Delayed-Onset Hypnopompic Visual Hallucinations 20 Years After Initiation of Propranolol Therapy for Systemic Hypertension: A Case Report.

BACKGROUND Visual hallucinations occur in a variety of clinical settings and may be extremely troubling to individuals experiencing them. We report a case of delayed-onset visual hallucinations 20 years after initiation of medical therapy to highlight the importance of considering iatrogenic causes when managing such patients. CASE REPORT An 88-year-old woman presented with recurring hypnopompic formed visual hallucinations for the past 20 years. These hallucinations began 20 years after she was started on propranolol to treat her systemic hypertension 40 years earlier. Her hallucinations began with plants and insects. They later progressed to vivid, detailed human figures of different races, ages, genders, and religious personnel such as monks, nuns, and priests. The hallucinations occurred almost daily and upon awakening from sleep. Each episode of visual hallucinations lasted for 10 to 20 seconds, occurring when she awoke after dozing off, multiple times each day. The patient became mentally distressed by her visual hallucinations and began to attribute them to supernatural causes. After substituting her propranolol with atenolol, the patient's hallucinations decreased dramatically and became rare and non-frightening. The dramatic improvement suggested a drug-induced etiology. CONCLUSIONS Our case illustrates the importance of considering iatrogenic causes in the diagnosis of visual hallucinations and having a high index of suspicion, even if the onset of symptoms is delayed for many years after initiation of therapy. This iatrogenic condition can easily be rectified to drastically improve the quality of life in affected patients.

Mucus fishing syndrome.

Mucus fishing syndrome is a chronic inflammatory ocular surface condition characterised by repetitive self-extraction of mucous strands from the eye.A man in his 30s presented with bilateral ocular redness, itch, irritation, tearing and sticky mucoid discharge for 3 months. Examination disclosed bilateral bulbar and tarsal conjunctival injection. Fluorescein staining disclosed a well-circumscribed area of tarsal conjunctival epithelial defect near the inferior lacrimal punctum in both eyes. The patient admitted to a habit of mechanically removing mucus from his eyes several times a day. Demonstration of the mucus extraction process disclosed direct contact of his fingers with the excoriated tarsal conjunctiva in each eye. He was diagnosed with mucus fishing syndrome and his condition resolved within a month after he stopped fishing mucus from his eyes and had a course of topical antibiotics and steroids.Mucus fishing syndrome is an important diagnostic consideration in patients with chronic conjunctivitis.

Tracking gastrointestinal transit of solids in aged rats as pharmacological models of chronic dysmotility.

BACKGROUND: Dysmotility in the gastrointestinal (GI) tract often leads to impaired transit of luminal contents leading to symptoms of diarrhea or constipation. The aim of this research was to develop a technique using high resolution X-ray imaging to study pharmacologically induced aged rat models of chronic GI dysmotility that mimic accelerated transit (diarrhea) or constipation. The 5-hydroxytryptamine type 4 (5-HT4 ) receptor agonist prucalopride was used to accelerate transit, and the opioid agonist loperamide was used to delay transit. METHODS: Male rats (18 months) were given 0, 1, 2, or 4 mg/kg/day prucalopride or loperamide (in dimethyl sulfoxide, DMSO) for 7 days by continuous 7-day dosing. To determine the GI region-specific effect, transit of six metallic beads was tracked over 12 h using high resolution X-ray imaging. An established rating scale was used to classify GI bead location in vivo and the distance beads had propagated from the caecum was confirmed postmortem. KEY RESULTS: Loperamide (1 mg/kg) slowed stomach emptying and GI transit at 9 and 12 h. Prucalopride (4 mg/kg) did not significantly alter GI transit scores, but at a dose of 4 mg/kg beads had moved significantly more distal than the caecum in 12 h compared to controls. CONCLUSIONS & INFERENCES: We report a novel high-resolution, non-invasive, X-ray imaging technique that provides new insights into GI transit rates in live rats. The results demonstrate that loperamide slowed overall transit in aged rats, while prucalopride increased stomach emptying and accelerates colonic transit.

Effects of STN lesions on simple vs choice reaction time tasks in the rat: preserved motor readiness, but impaired response selection.

