Positive and negative affect after diagnosis of advanced cancer.

Anxiety and depression are studied thoroughly in patients with advanced cancer. However, little is known about the nature of mood disorders in this stage of the disease. We studied positive and negative affect in patients who have had a diagnosis of advanced cancer, and examined how these are related to anxiety and depression, and to other patient and care factors. One hundred and five patients filled out a written questionnaire and were interviewed personally. The PANAS positive affect scores were lower than those in the general population, but the negative affect scores were fairly similar. We found a rather low prevalence of depression (13%) and anxiety (8%) as measured by the HADS. The emotional problems patients mentioned most frequently were anxiety about metastases (26%), the unpredictability of the future (18%) and anxiety about physical suffering (15%). Both positive and negative affect were most strongly related to patient's sense of meaning and peace. We conclude that distinguishing positive and negative affect enhances the understanding of psychological distress of patients with advanced cancer, that seems to be mainly caused by low levels of positive affect. Several theories are discussed to explain this finding, that may contribute to efforts to improve care for these patients.

Saccadic binocular coordination in alternating exotropia.

We studied the coordination of binocular eye movements in human subjects with alternating exotropia (divergent strabismus). Binocular saccades were recorded in six subjects during binocular and monocular viewing. Subjects were instructed to make saccades between two continuously lit targets (LED's) presented in an isovergence array (with the straight-ahead target 130 cm from the eyes) in a dimly lit room. For saccades up to 20 degrees amplitude, there were no large differences in the dynamics of the saccades between control and exotropic subjects. However, for larger amplitudes subjects frequently alternated the eye of fixation during saccades. That is, subjects fixated the left target with the left eye and the right target with the right eye. The alternation in eye fixation at the end of the saccade was taken into account in the programming of the saccades. The amplitudes of the alternating saccades were approximately equal to the target amplitude minus the strabismus angle. We conclude that for those saccades where alternation occurs, there is not only a change in the eye of fixation, but also a change in the target representation provided by either eye. Thus, in this group of strabismic patients, saccades may be programmed in a retina-centered coordinate system, if we assume that for making a saccade to a new target in the contralateral visual field its representation on the temporal retinal field of the currently fixating eye is suppressed and the retinotopic target information is derived from the non-fixating eye. In executing the saccade, the non-fixating eye automatically becomes the fixating eye.

Dexmedetomidine and haemodynamic responses to acute central hypovolaemia in conscious rabbits.

1. Effects of the alpha2-adrenoceptor agonist dexmedetomidine on vasoconstrictor and heart rate (HR) responses to acute central hypovolaemia were studied in eight chronically instrumented rabbits. We compared intravenous (i.v.) and fourth ventricular (V4) dexmedetomidine (0.1-10 microg/kg) and the reversal of effects by the alpha2-adrenoceptor antagonist idazoxan and the opioid agonist alfentanil. 2. Gradual inflation of an inferior vena cava (IVC) cuff reduced cardiac index (CI) by 8%/min, with progressive vasoconstriction and increased HR. In control rabbits, at approximately 40% baseline CI, there was sudden decompensation with failure of vasoconstriction and a fall in mean arterial pressure (MAP). 3. Dexmedetomidine (i.v. and V4) reduced resting MAP and HR and caused an earlier decompensation during central hypovolaemia. Intravenous dexmedetomidine (3 and 10 microg/kg) also reduced the slope of the initial vasoconstrictor response and the maximum HR. 4. The effects of dexmedetomidine were reversed by the antagonist idazoxan, which prevented the decompensation phase. Intravenous alfentanil was also effective in restoring the vasoconstrictor response and delaying decompensation with hypovolaemia after dexmedetomidine. Combining dexmedetomidine with an opioid, such as alfentanil, may provide the benefit of reduced sympathetic tone without increased risk of cardiovascular collapse.

Gaze-shift dynamics in subjects with and without symptoms of convergence insufficiency: influence of monocular preference and the effect of training.

