Digoxin delays recovery from tachycardia-induced electrical remodeling of the atria.

BACKGROUND: Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. METHODS AND RESULTS: We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF. CONCLUSIONS: Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

Differential effects of procainamide, lidocaine and acetylstrophanthidin on body surface potentials and epicardial conduction in dogs with chronic myocardial infarction.

Twenty-eight anesthetized mongrel dogs were studied 2 to 74 months after experimental myocardial infarction in order to examine the effects of procainamide, lidocaine and acetylstrophanthidin on conduction within the infarcted region and the way such effects relate to changes in body surface potentials and antiarrhythmic efficacy. In each animal, 100 to 200 QRS complexes in the X, Y, Z leads were signal averaged, vector summed and high pass filtered at 50 Hz. Susceptibility to ventricular arrhythmia was evaluated using routine programmed ventricular extrastimulation in the anesthetized open chest animal. Epicardial electrograms were sequentially recorded at 45 standard sites within the infarcted region and referenced to the beginning of the QRS complex. Of the three agents, only procainamide exhibited antiarrhythmic action whereas lidocaine and acetylstrophanthidin produced inconsistent effects. Procainamide prolonged the time at which activity in the epicardial electrographic recordings ended relative to the beginning of the body surface QRS complex. This effect was significantly greater in electrograms that ended late in the QRS complex in the control state than for those that ended earlier. Such preferential effect on more abnormal sites was reflected on the body surface as a greater effect of procainamide in prolonging the lower energy terminal portion of the signal-averaged QRS complex than the earlier high energy portion. In contrast, lidocaine significantly prolonged the time at which electrograms ended only for those relatively normal electrograms that ended early in the QRS complex in the control state. In the signal-averaged body surface QRS complex, lidocaine produced a small but significant prolongation of the early high energy portion of the QRS complex but no change in the late portion. Acetylstrophanthidin produced a significant prolongation in early-ending electrograms and, surprisingly, significantly shortened the end time of electrograms that ended late in the QRS complex in the control state. Such effects were not reflected, however, on the body surface because acetylstrophanthidin had no significant effect on either the early or the late portion of the QRS complex. It is concluded that procainamide's differential effect between early- and late-ending electrograms is detected on the body surface by a greater prolongation in the terminal portion of the QRS complex. The signal-averaged body surface QRS complex is less sensitive in detecting the more subtle effects on conduction caused by lidocaine and acetylstrophanthidin.(ABSTRACT TRUNCATED AT 400 WORDS)

Late potentials in a bradycardia-dependent long QT syndrome associated with sudden death during sleep.

The purpose of this study was to determine the incidence of late potentials and their relation to QT prolongation in a family with a high incidence of sudden death during sleep at a young age and bradycardia-dependent QT prolongation (n = 9) and to compare the findings with those in consanguineous family members without QT prolongation (n = 13). Six (67%) of the 9 family members with QT prolongation had late potentials on the signal-averaged electrocardiogram (ECG) compared with 1 of the 13 normal subjects (p less than 0.007). Positive predictive accuracy of the signal-averaged ECG for the detection of subjects with QT prolongation was 86%; negative predictive accuracy was 80%. During exercise testing, the QT interval normalized, whereas late potentials did not change significantly. Exercise testing did not reveal the presence of coronary artery disease as a possible cause of late potentials. It is concluded that 1) compared with family members with a normal QT interval, patients with this type of bradycardia-dependent QT prolongation have a high incidence of late potentials; 2) late potentials persist despite normalization of the QT interval at high heart rates, indicating that there is no direct relation between late potentials and QT prolongation; and 3) late potentials are not caused by coronary artery disease in these subjects. Therefore, the detection of late potentials might be a new aid in the detection and risk stratification of patients with the long QT syndrome. Late potentials possibly indicate a substrate for ventricular tachyarrhythmias in this type of bradycardia-dependent QT prolongation.

Converting enzyme inhibition after experimental myocardial infarction in rats: comparative study between spirapril and zofenopril.