The subthalamic nucleus (STN) is a key structure within the basal ganglia, inactivation of which is a current strategy for treating parkinsonism. We have previously shown that bilateral lesions of the STN or pharmacological inactivation of this structure in the rat induce multiple deficits in serial reaction time tasks. The aim of the present study was to investigate further a possible role for the STN in response preparatory processes by using simple (SRT) and choice (CRT) reaction time tasks. In contrast to the CRT procedure, the information related to the location of where the response had to be made was given in advance in the SRT procedure. Accurate performance on these tasks requires not only the selection of the correct response (i.e. which response), but also preparation in order to perform when required. A comparison between the two tasks allows assessment of whether STN lesions affect which response ("which") or when to perform it ("when"). As previously observed in these procedures, the responses were faster as a function of the variable foreperiod preceding the trigger stimulus. This well-known effect, termed "motor readiness, was maintained after STN lesions, suggesting that STN lesions did not affect the "when" phase of action preparation. However, while performance on the SRT was faster than on the CRT task preoperatively, STN lesions slowed RTs and abolished the beneficial effect of advance information, suggesting a deficit in the selection ("which") phase of response preparation. This deficit in the selection phase was further supported by deficits in accuracy of responding after STN lesions, as well as increases in mislocated premature responding in the SRT condition. Together, these results suggest that the STN plays an important role in response preparatory processes, including response selection and inhibitory control processes.

Lesion of the subthalamic nucleus or globus pallidus does not cause chaotic firing patterns in basal ganglia neurons in rats.

The basal ganglia appears to play an important role in behavioral selection. One model (Berns and Sejnowski's) of basal ganglia function argues that the subthalamic nucleus plays a critical role in this selection process and predicts that the subthalamic nucleus prevents the basal ganglia and its re-entrant circuits with the thalamus and cerebral cortex from developing chaotic oscillations. We tested this prediction by generating three-dimensional sequential interval state space plots of the spike trains from 684 globus pallidus, substantia nigra pars reticulata and subthalamic neurons recorded in intact, subthalamic lesioned and globus pallidus lesioned rats, neurons which had previously been analyzed with more standard statistical methods. Only 1 neuron (a globus pallidus neuron in a subthalamic lesioned rat) of the 684 showed a chaotic attractor. In no case did subthalamic nucleus lesion induce a chaotic firing pattern elsewhere in the basal ganglia.

Subthalamic nucleus lesions induce deficits as well as benefits in the hemiparkinsonian rat.

Lesions of the subthalamic nucleus can restore some imbalances in motor output of the basal ganglia induced by nigrostriatal dopamine depletion, and have been proposed as a potential therapy for Parkinson's disease. Although there is substantial supporting evidence from experimental studies in both rats and primates, there is less information on the effects of subthalamic lesions alone. In order to characterize potential side effects, the present study evaluates the behavioural effects of unilateral excitotoxic lesions of the subthalamic nucleus in rats that have previously received either unilateral saline or 6-hydroxydopamine injections into the nigrostriatal bundle on the same side. The 6-hydroxydopamine lesions induced ipsilateral orientation asymmetries in head position and body axis bias, rotational asymmetries following injections of direct or indirect dopamine agonists, neglect of contralateral stimuli, and a reduction in the numbers of pellets retrieved with the contralateral paw in a skilled reaching task. Subsequent excitotoxic lesions of the subthalamic nucleus reduced (but did not abolish) rotational asymmetries, had no effects on the measures of neglect and skilled paw-reaching, and produced contralateral orientation biases in head turning and body axis curling. Rats that received subthalamic lesions alone exhibited de novo impairments comprising contralateral biases in the orientation tests. These results support a neuromodulatory role of the subthalamic nucleus in regulating motor outputs of the basal ganglia, and caution that there may be distinct side effects of the lesion by itself. Whereas some impairments attributable to dopamine depletion may be alleviated by subthalamic manipulations, other symptoms are not, or may even be aggravated.

Occupational health and safety in the biotechnology industry--a survey of practicing professionals.

