Key Aspects of Neurovascular Control Mediated by Specific Populations of Inhibitory Cortical Interneurons.

Inhibitory interneurons can evoke vasodilation and vasoconstriction, making them potential cellular drivers of neurovascular coupling. However, the specific regulatory roles played by particular interneuron subpopulations remain unclear. Our purpose was therefore to adopt a cell-specific optogenetic approach to investigate how somatostatin (SST) and neuronal nitric oxide synthase (nNOS)-expressing interneurons might influence the neurovascular relationship. In mice, specific activation of SST- or nNOS-interneurons was sufficient to evoke hemodynamic changes. In the case of nNOS-interneurons, robust hemodynamic changes occurred with minimal changes in neural activity, suggesting that the ability of blood oxygen level dependent functional magnetic resonance imaging (BOLD fMRI) to reliably reflect changes in neuronal activity may be dependent on type of neuron recruited. Conversely, activation of SST-interneurons produced robust changes in evoked neural activity with shallow cortical excitation and pronounced deep layer cortical inhibition. Prolonged activation of SST-interneurons often resulted in an increase in blood volume in the centrally activated area with an accompanying decrease in blood volume in the surrounding brain regions, analogous to the negative BOLD signal. These results demonstrate the role of specific populations of cortical interneurons in the active control of neurovascular function.

Terlipressin infusion induces ischemia of breast skin in a cirrothic patient with hepatorenal syndrome.

We report a case of a 65-year-old woman with hepatitis C virus-related decompensated cirrhosis with hepatorenal syndrome, treated by high dose of terlipressin. Few hours after the highest dose was started, the patient complained burning pain in breasts, followed by the development of extensive bilateral cyanosis of breast's skin. When terlipressin was immediately stopped, pain and skin cyanosis rapidly disappeared. The peculiarity of our case is that cyanosis did not develop in common peripheral sites (e.g. fingers, toes, etc.) but in an atypical area, as skin of the breasts. Probably, this particular behaviour could be explained by the anatomical position of her large size breasts, that resulting as an extremely sloping and stretching region thus filling the maximum effect of gravity.

On the synchronizing mechanisms of tetanically induced hippocampal oscillations.

gamma (30-100 Hz) and beta (10-30 Hz) oscillations follow tetanic stimulation in the CA1 region of the rat hippocampal slice. Pyramidal neurons undergo a slow depolarization after the tetanus and generate synchronous action potentials. The slow depolarization was previously attributed to metabotropic glutamate receptor (mGluR) activation. However, we found that this event was mediated by GABA(A) receptors, being blocked by bicuculline (50 microM) and accompanied by a dramatic drop in input resistance. Experiments with NMDA and non-NMDA glutamate receptor antagonists revealed that fast synaptic excitation was not necessary for oscillations. IPSPs were strongly depressed during the oscillations. Instead, synchronization was caused by field effects, as shown by: (1) Action potentials of pyramidal neurons proximal (<200 micrometer) to the stimulation site were often preceded by negative deflections of the intracellular potential that masked a net transmembrane depolarization caused by the population spike. (2) Pyramidal neurons located on the surface of the slice, where field effects are weak, fired repetitively but were not synchronized to the network activity. (3) A moderate decrease (50 mOsm) in artificial CSF (ACSF) osmolality did not affect the slow depolarization but increased oscillation amplitude and duration and recruited previously silent neurons into oscillations. (4) 50 mOsm increase in ACSF osmolality dramatically reduced, or abolished, post-tetanic oscillations. Phasic IPSPs, not detectable in proximal neurons, were present, late in the oscillation, in cells located 200-400 micrometer from the stimulation site and possibly contributed to slowing the rhythm during the gamma to beta transition.

Prolonged epileptiform bursting induced by 0-Mg(2+) in rat hippocampal slices depends on gap junctional coupling.