STUDY OBJECTIVE: The aim was to compare the effects of two novel angiotensin converting enzyme (ACE) inhibitors, spirapril and zofenopril, on cardiac remodelling in rats with congestive heart failure after myocardial infarction. Spirapril contains no sulphydryl group, whereas zofenopril is a sulphydryl containing ACE inhibitor. DESIGN: Experimental myocardial infarction was induced by ligation of the left coronary artery. Sham operated animals served as controls. Treatment with spirapril (2-2.5 mg.kg-1.d-1) or zofenopril (12-15 mg.kg-1.d-1) added to the drinking water was started immediately after myocardial infarction or sham operation and continued for six weeks. After the treatment period, all rats were killed. The heart was rapidly removed and perfused as described by Langendorff. Heart rate and left ventricular pressure were measured both at baseline and during stimulation with isoprenaline (6 nM). Heart and lung weights were determined. SUBJECTS: Normotensive male Wistar rats (220-240 g) were used. MEASUREMENTS AND MAIN RESULTS: Experimental myocardial infarction considerably increased left ventricular cavity volume. Chronic treatment with either spirapril or zofenopril significantly attenuated this increase in volume. In infarcted rats, the increase in total heart and lung weight was also significantly reduced by chronic treatment with spirapril and zofenopril, indicating that these compounds reduce cardiac mass and pulmonary congestion in congestive heart failure due to myocardial infarction. There were no significant differences between treatment with spirapril and zofenopril. In the isolated and perfused rat heart, myocardial infarction significantly decreased both heart rate and left ventricular pressure. Converting enzyme inhibition only affected heart rate. Heart rate was significantly higher in infarcted animals treated with spirapril and zofenopril than in untreated infarcted animals. CONCLUSIONS: Both spirapril and zofenopril attenuated ventricular enlargement and cardiac hypertrophy in rats with congestive heart failure after myocardial infarction when treatment was started in the acute phase of myocardial infarction. No additional role could be attributed to the sulphydryl moiety of zofenopril. It is also suggested that these two ACE inhibitors modify cardiac sympathetic activity in rats with congestive heart failure, but more studies are needed to confirm these findings.

Comparative neuropsychiatry: white matter abnormalities in children and adolescents with schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder.

BACKGROUND: There is considerable evidence that white matter abnormalities play a key role in the pathogenesis of a number of major psychiatric disorders, including schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder. Few studies, however, have compared white matter abnormalities early in the course of the illness. METHODS: A total of 102 children and adolescents participated in the study, including 43 with early-onset schizophrenia, 13 with early-onset bipolar affective disorder, 17 with obsessive-compulsive disorder, and 29 healthy controls. Diffusion tensor imaging scans were obtained on all children and the images were assessed for the presence of non-spatially overlapping regions of white matter differences, a novel algorithm known as the pothole approach. RESULTS: Patients with early-onset schizophrenia and early-onset bipolar affective disorder had a significantly greater number of white matter potholes compared to controls, but the total number of potholes did not differ between the two groups. The volumes of the potholes were significantly larger in patients with early-onset bipolar affective disorder compared to the early-onset schizophrenia group. Children and adolescents with obsessive-compulsive disorder showed no differences in the total number of white matter potholes compared to controls. CONCLUSIONS: White matter abnormalities in early-onset schizophrenia and bipolar affective disorder are more global in nature, whereas children and adolescents with obsessive-compulsive disorder do not show widespread differences in FA.

Effects of streptokinase during acute myocardial infarction on the signal-averaged electrocardiogram and on the frequency of late arrhythmias.

