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We hypothesized that in patients with chronic heart failure mesenteric venous congestion leads to increased bowel permeability, bacterial translocation, and thereby endotoxin release; the increased endotoxin challenge then causes immune activation with increased soluble CD14 levels and tumor necrosis factor (TNF)-alpha production. Patients with high soluble CD14 levels (indicative of endotoxin-cell interaction) have markedly increased plasma levels of TNF-alpha, soluble TNF receptors 1 and 2, and intracellular adhesion molecule-1, supporting this hypothesis.

Background: Elevated serum uric acid concentrations have been observed in clinical conditions associated with hypoxia. Since chronic heart failure is a state of impaired oxidative metabolism, we sought to determine whether serum uric acid concentrations correlate with measures of functional capacity and disease severity., Methods: Fifty nine patients with a diagnosis of chronic heart failure due to coronary heart disease (n = 34) or idiopathic dilated cardiomyopathy (n = 25) and 20 healthy controls underwent assessment of functional capacity. Maximal oxygen uptake (MVO2) and regression slope relating to minute ventilation to carbon dioxide output (VE-VCO2) were measured during a maximal treadmill exercise test. Metabolic assessment consisted of measuring serum uric acid and fasting lipids, and insulin sensitivity, obtained by minimal modelling analysis of glucose and insulin responses during an intravenous glucose tolerance test. Clustering of indices of functional disease capacity and metabolic factors was explored using factor analysis and multivariate regression analysis., Results: Compared to 20 healthy controls, patients with chronic heart failure had a 52% lower MVO2 (P < 0.001), 56.8% higher serum uric acid concentrations (P < 0.001) as well as a 60.5% lower insulin sensitivity (P < 0.001). Salient univariate correlations in the chronic heart failure group included serum uric acid concentrations with exercise time during the exercise test (r = -0.53), MVO2 (r = -0.50) (both P < 0.001), VE-VCO2 slope (r = 0.45), and NYHA functional class (r = 0.36) (both P < 0.01). In factor analysis of the chronic heart failure group, serum uric acid formed part of a principal cluster of metabolic variables which included MVO2 and VE-VCO2 slope. In multivariate regression analysis, serum uric acid concentrations emerged as a significant predictor of MVO2, exercise time (both P < 0.001,) VE-VCO2 slope and NYHA functional class (both P < 0.02), independent of diuretic dose, age, body mass index, serum creatinine, alcohol intake, plasma insulin levels, and insulin sensitivity index., Conclusions: There is an inverse relationship between serum uric acid concentrations and measures of functional capacity in patients with cardiac failure. The strong correlation between serum uric acid and MVO2 suggests that in chronic heart failure, serum uric acid concentrations reflect an impairment of oxidative metabolism.

Background: Wasting in chronic heart failure (CHF) has long been known but is little investigated. We sought to find out whether the cachectic state in CHF provides additional prognostic information about all-cause mortality., Methods: Between June, 1993, and May, 1995, we studied 171 consecutive patients with CHF (mean age 60 years [SD 11; range 27-86]; 17 female). We assessed exercise capacity (peak oxygen consumption; mean 17.5 mL kg-1 min-1 [6.7]), functional status (New York Heart Association [NYHA] class: 21 class I, 63 class II, 68 class III, 19 class IV), and left-ventricular ejection fraction (mean 30% [SD 15]; n = 115). The cachectic status was defined prospectively as a non-intentional documented weight loss of at least 7.5% of previous normal weight (28 patients; range 9-36% or 6-30 kg) during at least 6 months. The Cox proportional-hazards model was used to assess the association of variables with survival, and Kaplan-Meier cumulative survival plots were constructed to estimate the influence of risk factors., Findings: At the end of follow-up in November, 1996, 49 patients had died (after a mean 324 days [SD 283]). The mean follow-up of the survivors was 834 days (SD 186; range 549-1269). The cachectic state was predictive of 18-month mortality independent of age, NYHA class, left-ventricular ejection fraction, and peak oxygen consumption. Mortality in the cachectic patients (n = 28) was 18% at 3 months, 29% at 6 months, 39% at 12 months, and 50% at 18 months. Patients who had a peak oxygen consumption below 14 mL kg-1 min-1 (n = 53) had mortality at 3, 6, 12, and 18 months of 19%, 30%, 40%, and 51%. 18-month survival was 23% (95% CI 0-46) for the 13 patients with both of these risk factors (cachexia and low peak oxygen consumption) compared with 93% (88-98) in those (n = 103) with neither risk factor (p < 0.0001)., Interpretation: The cachectic state is a strong independent risk factor for mortality in patients with CHF. Combined with a low peak oxygen consumption, it identifies a subset of patients at extremely high risk of death. Assessment of cachexia should be included in transplant programmes and studies that investigate the effect of interventions by survival analyses.

