a subsequent boundary segmentation that generates illusory contours through them. Simulations also show that the same mechanisms explain properties of residual traces, which increase in duration with stimulus duration and luminance. The model hereby discloses previously unsuspected mechanistic links between data about persistence and afterimages, and helps to clarify the sometimes controversial issues surrounding distinctions between persistence, residual traces, and afterimages.
Afterimage↗
Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy.
Quantitative measurement of MRI-defined brain lesions can provide an index of the extent and activity of disease in multiple sclerosis patients. However, the relationships between these indices and clinical features are not well-understood. Heterogeneity of the pathological changes underlying MRI lesions may be an important factor determining the correlation between MRI lesion volumes and clinical measures. Recent studies have suggested that with magnetic resonance spectroscopy (MRS), it may be possible to define chemical changes that better reflect the pathological changes in multiple sclerosis. Here we report results of combined quantitative brain T2-weighted MRI lesion volume and proton MRS examinations that demonstrate heterogeneity of the chemical pathology underlying brain lesions in patients selected on the basis of similar clinical disability but differing with respect to the presence or absence of clinical relapses. We examined 29 patients with disease characterized by either clear relapses with at least partial remissions (RR) or secondary, chronic progression after an earlier history of a more relapsing and remitting course (SP). Total hemispheric lesion volume was greater (P < 0.04) in the RR (32.5 +/- 20.9 cm3) than in the SP (16.2 +/- 9.0 cm3) patients, despite the longer duration of disease in the latter group. Central brain N-acetyl aspartate: creatine (NAA:Cr) ratios were reduced relative to normal controls (4.0 +/- 0.3, n = 19) by similar amounts in the two patients groups (RR, 3.1 +/- 0.5; SP, 3.2 +/- 0.4; P < 0.0001). The ratio lesion volume:(NAA:Cr) was greater for the RR group (11.7 +/- 9.3 cm3) than for the SP group (5.4 +/- 3.3 cm3, P < 0.05), implying a greater average degree of axonal loss per unit lesion volume defined by MRI for subjects in the SP group or, alternatively, a greater proportion of lesions without axonal damage or loss in the RR group. Our results emphasize a limitation of using T2-weighted MRI lesion volume alone and suggest that combined analysis of MR-based chemical and imaging data might allow improved non-invasive assessment of lesion pathology in order to better understand its relationship to clinical features of multiple sclerosis.
Adult↗
Borderline personality disorder in adolescents: affective and cognitive features.
OBJECTIVE: To examine systematically the affective and cognitive features of borderline personality disorder (BPD) in adolescence, using standardized measures of these constructs and controlling for depression. METHOD: Nineteen depressed female adolescents with BPD were compared with 21 non-BPD depressed inpatients on measures of affect and cognitive style. RESULTS: Both BPD and non-BPD adolescents endorsed significantly elevated levels of self-reported depression, anger, anxiety, hopelessness, self-deprecatory attributional style, and external locus of control. Adolescents with BPD endorsed significantly poorer self-concept than their non-BPD peers; this difference was not an artifact of depressive severity. CONCLUSIONS: The findings indicate that adolescents with BPD experience significant impairments in self-concept, suggestive of pervasive emptiness and identity disturbance associated with BPD.
Adolescent↗
Cortical dynamics of lateral inhibition: visual persistence and ISI.
Psychophysical studies show that increasing the interstimulus interval (ISI) between two stimuli decreases persistence of the first stimulus. While some researchers account for these results with interactions of transient and sustained inhibition, this paper describes an alternative explanation. In a neural-network model of boundary detection called the boundary contour system, persistence is the result of feedback-generated reverberations. Mechanisms to control these reverberations include lateral inhibition, which computer simulations show allows persistence in the network to qualitatively match the psychophysical data. Additional simulations predict that increasing the duration of the second stimulus should cause persistence to increase with ISI. The model links psychophysical data on visual persistence with computational requirements of spatial vision and properties of cells in visual cortex.
Feedback↗
Cortical dynamics of visual persistence and temporal integration.
In a temporal integration experiment, subjects must integrate two visual stimuli, presented at separate times, to perform an identification task. Many researchers have assumed that the persistence of the leading stimulus determines the ability to integrate the leading and trailing stimuli. However, recent studies of temporal integration have challenged that hypothesis by demonstrating that several theories of persistence are incompatible with data on temporal integration. This paper shows that an account of visual persistence given by a neural network model of preattentive vision, called the boundary contour system, explains data on temporal integration. Computer simulations of the model explain why temporal integration becomes more difficult when the display elements are separated by longer interstimulus intervals or are of longer duration or of higher luminance, or are spatially closer together. The model suggests that different mechanisms underlie the inverse duration effects for leading and for trailing elements. The model further predicts interactions of spatial separation, duration, and luminance of the trailing display.
Attention↗
Bradykinin antagonism inhibits the antigrowth effect of converting enzyme inhibition in the dog myocardium after discrete transmural myocardial necrosis.