Although a number of studies have shown that the incidence of late potentials is lower after thrombolytic therapy, it is not known whether this is paralleled by fewer arrhythmic events during long-term follow-up. In patients with first acute myocardial infarction, filtered QRS duration was significantly shorter when treated with streptokinase (95 +/- 11 ms, n = 53) than when treated with conventional therapy (99 +/- 12 ms, n = 77, p < 0.05). The low-amplitude signal (D40) was shorter after thrombolysis (28 +/- 11 vs 33 +/- 12 ms, p < 0.02). Terminal root-mean-square voltage did not differ significantly (41 +/- 24 vs 35 +/- 23 microV). Irrespective of treatment, late potentials were predictive in the complete group (n = 171) for arrhythmic events during follow-up (13 +/- 6 months, range 6 to 24) (hazard ratio 7.7, p < 0.02, Cox proportional-hazards survival analysis), but treatment (streptokinase vs conventional) did not significantly affect outcome when added to the model. It is concluded that thrombolysis prevents the development of late potentials. However, this study does not confirm the hypothesis that prevention of late potentials leads to a decrease in arrhythmic events.

On the role of calcium ions in the presynaptic alpha-receptor mediated inhibition of [3H]noradrenaline release from rat brain cortex synaptosomes.

Rat brain cortex synaptosomes, previously labeled by incubation with [3H]noradrenaline ([3H]NA) were continuously superfused with Krebs-Ringer media. Release of [3H]NA was induced by superfusion with medium containing either 15 mM K+, 20 microM veratrine or 1 microM of the calcium-ionophore A 23187 and was strongly dependent on the concentration of Ca2+ in the medium. Noradrenaline (1 microM, in the presence of the uptake inhibitor desipramine) inhibited K+-induced [3H]NA release by activation of presynaptic alpha-receptors. When the Ca2+-concentration in the medium was reduced, or the Mg2+-concentration increased, [3H]NA release appeared to be more susceptible to alpha-receptor mediated inhibition. Noradrenaline (1 microM) inhibited [3H]NA release induced by 15 mM K+, in the presence of 0.075 Ca2+ and 10 mM Mg2+, by 86%. Veratrine-induced release was also inhibited by alpha-receptor activation. However, [3H]NA release induced by the calcium-ionophore was not affected by alpha-receptor agonists. These results strongly support the view that alpha-receptor activation results in a decrease of the availability of Ca2+ for stimulus-secretion coupling processes. Presumably this is effected by an inhibition of voltage-sensitive calcium channels in the neuronal membrane associated with neurotransmitter release.

Presynaptic noradrenergic alpha-receptors and modulation of 3H-noradrenaline release from rat brain synaptosomes.

The depolarization (15 mM K+)-induced release of 3H-NA from superfused rat brain synaptosomes and the effects of alpha-noradrenergic drugs thereon were studied. Noradrenaline (NA; in the presence of the uptake inhibitor desipramine) reduced synaptosomal 3H-NA release. Reduction of the concentration of calcium ions in the medium during K+ stimulation greatly enhanced the sensitivity of 3H-NA release to alpha-receptor-mediated inhibition. Under these conditions NA dose-dependently inhibited 3H-NA release from synaptosomes obtained from cortex or hypothalamus, but did not affect 3H-NA release from striatal (i.e dopaminergic) synaptosomes. Adrenaline, clonidine and oxymetazoline potently inhibited 3H-NA release from cortex synaptosomes at concentrations in the nanomolar range. Phentolamine by itself did not affect synaptosomal 3H-NA release, but antagonized the inhibitory effects of both noradrenaline and adrenaline. The data obtained further substantiate the hypothesis that the alpha-receptors mediating a local negative feedback control of NA release are localized on the varicosities of central noradrenergic neurons, Furthermore, noradrenergic nerve terminals in the hypothalamus appear to be less senstive to alpha-receptor-mediated presynaptic inhibition than those in the cortex.

Captopril reduces purine loss and reperfusion arrhythmias in the rat heart after coronary artery occlusion.

Captopril was perfused through isolated rat hearts; its effects after local ischemia and reperfusion were assessed. Upon reperfusion all untreated (10 out of 10) but only 4 (out of 10) captopril-treated (80 micrograms/ml) hearts fibrillated (P less than 0.02). Purine overflow increased upon reperfusion but was reduced by captopril (597 +/- 62 and 333 +/- 41 nmol/min gdwt respectively; P less than 0.05). The pressure-rate index and the apex displacement were severely impaired after 30 min of reperfusion (32 +/- 16 and 10 +/- 5% respectively of initial values) but captopril reduced the injury of mechanical function (60 +/- 8; P less than 0.05 and 61 +/- 11; P less than 0.05 respectively). These results show that captopril reduces ventricular fibrillation and the loss of high energy phosphate nucleotides and thereby partly maintains mechanical function impaired by ischemia and reperfusion.