Aims: The peripheral chemoreflex may be augmented in chronic heart failure and may play a role in its pathophysiology including the mediation of exercise hyperpnoea and sympathetic activation. The objective of this study was to characterize the patients with an augmented peripheral chemoreflex., Methods and Results: Peripheral chemoreflex sensitivity was assessed by measuring the ventilatory response to hypoxia using transient inhalations of pure nitrogen in 50 patients with chronic heart failure (age 58.7 +/- 12.1 (SD) years; radionuclide left ventricular ejection fraction 26.5 +/- 13.0%). The peripheral chemoreflex of 12 healthy controls with similar demographic characteristics was 0.272 +/- 0.201l.min-1.%Sao(2)-1 compared with 0.673 +/- 0.410l. min-1.%Sao(2)-1 (P < 0.0001) in the chronic heart failure patients. Using 2 standard deviations above the mean level of the controls peripheral chemoreflex sensitivity as the upper limit of normal, we defined an augmented chemoreflex as greater than 0.6751.min-1.%Sao(2)-1. Twenty of the chronic heart failure patients (40%) demonstrated such an augmented peripheral chemoreflex. Compared with patients with peripheral chemoreflex sensitivity within the normal range, they had a reduced peak oxygen consumption during cardiopulmonary exercise (15.1 +/- 4.4 vs 18.5 +/- 5.8 ml.kg-1.min-1, P = 0.02), reduced radionuclide left ventricular ejection fraction (21.8 +/- 11.8 vs 29.4 +/- 13.1%, P = 0.046) and were in a worse New York Heart Association functional class (2.8 vs 2.4, P = 0.05). The ventilatory response to exercise, as characterized by the regression slope relating minute ventilation to carbon dioxide output during exercise, was also higher (40.48 +/- 9.32 vs 34.54 +/- 7.19, P = 0.02), consistent with the role of the peripheral chemoreflex in mediating exercise hyperpnoea. There was also an increased proportion of patients with non-sustained ventricular tachycardia in the group with an augmented peripheral chemoreflex (61% vs 21%, chi-squared 7.08, P < 0.01). No difference was seen in the age, height, weight and lung function measurements of these patients compared with the normal chemoreflex group., Conclusion: An augmented peripheral chemoreflex is a common finding in chronic heart failure patients, one associated with increasing severity and with the exercise hyperpnoea seen in the condition. That there was an excess of patients with non-sustained ventricular tachycardia in the group with an augmented peripheral chemoreflex may be related to the chemoreflex-driven sympathetic stimulation. The peripheral chemoreflex may be important in the pathophysiology of chronic heart failure, both in terms of symptoms and exercise limitation.

Background: The influence of age, skeletal muscle function and peripheral blood flow on exercise capacity in chronic heart failure patients is controversial, possibly due to variations in skeletal muscle atrophy., Methods and Results: To assess predictors of exercise capacity in patients with clinical cardiac cachexia, we studied 16 cachectic and 39 non-cachectic male chronic heart failure patients of similar age and ejection fraction. All cachectic patients were wasted (% ideal body weight: 81.2 +/- 1.9 vs 105.2 +/- 2.1, P < 0.0001, mean +/- SEM) and had documented weight loss (5-30 kg). Peak oxygen consumption (14.9 +/- 1.4 vs 16.3 +/- 0.6 ml.kg-1, min-1, resting and peak blood flow (plethysmography) and 20 min fatigability (% baseline strength) were all similar between the two groups. Quadriceps strength, muscle size (all P < 0.0001), strength per unit muscle (right: P < 0.05: left: P < 0.001) and 5 min fatigability (P < 0.05) were all lower in cachectic patients. In non-cachectic patients, age (R = 0.48) and quadriceps strength (R = 0.43, all P < 0.01) predicted peak oxygen consumption. Only in cachectic patients did peak blood flow predict peak oxygen consumption significantly (R = 0.72, P = 0.005), whereas age and strength did not. Similar findings were confirmed using other previously published definitions of cardiac cachexia., Conclusions: The predictors of exercise capacity change with the development of cardiac cachexia from age and strength to peak blood flow. This shift may be caused by additional endocrine or catabolic, abnormalities active in end stage heart failure.