The transition from brief interictal to prolonged seizure, or 'ictal', activity is a crucial event in epilepsy. In vitro slice models can mimic many phenomena observed in the electroencephalogram of patients, including transition from interictal to ictaform or seizure-like activity. In field potential recordings, three discharge types can be distinguished: (1) primary discharges making up the typical interictal burst, (2) secondary bursts, lasting several hundred milliseconds, and (3) tertiary discharges lasting for seconds, constituting the ictal series of bursts. The roles of chemical synapses in these classes of burst have been explored in detail. Here we test the hypothesis that gap junctions are necessary for the generation of secondary bursts. In rat hippocampal slices, epileptiform activity was induced by exposure to 0-Mg(2+). Epileptiform discharges started in the CA3 subfield, and generally consisted of primary discharges followed by 4-13 secondary bursts. Three drugs that block gap junctions, halothane (5-10 mM), carbenoxolone (100 microM) and octanol (0.2-1.0 mM), abolished the secondary discharges, but left the primary bursts intact. The gap junction opener trimethylamine (10 mM) reversibly induced secondary and tertiary discharges. None of these agents altered intrinsic or synaptic properties of CA3 pyramidal cells at the doses used. Surgically isolating the CA3 subfield made secondary discharges disappear, and trimethylamine under these conditions was able to restore them.We conclude that gap junctions can contribute to the prolongation of epileptiform discharges.

Differential contribution of dopamine D2S and D2L receptors in the modulation of glutamate and GABA transmission in the striatum.

Compelling evidence indicates that the long (D2L) and the short (D2S) isoform of dopamine (DA) D2 receptors serve distinct physiological functions in vivo. To address the involvement of these isoforms in the control of synaptic transmission in the striatum, we measured the sensitivity to D2 receptor stimulation of glutamate- and GABA-mediated currents recorded from striatal neurons of three mutant mice, in which the expression of D2L and D2S receptors was either ablated or variably altered. Our data indicate that both isoforms participate in the presynaptic inhibition of GABA transmission in the striatum, while the D2-receptor-dependent modulation of glutamate release preferentially involves the D2S receptor. Accordingly, the inhibitory effects of the DA D2 receptor agonist quinpirole (10 microM) on GABA(A)-mediated spontaneous inhibitory postsynaptic currents (IPSCs)correlate with the total number of D2 receptor sites in the striatum, irrespective of the specific receptor isoform expressed. In contrast, glutamate-mediated spontaneous excitatory postsynaptic currents (EPSCs) were significantly inhibited by quinpirole only when the total number of D2 receptor sites, normally composed by both D2L and D2S receptors in a ratio favoring the D2L isoform, was modified to express only the D2S isoform at higher than normal levels. Understanding the physiological roles of DA D2 receptors in the striatum is essential for the treatment of several neuropsychiatric conditions, such as Parkinson's disease, Tourette's syndrome, schizophrenia, and drug addiction.

Contribution of NMDA and non-NMDA glutamate receptors to locomotor pattern generation in the neonatal rat spinal cord.

The motor programme executed by the spinal cord to generate locomotion involves glutamate-mediated excitatory synaptic transmission. Using the neonatal rat spinal cord as an in vitro model in which the locomotor pattern was evoked by 5-hydroxytryptamine (5-HT), we investigated the role of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in the generation of locomotor patterns recorded electrophysiologically from pairs of ventral roots. In a control solution, 5-HT (2.5-30 microM) elicited persistent alternating activity in left and right lumbar ventral roots. Increasing 5-HT concentration within this range resulted in increased cycle frequency (on average from 8 to 20 cycles min-1). In the presence of NMDA receptor antagonism, persistent alternating activity was still observed as long as 5-HT doses were increased (range 20-40 microM), even if locomotor pattern frequency was lower than in the control solution. In the presence of non-NMDA receptor antagonism, stable locomotor activity (with lower cycle frequency) was also elicited by 5-HT, albeit with doses larger than in the control solution (15-40 microM). When NMDA and non-NMDA receptors were simultaneously blocked, 5-HT (5-120 microM) always failed to elicit locomotor activity. These data show that the operation of one glutamate receptor class was sufficient to express locomotor activity. As locomotor activity developed at a lower frequency than in the control solution after pharmacological block of either NMDA or non-NMDA receptors, it is suggested that both receptor classes were involved in locomotor pattern generation.

"Torsade de pointes" during amiodarone infusion in a cirrhotic woman with a prolonged QT interval.