Alpha-receptor-mediated modulation of 3H-noradrenaline release from rat brain cortex synaptosomes.

The effects of oxymetazoline and noradrenaline (in the presence of desipramine) on the release of 3H-noradrenaline from rat brain cortex synaptosomes were studied using a superfusion technique. Both drugs (at 1 micrometer concentrations) were found to reduce the depolarization-induced (15 mM K+) release of 3H-noradrenaline. The release-modulating effect of noradrenaline was antagonized by phentolamine and yohimbine. The data provide direct evidence for the hypothesis that alpha-receptors modulating the release of noradrenaline are localized on varicosities of central noradrenergic neurones.

Coronary vasodilation induced by captopril and zofenoprilat: evidence for a prostaglandin-independent mechanism.

In this study, the vasodilating properties of captopril and zofenoprilat, two angiotensin-converting enzyme (ACE) inhibitors containing the sulfhydryl group, are investigated in the isolated rat heart. It is demonstrated that both compounds increase coronary flow in a dose-dependent manner. However, the mean pD2 of zofenoprilat appears to be significantly higher than the mean pD2 of captopril (4.55 +/- 0.06 and 3.35 +/- 0.02 respectively), indicating that zofenoprilat is about ten times more potent in increasing coronary flow than captopril. Possibly this difference in potency between captopril and zofenoprilat can be explained by their physicochemical properties. Since zofenoprilat is more lipophilic than captopril, its concentration in cardiac and vascular tissues at distribution equilibrium is thought to be higher than the tissue concentration of captopril, which may result in a more pronounced vasodilatory action. The precise mechanism of coronary vasodilation induced by ACE inhibitors containing the sulfhydryl group is not yet understood. Several factors have been proposed, such as stimulation of prostacyclin production. However, in this study, concomitant administration of 10(-6) mol/l acetylsalicylic acid shows no antagonism, indicating that under normoxic conditions the vasodilatory effects of captopril and zofenoprilat are independent of the production of vasodilating prostaglandins. Therefore, other factors than stimulation of prostacyclin synthesis seem to be involved, such as prevention of bradykinin breakdown and/or potentiation of endothelium derived relaxing factor (EDRF). Furthermore, despite a marked inhibition of prostacyclin production, 10(-6) mol/l acetylsalicylic acid itself has no effect on coronary flow. These results suggest that prostacyclin does not play an important role in the regulation of coronary flow, at least in the normoxic isolated rat heart.

Cardiac arrhythmias--a new indication for angiotensin-converting enzyme inhibitors?

Ventricular arrhythmias (VA) are a major cause of sudden death. Life-threatening VA may be present in a variety of both acute and chronic conditions in which cardiac function is compromised: during acute myocardial infarction and subsequent reperfusion; some weeks after acute myocardial infarction, due to residual damage (scar formation with zones of heterogeneity); and as a consequence of congestive heart failure (CHF) resulting from myocardial infarction, dilated cardiomyopathy, hypertension or other causes. Symptomatic suppression of potentially life-threatening VA is unlikely to decrease mortality, since classical antiarrhythmic drugs have failed, so far, to improve life expectancy. Drugs that influence the underlying causes of CHF seem to have a better chance of reducing mortality. There is evidence that ACE inhibitors may exert beneficial effects on arrhythmogenicity by several mechanisms in these situations. Under acute ischaemic conditions both cellular damage and undue increases in circulating catecholamines and angiotensin II may be prevented. This has been demonstrated in various animal models and confirmatory clinical evidence is emerging. Two week after experimental myocardial infarction, the pig heart is less vulnerable to programmed electrical stimulation when ACE inhibitors are administered. Finally, in CHF a variety of proarrhythmic factors, such as left ventricular dysfunction, raised catecholamine levels and, in particular, decreased potassium concentrations, are influenced beneficially by ACE inhibitors.