We studied gaze-shift dynamics during several gaze-shift tasks and during reading, in five subjects with convergence insufficiency (C.I., a diminished ability to converge), and in ten subjects without C.I. Furthermore, we studied the effect of vergence training in order to verify previous claims that orthoptic exercises can improve vergence performance. We recorded binocular eye movements with the scleral coil technique. Subjects switched fixation between nearby and distant light emitting diodes (LEDs) arranged in isovergence arrays (distances 35 and 130 cm) in a dimly lit room. In both the C.I. and non-C.I. group, two classes of subjects occurred: vergence responders and saccadic responders. During pure vergence tasks, saccadic responders made saccades with no or little vergence; vergence responders made vergence movements with no or small saccadic components. In saccadic responders, fixation of nearby targets was monocular. Subjects with a preferred eye, according to our determination, used the preferred eye. The five C.I. subjects showed idiosyncratic responses with insufficient vergence during most trials. They all had a tendency to alternate fixation between the left and right eye. Vergence-version tasks always elicited larger vergence components than pure vergence tasks. During a reading task, vergence angles were more accurate than during gaze-shifts between LEDs. After the pre-training sessions, nine subjects (one of which had C.I.) practised a pure vergence task three times a day for at least 2 weeks. Vergence amplitudes of four of these subjects were larger after training. We conclude that vergence training can change oculomotor performance. Although C.I. is often associated with abnormal vergence dynamics, there are no typical C.I. vergence dynamics. Unstable monocular preferences may play a role in the aetiology of C.I.

Correction of hypovolemic hypotension by centrally administered naloxone in conscious rabbits.

Our goal was to test directly whether the vasoconstrictor action of naloxone during hypovolemic hypotension is centrally mediated. In eight chronically instrumented rabbits, progressive central hypovolemia and fall in cardiac output (CO) were produced by gradually inflating a cuff on the thoracic vena cava. Central hypovolemia was then sustained for 8 min by holding CO constant. In the main experiment (n = 4), each rabbit was studied eight times over 4 experimental days. Saline or naloxone treatment commenced 10 min before progressive hypovolemia (early treatment) or 2 min after the onset of sustained hypovolemia (late treatment), given by intravenous infusion or into the fourth ventricle (V4). With saline treatment, there was spontaneous recovery of systemic vasoconstriction and arterial pressure during sustained hypovolemia. Late treatment with naloxone (4 mg/kg i.v.; 4-37 micrograms/kg V4) accelerated and exaggerated these changes. Thus, under conditions of constant CO and central blood volume, the vasodilatation of the decompensatory phase of acute hypovolemia is not sustained, and intravenous nalox one's vasoconstrictor action is via a brain stem mechanism.

Dynamics of horizontal vergence movements: interaction with horizontal and vertical saccades and relation with monocular preferences.

We studied the dynamics of pure vergence shifts and vergence shifts combined with vertical and horizontal saccades. It is known from earlier studies that horizontal saccades accelerate horizontal vergence. We wanted to obtain a more complete picture of the interactions between version and vergence. Therefore we studied pure version (horizontal and vertical), pure vergence (divergence and convergence) and combinations of both in five adult subjects with normal binocular vision and little phoria (< 5 degrees). The visual targets were LED's in isovergence arrays presented at two distances (35 and 130 cm) in a dimly lit room. Two targets were continuously lit during each trial and gaze-shifts were paced by a metronome. The two subjects with a strong monocular preference made vergence eye movements together with small horizontal saccades during pure vergence tasks. The other subjects, who did not have a strong monocular preference, made pure vergence movements (without saccades). These findings, suggest that monocular preferences influence the oculomotor strategy during vergence tasks. Vergence was facilitated by both horizontal and vertical saccades but vergence peak-velocity during horizontal saccades was higher than during vertical saccades.

Binocular saccadic eye movements in multiple sclerosis.