We describe an interesting case of a woman with decompensated cirrhosis, ischaemic heart disease and prolonged QT interval, who developed a new-onset atrial fibrillation. During amiodarone infusion a torsade de pointes occurred, which was immediately converted to sinus rhythm by synchronized cardioversion. A new episode of atrial fibrillation was treated with infusion of a beta-blocker (metoprolol) that restored sinus rhythm and normalized the QT interval. Delayed repolarization, frequently observed in ischaemic heart disease, cirrhosis and pro-arrhythmic drugs administration, represents the background for the development of torsade de pointes. Our report underlines that the potential harmfulness of a prolonged QT interval in cirrhotic patients is currently not perceived in its entirety, so that various categories of drugs affecting ventricular repolarization are rather thoughtlessly used in clinical practice without monitoring the QT interval. Thus, amiodarone should be avoided, if possible, or used with extreme care in arrhythmic patients with advanced liver disease. Moreover, beta-blockers may be considered the first-line treatment for rate-control during supraventricular tachyarrhythmias in cirrhotic patients with delayed repolarization.

Desensitization of AMPA receptors limits the amplitude of EPSPs and the excitability of motoneurons of the rat isolated spinal cord.

Intracellular recording was used to study the effect of cyclothiazide, a selective blocker of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor desensitization, on lumbar motoneurons of the rat isolated spinal cord. Cyclothiazide (25 microM) enhanced the responses to AMPA in a tetrodotoxin-insensitive fashion, without affecting those produced by N-methyl-D-aspartate or gamma-aminobutyric acid. Excitatory postsynaptic potentials (EPSPs) evoked by dorsal root stimulation were strongly potentiated in amplitude while paired-pulse depression (produced by applying pairs of pulses at 2 s interval) of the EPSP was decreased. In the presence of cyclothiazide the frequency of spontaneous synaptic events was greatly increased and network-driven bursting activity developed with eventual loss of electrical excitability. The present results suggest that pharmacological block of AMPA receptor desensitization led to strong excitation of motoneurons and indicate a physiological role of desensitization in protecting these nerve cells from overactivity.

Afferent inputs modulate the activity of a rhythmic burst generator in the rat disinhibited spinal cord in vitro.

Application of strychnine and bicuculline to the isolated spinal cord of the neonatal rat induces spontaneous bursting of regular rhythmicity (cycle period approximately 30 s). This phenomenon is important because it shows that a spinal network, made up by excitatory connections only, generates a very reliable rhythmic pattern. To find out how signals from the periphery or higher centres might influence the operation of the rhythmogenic network, the present experiments examined whether synaptic inputs from dorsal root (DR) or ventrolateral (VL) afferent fibers could modulate this spontaneous rhythmicity. This issue was addressed with intracellular recording from motoneurons or extracellular recording from ventral roots after eliciting bursting with strychnine plus bicuculline. Single electrical shocks (0.1 ms; intensity 1-4 times threshold) applied to one DR reset spontaneous bursting without altering its period or duration. Repetitive stimulations at periods ranging from 20 to 2 s entrained bursts on a 1:1 basis. Burst duration was shorter at lower stimulation periods whereas burst amplitude was unchanged. The lowest stimulation period compatible with burst entrainment depended on stimulus strength. At stimulation periods <2-s entrainment was always lost and spontaneous bursts unexpectedly returned even if electrical pulses still elicited ventral root reflexes. Such spontaneous bursts had similar properties as those recorded in the absence of electrical pulses. Analogous results were obtained with VL stimulations. It is concluded that the spinal rhythmogenic network was highly susceptible to external synaptic inputs, which paced burst generation whereas burst duration was adapted to interstimulus interval. A scheme is provided to explain the modulatory role of synaptic inputs as well as the escape of bursting from fast stimulus entrainment in terms of a rhythmogenic network functionally separated from reflex pathways activated by DR or VL tracts.

Localization of rhythmogenic networks responsible for spontaneous bursts induced by strychnine and bicuculline in the rat isolated spinal cord.