Late potentials, QTc prolongation, and prediction of arrhythmic events after myocardial infarction.

In a series of 171 consecutive survivors of acute myocardial infarction, the predictive value of late potentials and QTc prolongation was prospectively assessed. QT intervals were measured in lead V2, corrected QT (QTc) was calculated using Bazett's equation (cut-off value 440 ms). Late potentials were considered to be present when all of the three signal-averaged electrocardiographic variables were abnormal (i.e. QRS > 114 ms, D40 > 38 ms, and V40 < 20 microV). Complete follow-up was obtained (mean 13 +/- 6 months, range 6-24 months). Six percent of the patients had an arrhythmic event (i.e. sustained ventricular tachycardia or sudden death). The relative risk of late potentials for arrhythmic events was 7.7 (P < 0.02). The relative risk of QTc > 440 ms was 1.1 (NS). In a multivariate analysis, the addition of QTc prolongation did not significantly improve the prognostic value of late potentials alone. It is concluded that late potentials are predictive of arrhythmic events after myocardial infarction, but the presence of concomitant QTc prolongation does not worsen the prognosis.

Prediction of lesion size through monitoring the 0 degree C isothermic period following transcatheter cryoablation.

A prototype steerable 8.5 F bipolar catheter fitted with a feedback thermocouple was tested in 7 anaesthetized pigs (30 kg) guided by the electrocardiogram in order to modify the AV nodal and His-Purkinje system conductive properties. Thermal energy was delivered by a pressurized N2O tank (> 650 psi) via a cardiac cryo unit (Spembly, Hampshire, UK) into the catheter wherein gas expands resulting in a tip temperature as low as -70 +/- 2 degrees C within 10 seconds. Cryoablation under fluoroscopic and electrocardiographic guidance was applied at distinct sites in both ventricles for 60 or 120 seconds. After a follow-up period of 6 weeks, the ablation lesions found were well demarcated with small margins of hypertrophy of myocardial cells. With respect to lesion volume variability (8-207 mm3) and geometry, a relationship between the 0 degree C isothermic period and cryolesion volume was found. Results of an in vitro model corroborated this relationship. Therefore, an isothermic period probably can predict the lesion size and its geometry in terms of lesion depth. This potential therapeutic mode of transcatheter cryoablation deserves further investigation.

[Vascular architecture of the skin in the postmortem microangiogram]. / Gefässarchitektur der Haut im Mikroangiogramm post mortem.

To demonstrate the detailed vascular architecture of the skin, barium sulphate suspension was injected into the arteries of nine amputated lower limbs. Sections of skin from the foot were fixed in formalin and embedded in paraffin and then examined by high resolution radiography. Subsequently histological sections were prepared and correlated with the micro-angiographic appearances. This technique provided demonstration of the detailed vascular structure of the skin with very little super imposition. The capillary loops in the papillae, the sub-papillary plexus, the glandular components (with the capillaries surrounding the sweat glands), the fine arteries and smallest veins in the cutis could be demonstrated over a prolonged course. Microangiographic and histologic sections were carried out in parallel. These eliminated artifacts and clarified the micro-angiographic appearances. The value of microangiography for demonstrating the vascularity of the skin under normal, pathological and experimental conditions is the subject of further studies.

Treatment of chronic subdural haematoma with percutaneous needle trephination and open system drainage with repeated saline rinsing.

Fifty three patients with symptomatic chronic subdural haematomas were treated with single needle trephination followed by open system drainage with repeated saline rinsing for two days. After single trephination good outcome was achieved in 84% of the patients. Early recurrence was found in 11.3% of the cases. After a second needle trephination good outcome increased to 89%. Mortality rate was 4%. Long term follow up (mean 30 months) showed 6.7% recurrence rate. There were no complications. Single needle trephination with open system drainage and repeated rinsing is an effective and safe minimal invasive procedure for patients with chronic subdural haematomas.

Semi-automatic external defibrillation.