We attempted to increase the sensitivity for detection of abnormal binocular saccadic eye movements, particularly of the internuclear ophthalmoplegia (INO) type associated with multiple sclerosis (MS). Saccades of 10 and 20 degrees were binocularly recorded with scleral sensor coils in 10 normal control subjects and 26 patients with definite or probable MS, seven of whom had a clinically manifest INO in one or both directions. In the cases in which this was accompanied by a dissociated nystagmus of the abducting eye, our recordings showed that such secondary saccades were also expressed, in a strongly reduced form, by the adducting eye. The patients with manifest INO showed lower average peak velocities and peak accelerations, especially for adduction of the eye on the affected side, but the distribution of these parameters overlapped with the normal distribution. A much sharper distinction between normals and patients with INOs was found by considering the ratios between peak accelerations and velocities of saccade pairs (abducting eye/adducting eye). These ratios, which eliminate much intra- and inter-individual variability, had a narrow range in normals, and all values for INOs were outside this range. On this basis, the 19 patients without clinically manifest INO were easily separated into subgroups of 14 patients with completely normal interocular ratios and five patients with elevated peak velocity and acceleration ratios, identified as sub-clinical (uni- or bilateral) INOs. Measurements of vertical saccades and of interocular timing differences provided no useful criteria for disturbances of binocular coordination in MS. We conclude that in particular, the acceleration of the adducting eye is strongly reduced in patients with an INO, and that this reduction is best identified by interocular comparison between binocular pairs of saccades.

Haemodynamic response to simulated haemorrhage in the rabbit: interaction of i.v. anaesthesia and hypoxia.

We have studied in eight rabbits the cardiovascular effects of midazolam, propofol and alfentanil with graded hypoxia. Central blood volume was reduced progressively by gradual inflation of a thoracic vena cava cuff so that cardiac index (CI) decreased at a constant rate. Under control conditions the haemodynamic response was biphasic. During phase I, mean arterial pressure (MAP) was maintained by a progressive decrease in systemic vascular conductance (SVCI). When CI had declined to a critical level, phase II occurred with an abrupt increase in SVCI and decrease in MAP. Phase I was prolonged by hypoxia, alfentanil and midazolam, but the effects were not additive. Phase I was shortened by propofol and this effect increased with hypoxia. The gradient of the SVCI response in phase I was also reduced by propofol > midazolam, but not by alfentanil. The occurrence of phase II was less frequent during alfentanil infusion than midazolam and propofol with all of the inspired gas mixtures. Thus the opioid was protective against circulatory collapse with hypoxia and simulated hypovalaemia.

Effects of halothane, ketamine, propofol and alfentanil anaesthesia on circulatory control in rabbits.

1. We have made a within-rabbit comparison of the effects of four general anaesthetic regimens on the haemodynamic response to acute reduction in central blood volume and on baroreflex control of heart rate. 2. Acute haemorrhage was simulated by gradually inflating a cuff on the inferior vena cava in order to cause cardiac output to fall at a constant rate of 8.5%/min while the responses of systemic vascular resistance, arterial pressure and heart rate were measured. The full range of the baroreceptor-heart rate reflex was elicited by inflating aortic and vena caval cuffs. These indices of circulatory control were repeatedly measured within five protocols, to which each rabbit was exposed in randomized order. 3. In each protocol the rabbit was first studied unanaesthetized. Then a small dose of thiopentone sodium was given (16 mg/kg). In the four main protocols the rabbit was then intubated and ventilated, first with 100% oxygen and then with 50% nitrous oxide, during administration of one of four anaesthetic agents. These were halothane (2.0 and 2.5%), ketamine (2.5 mg/kg per min), propofol (0.83 and 1.25 mg/kg per min) and alfentanil (2.5 and 3.33 micrograms/kg per min). In a sham protocol the effects of 100% oxygen, then those of 50 and 75% nitrous oxide, were studied while the rabbit remained conscious. 4. In unanaesthetized rabbits, in the presence or absence of nitrous oxide, the normal biphasic haemodynamic response to simulated haemorrhage occurred. The first, vasoconstrictor, phase was attenuated by halothane, ketamine and propofol, so that arterial pressure fell more steeply than normal. Not only was the vasoconstrictor phase unaffected by alfentanil but it was extended, so that arterial pressure remained at a normal level even when cardiac output had fallen by 59%. This effect of alfentanil appeared to be mediated centrally, since it could be reproduced by injecting small doses (1.5-7.5 micrograms) into the fourth ventricle. All four anaesthetic agents and nitrous oxide attenuated the baroreceptor control of heart rate. The effect was least with nitrous oxide and alfentanil, greatest with halothane.