BACKGROUND: Converting enzyme inhibitor (CEI) therapy, but not angiotensin II subtype I receptor blockade, has been shown to attenuate left ventricular remodeling in the dog after transmyocardial direct current (DC) shock. The purpose of this study was to address the importance of preservation of bradykinin to the antiremodeling effect of CEI treatment in this model. METHODS AND RESULTS: Twenty-four hours after DC shock, adult mongrel dogs were assigned to one of three groups: a control group; a group treated with ramipril 10 mg BID; and a group treated with ramipril 10 mg BID along with a continuous subcutaneous infusion of HOE 140, a bradykinin antagonist. To assess change in left and right ventricular structure, a magnetic resonance imaging (MRI) study was performed 4 weeks after DC shock and compared with a baseline MRI study performed before DC shock. The increase in left ventricular mass (mean +/- SEM) in the control group was similar to that observed in the CEI-HOE 140 group (+0.73 +/- 0.19 versus +0.75 +/- 0.18 g/kg, P = NS), but both were greater than the change in mass in the ramipril group (-0.48 +/- 0.13 g/kg, P = .004 and P = .0005, respectively). No significant change occurred in left ventricular volume or right ventricular structure in any group. Mean arterial pressure was reduced by ramipril compared with the control group (-8 +/- 2 versus +7 +/- 2 mm Hg, P = .03), and this effect was not blunted by the addition of HOE 140 (-7 +/- 3 mm Hg). CONCLUSIONS: Prevention by ramipril of the early increase in left ventricular mass in the DC shock model appears to be related to the preservation of bradykinin.
Angiotensin-Converting Enzyme Inhibitors↗
Neurohumoral variability in left ventricular dysfunction. SOLVD Investigators. Studies of Left Ventricular Dysfunction.
The immediate and longer term variability of selected vasoactive- and volume-regulating neurohormones were measured in patients entering a substudy of the Studies of Left Ventricular Dysfunction--a randomized clinical trial in patients with left ventricular ejection fraction < or = 35%. The variability of these hormones has not been determined in a large cohort of patients. Immediate (short-term) variability was assessed by systematically comparing levels after 15 and 30 minutes of supine rest at the initial visit, and longer term variability was assessed by comparing 30-minute supine rest values at the initial visit with corresponding values taken at 30 minutes after 16 to 24 days of stable therapy. Initial values obtained at the first visit after 30-minute supine rest for all 209 patients were (mean +/- SEM) 512 +/- 21 pg/ml pg/ml for plasma norepinephrine, 1.9 +/- 0.2 ng/ml/hr for plasma renin activity, 3.0 +/- 0.1 pg/ml for plasma arginine vasopressin, and 129 +/- 5.3 pg/ml for plasma atrial natriuretic peptide. All variables were moderately increased relative to established normal values. There was a small but significant decrease from 15- to 30-minute supine posture in all neurohormones, except arginine vasopressin. In the presence of stable background therapy, no significant differences were found between measurements obtained after 30 minutes supine rest at the initial visit and 16 to 24 days later. Spearman correlation coefficients corresponding to immediate and longer term variability were high (range 0.55 to 0.79) (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Chemical pathology of acute demyelinating lesions and its correlation with disability.
We report the chemical pathological changes on magnetic resonance spectroscopic images of 4 patients, each of whom had a single large demyelinating plaque. The patients were followed from soon after the onset of the symptoms for a minimum of 7 months to a maximum of 3 1/2 years. We observed increases in the relative resonance intensities of choline-containing compounds, lactate, and myo-inositol inside the lesion acutely. Decreases in relative resonance intensities of N-acetylaspartate and creatine were seen both in and around the magnetic resonance imaging-detected lesions. In all patients neurological deficits improved and creatine, lactate, and myo-inositol resonance intensities normalized during the follow-up. Choline compounds recovered more slowly and were still abnormally high in 1 patient after 7 months. Partial recovery of the N-acetylaspartate resonance was seen for all patients. Evaluation of the relationships between indices of cerebral chemical pathology, brain lesion volumes, and functional disability showed highly significant negative correlations between N-acetylaspartate resonance intensities and both brain lesion volumes (r = -0.80, p < 0.0001) and clinical disability (r = -0.73, p < 0.0001). As N-acetylaspartate is localized solely in neurons in the adult central nervous system, our results suggest that neuronal dysfunction may be a proximate mechanism of disability even in inflammatory disorders primarily affecting myelin and oligodendroglial cells.
Adult↗
Cortical dynamics of feature binding and reset: control of visual persistence.
An analysis of the reset of visual cortical circuits responsible for the binding or segmentation of visual features into coherent visual forms yields a model that explains properties of visual persistence. The reset mechanisms prevent massive smearing of visual percepts in response to rapidly moving images. The model simulates relationships among psychophysical data showing inverse relations of persistence to flash luminance and duration, greater persistence of illusory contours than real contours, a U-shaped temporal function for persistence of illusory contours, a reduction of persistence due to adaptation with a stimulus of like orientation, an increase of persistence with spatial separation of a masking stimulus. The model suggests that a combination of habituative, opponent, and endstopping mechanisms prevent smearing and limit persistence. Earlier work with the model has analyzed data about boundary formation, texture segregation, shape-from-shading, and figure-ground separation. Thus, several types of data support each model mechanism and new predictions are made.
Adaptation, Ocular↗
Measured change in protein solvation with substrate binding and turnover.
Osmotic stress is used to measure solvation changes that accompany the conformational changes of an active enzyme. For hexokinase both the equilibrium dissociation constant and the kinetic Michaelis-Menten constant for glucose vary linearly, and to the same extent, with the activity of water in the protein medium, as adjusted with large molecular weight (> 2000) osmolytes. The variation over the whole osmotic pressure range studied indicates that glucose binding is accompanied by the release of at least 65 +/- 10 water molecules, and this is reversed on enzyme turnover. The results indicate that near the physiological range of pressures the number may be higher. Most of this water, which behaves like an inhibitor, likely comes from the cleft which is induced to close around the substrate. Such large dehydration/rehydration reactions during turnover imply a significant contribution of solvation to the energetics of the conformational changes. Osmotic stress is a method of general applicability to probe water's contribution to functioning molecules.
Catalysis↗