Malignant arrhythmia, which is responsible for most of the out-of-hospital cardiac arrests, is ventricular fibrillation (VF). The best treatment of VF is a controlled electric shock on the chest administered in a short delay. The emergency medical technicians (EMTs) qualified to carry out this treatment in Belgium and in districts often succeed in arriving on the spot 8 minutes earlier than the people of the Service Mobile d'Urgence et de Réanimation (SMUR). The delegation of defibrillation to ambulance crew members however implies a specific teaching, training and a medical control. The Brussels experience shows that semi-automatic external defibrillation by EMT-Ds (SAED) is feasible when criteria for applying SAED in the pre-hospital phase are applicable.

[Eyelid drooping: diagnosis on the basis of an algorithm]. / Een hangend ooglid; diagnostiek op basis van een algoritme.

Five patients presented with eyelid drooping (blepharoptosis). A 26-year-old man with oculomotor disorders without anisocoria and a slow progressive course without fluctuations had a myogenic condition. His diplopia was alleviated by prism glasses. Surgical correction of the ptosis was planned. An 81-year-old man in whom the symptoms showed a course that varied over time had a disordered neuromuscular transmission that responded well to pyridostigmine. A 57-year-old man with oculomotor disorders and a dilated pupil on the affected side had an injury to the oculomotor nerve (and other cranial nerves), which remained stable after endovascular treatment of the causative aneurysm. A 22-year-old man had a constricted pupil (Horner's syndrome) and pain in the head and neck due to dissection of the internal carotid; his symptoms disappeared spontaneously. A 34-year-old woman had an isolated ptosis due to detachment of the aponeurosis of the M. levator palpebrae superioris following the chronic use of hard contact lenses; she was advised as to how to remove the lenses cautiously, to prevent further detachment. Eyelid drooping can have many causes. A systematic arrangement of the information gathered by a careful medical history and neurological examination often provides a reasonably accurate indication of the possible causes of the complaints.

The haemodynamic effects of two angiotensin converting enzyme inhibitors, enalaprilat and zofenoprilat, in the rat: evidence for the involvement of bradykinin.

Since angiotensin converting enzyme (ACE) metabolizes bradykinin, the hypotensive effect of ACE inhibitors could be partly due to an increased bradykinin activity. We therefore investigated the influence of HOE K86-4321 [D-Arg-(Hyp2-Thi5,8-DPhe7)-bradykinin], a selective bradykinin-2 receptor antagonist, on the effects of enalaprilat (0.3 and 3.0 mg/kg) and zofenoprilat (0.1 and 1.0 mg/kg) on the heart rate, mean arterial blood pressure, cardiac output and total peripheral resistance in rats. Both enalaprilat and zofenoprilat reduced mean arterial pressure (from 110 +/- 7 to 85 +/- 6 and from 108 +/- 9 to 72 +/- 9 mmHg, respectively; P less than 0.05) and total peripheral resistance (from 515 +/- 35 to 413 +/- 29 and from 495 +/- 45 to 310 +/- 25 x 10(-3) mmHg/litre per min per kg, respectively; P less than 0.05); the heart rate and cardiac output changed little. In the presence of HOE K86-4321, which by itself did not affect the haemodynamic variables measured, the effects of the two ACE inhibitors were significantly reduced. These results suggest that bradykinin-2 receptor-mediated vasodilation, although not involved in blood pressure regulation, influences the reduction in blood pressure induced by enalaprilat and zofenoprilat in normotensive rats. Furthermore, at comparable ACE-inhibiting doses, zofenoprilat was more effective in reducing mean arterial pressure, which might be related to the presence of a sulphydryl group.

Fatal methylene blue associated serotonin toxicity.

This is the first report of a fatal outcome from serotonin toxicity, precipitated by an interaction between methylene blue and venlafaxine. Methylene blue-associated serotonin toxicity has been described before but usually as mild toxicity. Its presentation after general anaesthesia may be atypical and therefore more difficult to diagnose. However, the syndrome is completely preventable if serotonin re-uptake inhibiting agents are stopped beforehand.