Background: The aim of this study was to evaluate whether abnormalities in heart rate variability (HRV) could act as markers of ventricular tachycardia and prognosis in patients with advanced, chronic heart failure. Fifty patients with chronic heart failure (45 men; mean age, 59 +/- 9 years; New York Heart Association [NYHA] class II-III; left ventricular ejection fraction [LVEF], 19 +/- 9% and peak oxygen consumption, 16.6 +/- 5.4 mL/kg/min) caused by idiopathic dilated cardiomyopathy (n = 12) and ischemic heart disease (n = 38) were included in the study. Heart rate variability measures derived from 24-hour electrocardiographic (ECG) monitoring (Marquette 8500 recorder, Marquette Electronics, Milwaukee, WI) were calculated in the time domain and frequency domain., Methods and Results: Twenty-five patients (50%) revealed episodes of ventricular tachycardia on 24-hour ECG monitoring (1-143 episodes). The presence of ventricular tachycardia was associated with lower LVEF but there was no difference in NYHA class and peak oxygen consumption between patients with and without ventricular tachycardia (LVEF, 16 vs 22%, P = .01; NYHA class, 2.6 vs 2.4; peak oxygen consumption, 16.5 vs 16.8 mL/kg/min, not significant). Patients with ventricular tachycardia exhibited markedly lower HRV measures. Multiple regression analysis was used to test HRV parameters as potential predictors of ventricular tachycardia. Among them, high-frequency power was the only independent predictor of the presence of ventricular tachycardia, and this predictive correlation was independent of LVEF and mean R-R interval duration. During a follow-up period of 24 +/- 18 months, 12 patients (24%) died. No difference was found in age, etiology, NYHA class, peak oxygen consumption, or occurrence of ventricular tachycardia, but a lower LVEF (15 +/- 6 vs 21 +/- 9%, P = .046) was observed in those who died compared with those who survived. Certain estimates of HRV were in contrast, lower in those who subsequently died: standard deviation of all normal R-R intervals (61 +/- 30 vs 101 +/- 33 ms), standard deviation of 5-minute mean R-R intervals (55 +/- 27 vs 92 +/- 31 ms), mean of all 5-minute standard deviations of R-R intervals (22 +/- 12 vs 37 +/- 11 ms), and the low-frequency (3.2 +/- 1.8 vs 4.8 +/- 0.9 ln ms2) and high-frequency (3.0 +/- 1.1 vs 3.8 +/- 0.8 ln ms2) components of the HRV spectrum (all differences, P < .01). In univariate Cox analysis, all of these HRV measures were independent predictors of death. Kaplan-Meier survival analysis revealed that the standard deviations of all normal R-R intervals and of 5-minute mean R-R intervals dichotomized at median values (99 and 90.5 ms, respectively) were the best predictors of mortality., Conclusions: In patients with moderate to severe chronic heart failure, depressed indices of HRV on 24-hour ambulatory ECG monitoring could be related to higher risk of ventricular tachycardia and death, suggesting that analysis of HRV could be usefully applied to risk stratification in chronic heart failure patients.

Aims: To evaluate the visual function of infants with perinatal cerebral infarction in whom the site and size of the lesion has been determined using magnetic resonance imaging (MRI)., Methods: Twelve infants with cerebral infarction on MRI were studied with a battery of tests specifically designed to evaluate visual function in infancy. This included tests: for visual attention (fixation shifts); of cerebral asymmetry (optokinetic nystagmus, visual fields); for assessment of acuity (forced choice preferential looking); and neurophysiological measures of vision (phase reversal and orientation reversal visual evoked potential)., Results: A considerable incidence of abnormalities on at least one of the tests for visual function used was observed. The presence or severity of visual abnormalities could not always be predicted by the site and extent of the lesion seen on imaging., Conclusions: Early focal lesions affecting the visual pathway can, to some extent, be compensated for by the immature developing brain. These data suggest that all the infants presenting with focal lesions need to be investigated with a detailed assessment of various aspects of vision.

Two infant vision screening programmes on total populations in the Cambridge Health District have been designed to identify manifest strabismus and strabismogenic and amblyogenic refractive errors at 7-9 months of age. The first, completed, programme used the isotropic photorefractor with cycloplegia together with a standard orthoptic examination. The second, current, programme uses the VRP-1 isotropic videorefractor to identify infants with accommodative lags which are followed up by refraction under cycloplegia. Both programmes show good agreement between infants identified at screening and retinoscopic refractions at follow-up, showing that photo- and videorefraction (with or without cycloplegia) can be effective methods for screening for ametropia in infants and young children. In each programme 5-6% of infants showed abnormal levels of hyperopia (> or = 3.5 D in any meridian), less than 1% showed anisometropia > or = 1.5 D; very few infants (0.25%) showed -3D myopia or greater. Less than 1% showed manifest strabismus. Hyperopic and anisometropic children entered a randomised controlled trial of partial refractive correction. All children identified at screening, alongside appropriate control groups, are extensively followed up to age 4 years. The first programme has found that children who were hyperopic in infancy were 13 times more likely to become strabismic, and 6 times more likely to show measurable acuity deficits by 4 years, compared with controls. Wearing a partial spectacle correction reduced these risk ratios to 4:1 and 2.5:1 respectively. The impaired acuity can be attributed, in part, to meridional amblyopia resulting from persisting astigmatism. Both hyperopic and myopic infants showed refractive changes in the direction of emmetropia between 9 months and 4 years. Wearing a partial spectacle correction did not affect this process of emmetropisation, but does provide the possibility of reducing the incidence of common pre-school vision problems.