Spontaneous rhythmic bursting induced by coapplication of strychnine (1 microM) and bicuculline (20 microM) was observed with electrophysiological recording from pairs of lumbar ventral roots (usually L5) in an isolated preparation of the neonatal rat spinal cord. Bursting was insensitive to exogenously applied GABA or glycine, confirming that it was attributable to block of glycine and GABAA receptor-mediated inhibition. NMDA accelerated bursting in a dose-dependent manner. Complete coronal spinal transection at L3 or L6 level did not block bursting recorded from L5 or L2 roots, respectively. Gradual cutting of the cord along the midline through a sagittal plane preserved bursting activity in both disconnected sides but led to loss of synchronicity. Once the spinal cord was fully separated into left and right halves, regular bursting persisted on each side with no phase-coupling between the two preparations. Section along a frontal plane to remove dorsal horns and much of the central canal area did not affect burst frequency or left-to-right synchronicity, whereas it reduced burst duration. A quadrant preparation containing mainly a single ventral horn displayed enhanced burst frequency while bursts became very short events. Bath application of 5-hydroxytryptamine (30 microM) or NMDA (5 microM) increased burst frequency and decreased burst duration in all types of preparation except the isolated quadrants, in which brief bursts were accelerated but not shortened by these chemical agents. These results suggest that bursting induced by strychnine and bicuculline apparently relied on distinct mechanisms for burst triggering and intraburst structure. The first required a relatively smaller neuronal network that was confined to a ventral quadrant. Intraburst structure was dependent on a larger circuitry comprising either both ventral horns or one side of the spinal cord including more than two segments.

Extracellular K+ induces locomotor-like patterns in the rat spinal cord in vitro: comparison with NMDA or 5-HT induced activity.

Bath-application of increasing concentrations of extracellular K+ elicited alternating motor patterns recorded from pairs of various lumbar ventral roots of the neonatal rat (0-2 days old) spinal cord in vitro. The threshold concentration of K+ for this effect was 7.9 +/- 0.8 mM (mean +/- SD). The suprathreshold concentration range useful to evoke persistent motor patterns (lasting >/=10 min) was very narrow ( approximately 1 mM) as further increments elicited only rhythmic activity lasting from 20 s to a few minutes. On average, the fastest period of rhythmic patterns was 1.1 +/- 0.3 s. Intracellular recording from lumbar motoneurons showed that raised extracellular K+ elicited membrane potential oscillations with superimposed repetitive firing. In the presence of N-methyl--aspartate (NMDA) or non-NMDA receptor blockers [R(-)-2-amino-phosphonovaleric acid or 6-cyano-7-nitroquinoxaline-2,3-dione, respectively] extracellular K+ increases could still induce motor patterns although the threshold concentration was raised. Serotonin (5-HT) also induced alternating motor patterns (threshold 15 +/- 7 microM) that were consistently slower than those induced by high K+ or NMDA. Ritanserin (1 microM) prevented the locomotor-like activity of 5-HT but not that of high K+ provided the concentration of the latter was further increased. Subthreshold concentrations of K+ became effective in the presence of subthreshold doses of 5-HT or NMDA, indicating mutual facilitation between these substances. The fastest pattern frequency was observed by raising K+ or by adding NMDA. In the presence of 5-HT, the pattern frequency was never as fast even if NMDA (or high K+) was coapplied. Furthermore, application of 5-HT significantly slowed down the K+- or NMDA-induced rhythm, an effect strongly potentiated in the presence of ritanserin. It is suggested that the operation of the spinal locomotor network was activated by rises in extracellular K+, which presumably led to a broad increase in neuronal excitability. Whenever the efficiency of excitatory synaptic transmission was diminished (for example by glutamate receptor antagonism), a larger concentration of K+ was required to evoke locomotor-like patterns. The complex effect (comprising stimulation and inhibition) of 5-HT on alternating pattern generation appeared to result from a dual action of this substance on the spinal locomotor network.

Spontaneous rhythmic bursts induced by pharmacological block of inhibition in lumbar motoneurons of the neonatal rat spinal cord.

1. The effects of blocking gamma-aminobutyric acid- and glycine-mediated synaptic transmission by bicuculline and strychnine on the neonatal rat isolated spinal cord were investigated by intracellular recording from motoneurons with the use of current-clamp and voltage-clamp techniques and by extracellular recording from homologous ventral roots of the L5 segment. 2. Bicuculline per se evoked irregular bursts of motoneuron membrane potential, often comprising individual events fused together. Strychnine alone did not elicit spontaneous bursting in the large majority of preparations. Simultaneous application of bicuculline and strychnine consistently induced regular rhythmic bursts (frequency approximately 2 per min, duration approximately 7 s), comprising a rapid depolarization followed by large-amplitude oscillations. 3. Burst frequency, duration, and intraburst oscillation time course were independent of motoneuron membrane potential. Burst and oscillation amplitude decreased with membrane depolarization and, under voltage-clamp conditions, inverted polarity near 0 mV. 4. The regular bursts produced by bicuculline and strychnine were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione, tetrodotoxin, or Cd2+. 5. N-methyl-D-aspartate antagonists [R-5-aminophosphonovalerate or 3-((RS)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate (CPP)] reversibly blocked or slowed down bursting induced by bicuculline and strychnine. Addition of cyclothiazide to the bicuculline and strychnine solution increased bursting frequency while preserving the regular burst structure; under these conditions bursts became insensitive to CPP. 6. In the presence of bicuculline and strychnine, 5-hydroxytryptamine (5-HT) increased burst frequency and decreased burst duration in a dose-dependent fashion. 7. In the presence of bicuculline and strychnine, L5 ventral roots developed synchronous rhythmic activity with a time course similar to that recorded from individual motoneurons. The rhythmic activity was accelerated by 5-HT on both roots, in accordance with observations on single motoneurons. 8. Rhythmic bursts thus appear to result from large, synchronous synaptic events generated by a network modulated by 5-HT and highly sensitive to variations in efficacy of glutamatergic synaptic transmission. These results show that in the rat spinal cord highly patterned motor output can occur despite block of inhibition.