Role of central opiate receptor subtypes in the circulatory responses of awake rabbits to graded caval occlusions.

1. In unanaesthetized rabbits, haemorrhage was simulated by inflating a cuff placed round the inferior vena cava so that cardiac output fell at a constant rate of approximately 8% of its resting value per minute. The circulatory responses were measured after injections into the fourth ventricle of saline vehicle, selective opioid antagonists, selective opioid agonists, and agonist-antagonist mixtures. Three sets of experiments were done to determine if a specific subtype of opiate receptor within the central nervous system is responsible for the circulatory decompensation that occurs during simulated haemorrhage. 2. In six rabbits the effects of ascending doses of the antagonists naloxone (mu-selective), Mr 2266 (kappa- and mu-selective), ICI 174864 (delta-selective) and nor-binaltorphimine (kappa-selective) were tested. In three rabbits the effects of the antagonist naloxone, the agonists HTyr-D-Ala-Gly-MePhe-NH(CH2)2OH (DAGO, mu-selective), U 50488H (kappa-selective), and [D-Pen2,D-Pen5]-enkephalin (DPDPE, delta-selective), and combinations of these agonists with naloxone were tested. In four rabbits the dose-related effects of DAGO on respiratory, as well as circulatory, functions were examined. 3. After injecting saline vehicle, the circulatory response to simulated haemorrhage had two phases. During the first phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only approximately 10 mmHg. A second, decompensatory, phase began when cardiac output had fallen to approximately 50% of its resting level. At this point, there was an abrupt rise in systemic vascular conductance and a fall in mean arterial pressure to less than or equal to 40 mmHg. 4. The lower range of doses of naloxone (3-30 nmol), Mr 2266 (10-100 nmol), ICI 174864 (10-30 nmol), and all doses of nor-binaltorphimine (1-100 nmol), were without effect on the circulatory response to stimulated haemorrhage. Higher doses of naloxone (30-100 nmol), Mr 2266 (100-300 nmol) and ICI 174864 (30-100 nmol) abolished the decompensatory phase. The relative order of antagonist potency was ICI 174864 greater than or equal to naloxone greater than Mr 2266 greater than or equal to nor-binaltorphimine. 5. In the second set of experiments, the critical dose of naloxone necessary to prevent circulatory decompensation during simulated haemorrhage was 30-150 nmol. The delta-agonist DPDPE (50 nmol) did not affect the haemodynamic response to simulated haemorrhage, but it did block the effect of naloxone on the response.(ABSTRACT TRUNCATED AT 400 WORDS)

Haemodynamic responses to acute blood loss: new roles for the heart, brain and endogenous opioids.

Information has come forward recently from several sources which provides new insights into the mechanisms that underlie the haemodynamic responses to acute blood loss. In unanaesthetised animals and human volunteers there are two distinct phases to these responses. At first, the engagement of baroreflexes results in a progressive rise in sympathetic vasoconstrictor drive and peripheral resistance, and the maintenance of arterial blood pressure at a near-normal level. When about one-third of blood volume has been lost, reflex sympathetic drive is switched off, and peripheral resistance and blood pressure fall abruptly to low levels despite a burst of vasopressin release. Research in conscious animals has now shown that the onset of this decompensatory phase is triggered by a signal from the heart, which activates an endogenous opioid mechanism in the brain. Activation of this mechanism can be prevented by administering a selective delta-receptor antagonist, or selective mu-receptor agonists (including alfentanil). It has not yet been established that this endogenous opioid mechanism is responsible for the decompensatory phase of acute blood loss in man, nor that it can be prevented or reversed by selective opioid agonists or antagonists.