Objective: To investigate the significance of respiratory muscle weakness in chronic heart failure and its relation both to maximum oxygen consumption during cardiopulmonary exercise testing and to skeletal muscle (quadriceps) strength., Subjects: Seven healthy men aged 54.9 (SEM 4.3) years and 20 men with chronic heart failure aged 61.4 (1.6) years (P = 0.20) with radionuclide left ventricular ejection fraction of 25.4 (3.0)%., Methods: Mouth pressures during maximum static inspiratory effort (PImax) at functional residual capacity (FRC) and residual volume (RV) were measured in all subjects and taken as indices of inspiratory muscle strength. Similarly, mouth pressures during maximum static expiratory effort (PEmax) at FRC and total lung capacity (TLC) were taken as indices of expiratory muscle strength. Cardiopulmonary exercise testing was performed in all subjects. All controls and 15 heart failure patients also had their right quadriceps muscle strength measured., Results: There was respiratory muscle weakness in heart failure patients, with reduction of PImax at FRC (59.7) (6.3) v 85.6 (9.6) cm H2O, P = 0.045), PEmax at FRC (94.8 (6.2) v 134.6 (9.1) cm H2O, P = 0.004), and PEmax at TLC (121.7 (8.5) v 160.7 (13) cm H2O, P = 0.028). PImax at RV was also reduced but this did not reach statistical significance (77.3 (6.6) v 89.3 (13) cm H2O, P = 0.44). There was also significant weakness of the right quadriceps muscle (308.5 (22) v 446.2 (28) N, P = 0.001). PImax at both FRC and RV correlated with maximum oxygen consumption (r = 0.59, P = 0.006, and r = 0.45, P = 0.048 respectively) but not PEmax. There was, however, no significant correlation between PImax and right quadriceps strength., Conclusions: Respiratory muscle weakness is seen in chronic heart failure. The results suggest that inspiratory muscles are important in determining maximum oxygen consumption and exercise tolerance in these patients. The lack of correlation between respiratory and right quadriceps muscle strength further suggests that the magnitude and time course of respiratory and locomotor muscle weakness may differ in individual patients. Treatment aimed at improving the function of the involved muscle groups may alleviate symptoms.

It has previously been found by us, with a visual evoked potential (VEP) measure, that orientation discrimination of dynamic patterns in infants can be demonstrated from around 6 weeks after birth. Experiments are reported in which orientation discrimination was measured behaviourally, in two infant control habituation procedures, with both dynamic and static patterns. When dynamic patterns identical to those in our previous VEP studies were used, the first positive evidence of orientation discrimination was found at around 6 weeks postnatally. The time course of both the VEP and the behavioural measures was similar. However, with static patterns, evidence of orientation discrimination by newborns was found if the infants were allowed to compare the habituated and novel orientations in a paired simultaneous comparison after habituation, but was not found when the habituated and novel stimulus were presented sequentially. The positive evidence of orientation discrimination in newborns supports the hypothesis that some form of orientationally tuned detectors can be used for discrimination of static patterns at birth. However, some developmental change over several weeks seems to be required before a positive electrophysiological VEP response can be measured for dynamic patterns changing in orientation.

A modification of the single optotype Sheridan Gardiner test for pre-school children has been used to measure visual crowding. A significant 'crowding effect' has been found in children between the ages of 3 and 6 years with a general decrease in the effect over the pre-school years. The 'crowding' in 5-7 year olds is not significantly greater than that found in adults. No significant difference has been found in the extent of crowding using the test at 3 m rather than the normal 6 m viewing distance, although in general the test has been found to be practically easier with better co-operation at 3 m for the younger children. For these reasons, this particular test at 3 m would seem to be well suited to acuity testing in pre-school children, when an acuity equivalent to Snellen values is required.

The present paper is a report on a case of nitrate poisoning in young calves. Supplying feed high in nitrates to these very young calves would appear to be more hazardous than it would to the older calves.