Pharmacological block of the electrogenic sodium pump disrupts rhythmic bursting induced by strychnine and bicuculline in the neonatal rat spinal cord.

The cellular mechanisms underlying rhythmic bursts induced in the isolated neonatal rat spinal cord by bath application of strychnine and bicuculline (which block glycine- and gamma-aminobutyric acid-A-receptor-mediated inhibition, respectively) were probed with pharmacological tools. Such spontaneous bursts were recorded either intracellularly from lumbar motoneurons or extracellularly from ventral roots. As previously described, these network-driven events consisted of large-amplitude depolarizations arising abruptly from baseline with a highly regular period (on average 28 s). Burst episodes (lasting on average 7 s) comprised several oscillations and appeared synchronously on flexor and extensor motoneuron pools of both sides of the spinal cord. Their diffuse location made convenient to use bath-applied substances in the attempt to selectively block distinct membrane processes operating through the network. Application of apamin (0.4 microM) shortened both cycle period and burst duration without changing their regular rhythmicity. Similar results were obtained with carbachol (10 microM). Cs+ (4 mM) reversibly hyperpolarized the motoneuron membrane potential and largely increased burst duration, which was characterized by a long series of repetitive oscillatory waves. Cycle period and rhythmicity remained unaltered. Ouabain (10 microM), strophanthidin (4 microM), or K(+)-free solutions disrupted rhythmic bursting, which was fragmented into irregularly occurring paroxysmal activity mixed with short depolarizing events, still developing simultaneously on both sides of the spinal cord. Bursting activity eventually ceased after approximately 30-40 min of application of ouabain or strophanthidin. Prolonged washout of strophanthidin or K(+)-free solutions reestablished regular bursting patterns, whereas no recovery from ouabain was observed. At the time of strong depression of bursting, it was still possible to evoke bursts by single electrical pulses applied to the segmental dorsal root. Antidromic spikes of motoneurons could still be evoked by ventral root stimulation. These results demonstrate that, in a spinal bursting network mainly made up by excitatory processes, blockers of slow Ca(2+)-dependent K+ currents, such as apamin or carbachol, or of the slow inward rectifier, such as Cs+, did not suppress rhythmicity, suggesting that these conductances simply contributed to control cycle period and/or burst duration. Conversely, pharmacological blockers of the electrogenic Na+ pump such as ouabain, strophanthidin, or K(+)-free solutions severely disrupted all characteristics of rhythmic bursting. It is proposed that the operation of the electrogenic Na+ pump of premotoneurons was a crucial element for rhythmic bursting.

Ictal epileptiform activity is facilitated by hippocampal GABAA receptor-mediated oscillations.

The cellular and network mechanisms of the transition of brief interictal discharges to prolonged seizures are a crucial issue in epilepsy. Here we used hippocampal slices exposed to ACSF containing 0 Mg(2+) to explore mechanisms for the transition to prolonged (3-42 sec) seizure-like ("ictal") discharges. Epileptiform activity, evoked by Shaffer collateral stimulation, triggered prolonged bursts in CA1, in 50-60% of slices, from both adult and young (postnatal day 13-21) rats. In these cases the first component of the CA1 epileptiform burst was followed by a train of population spikes at frequencies in the gamma band and above (30-120 Hz, reminiscent of tetanically evoked gamma oscillations). The gamma burst in turn could be followed by slower repetitive "tertiary" bursts. Intracellular recordings from CA1 during the gamma phase revealed long depolarizations, action potentials rising from brief apparent hyperpolarizations, and a drop of input resistance. The CA1 gamma rhythm was completely blocked by bicuculline (10-50 microm), by ethoxyzolamide (100 microm), and strongly attenuated in hyperosmolar perfusate (50 mm sucrose). Subsequent tertiary bursts were also blocked by bicuculline, ethoxyzolamide, and in hyperosmolar perfusate. In all these cases intracellular recordings from CA3 revealed only short depolarizations. We conclude that under epileptogenic conditions, gamma band oscillations arise from GABA(A)ergic depolarizations and that this activity may lead to the generation of ictal discharges.

Dynamic modulation of excitation and inhibition during stimulation at gamma and beta frequencies in the CA1 hippocampal region.

Fast oscillations at gamma and beta frequency are relevant to cognition. During this activity, excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs) are generated rhythmically and synchronously and are thought to play an essential role in pacing the oscillations. The dynamic changes occurring to excitatory and inhibitory synaptic events during repetitive activation of synapses are therefore relevant to fast oscillations. To cast light on this issue in the CA1 region of the hippocampal slice, we used a train of stimuli, to the pyramidal layer, comprising 1 s at 40 Hz followed by 2--3 s at 10 Hz, to mimic the frequency pattern observed during fast oscillations. Whole cell current-clamp recordings from CA1 pyramidal neurons revealed that individual stimuli at 40 Hz produced EPSPs riding on a slow biphasic hyperpolarizing-depolarizing waveform. EPSP amplitude initially increased; it then decreased concomitantly with the slow depolarization and with a large reduction in membrane resistance. During the subsequent 10-Hz train: the cells repolarized, EPSP amplitude and duration increased to above control, and no IPSPs were detected. In the presence of GABA(A) receptor antagonists, the slow depolarization was blocked, and EPSPs of constant amplitude were generated by 10-Hz stimuli. Altering pyramidal cell membrane potential affected the time course of the slow depolarization, with the peak being reached earlier at more negative potentials. Glial recordings revealed that the trains were associated with extracellular potassium accumulation, but the time course of this event was slower than the neuronal depolarization. Numerical simulations showed that intracellular chloride accumulation (due to massive GABAergic activation) can account for these observations. We conclude that synchronous activation of inhibitory synapses at gamma frequency causes a rapid chloride accumulation in pyramidal neurons, decreasing the efficacy of inhibitory potentials. The resulting transient disinhibition of the local network leads to a short-lasting facilitation of polysynaptic EPSPs. These results set constraints on the role that synchronous, rhythmic IPSPs may play in pacing oscillations at gamma frequency in the CA1 hippocampal region.

A reappraisal of the role of methimazole and other factors on the efficacy and outcome of radioiodine therapy of Graves' hyperthyroidism.

The outcome of radioiodine therapy of Graves' hyperthyroidism was retrospectively evaluated in 274 consecutive patients treated from 1975 to 1984. At 1-yr follow-up, permanent hypothyroidism occurred in 36.9% of patients and the cumulative incidence of hypothyroidism progressively increased up to 79.3% after 7-10 yr. At the end of the follow-up period, 148 patients (54%) were hypothyroid, 115 (42%) euthyroid and 11 (4%) still hyperthyroid. The prevalence of hypothyroidism was significantly higher in patients with small goiters (less than or equal to 50 g) than in those with large goiters (greater than 90 g). Moreover, hypothyroidism was more frequent in patients with high thyroglobulin antibodies titers (greater than or equal to 1:25,600) than in those with low titers or negative tests, and occurred earlier in the former group than in the latter ones Correction of thyrotoxicosis was obtained after the administration of a single dose of 131I in 187 patients (63.6%); 69 patients required two doses and 11 three or more doses. Seven patients refused further treatment with 131I after the first dose. In an effort to identify possible factors affecting the efficacy of 131I therapy, we evaluated the results obtained after the administration of the first dose of radioiodine. We found that large goiters, rapid iodide turnover and adjunctive therapy with methimazole shortly after radioiodine were associated with a higher rate of persistence of thyrotoxicosis, whereas an increased prevalence of hypothyroidism was observed in patients with small goiters and in those not treated with methimazole up to one week after 131I.(ABSTRACT TRUNCATED AT 250 WORDS)