A survey was created to gauge how health and safety (H&S) resources are allocated in the biotechnology industry and to help understand the concerns of industry H&S professionals. A questionnaire was distributed to "the person most responsible for health and safety" at 34 companies; 12 commercial firms responded. Nearly 68% of the work force monitored did not fall into any biohazard classification. Almost 80% of work involving biohazards was considered "exempt" or "BL-1" under the Centers for Disease Control and Prevention classification system, indicating that most work was performed involving organisms of low pathogenic potential. H&S program development and administration is mature; 100% of respondents report having written programs for chemical, biological, and physical hazards. Chemical safety programs occupied, on average, the greatest percentage of the H&S professionals' time (46%), followed by biosafety (29.6%) and physical hazards (16.4%). The person most responsible for H&S averaged 65% of work time on H&S issues, while only 25% described their full-time responsibilities as H&S related. Staffing levels for companies with more than about 100 technical workers approximated 1.0-1.5 full-time H&S staff equivalents per 100 technical workers. This figure compares favorably with levels reported in a benchmarking survey of hospitals. Investigation into accident rates as a measure of H&S program effectiveness suggests that the biotechnology industry is a relatively safe one. Lost time injury and illness rates were significantly lower for the 12 participating companies than the accident frequency rates in the Standard Industrial Classification codes selected for comparison.

Neostriatal modulation of motor cortex excitability.

The influence of the basal ganglia motor loop on motor cortex function was examined by pharmacologically altering neostriatal activity while monitoring the electrical stimulation thresholds for eliciting movements of the ipsilateral and contralateral motor cortex in ketamine anesthetized rats. Repeated unilateral intraneostriatal infusions (1-3) of the glutamate agonist, kainic acid (0.1 microliter, 75 ng), or glutamate (0.3 microliter, 1.65 micrograms) reliably increased ipsilateral but not contralateral cortical thresholds. Single infusions of kainic acid (0.3 microliter, 150 or 225 ng) elevated ipsilateral cortical thresholds for 30-45 min; with glutamate (0.3 microliter, 1.65 micrograms), the change lasted less than 10 min. Antidromically identified striatonigral projection neurons (n = 8) located approximately 500 microM from the infusion cannula, showed either increased firing (n = 4) for less than 10 min following glutamate infusion or no change from their non-firing state (n = 4). Non-antidromically activated neurons (n = 3) were all excited by the infusion, although an interval of inhibition preceded or followed the excitation in two cases. Infusions (0.3 microliter) of inhibitory agents (GABA, 31 and 310 ng; muscimol 34.2 ng; and DNQX 34.2 ng) did not alter cortical threshold, nor did saline vehicle. Lesion of the ventrolateral but not ventromedial thalamic nucleus prevented the modulation of cortical thresholds following intraneostriatal infusion of 225 ng kainic acid. Thus the neostriatal alteration of cortical thresholds indicates a modulation of cortical excitability via thalamic projections and not the outcome of competing descending cortical and neonstriatal influences converging on motorneurons. These results suggest that tonic feedforward modulation of the motor cortex and the pyramidal tract by the basal ganglia can be inhibitory.

Subthalamic nucleus and globus pallidus lesions alter activity in nigrothalamic neurons in rats.

Lesions of the subthalamic nucleus or the globus pallidus altered the response of substantia nigra pars reticulata neurons (antidromically identified as projecting to the thalamus) to electrical stimulation of the frontal agranular cortex. In intact animals, cortical stimulation evokes three independent responses (excitation, inhibition, excitation) that may occur singly or in various combinations. The independence of the various responses, especially the temporally coincident excitatory and inhibitory responses, suggests that the net inhibitory and excitatory pathways carrying these signals from the cortex may converge to varying degrees on individual nigrothalamic neurons. Subthalamic lesions increased total response duration (from 28.4 to 39.7 ms), increased the duration of inhibition (from 18 to 30 ms), decreased the occurrence of excitatory responses, and decreased the intensity of the second excitation (from 1.1 to 0.6 spikes/s). Lesion of the globus pallidus also increased total response duration (up to 38 ms), but by increasing the duration of the second excitation (from 15.1 up to 23.8 ms). The intensity of the second excitation (from 1.1 to 1.5 spikes/stimulus) and the number of cells showing the first and second excitations also increased. The incidence, but not the duration, of the inhibition increased. The mean firing rate increased after subthalamic nucleus lesion (34.2 spikes/s) as compared to intact (27.0) or globus pallidus lesion (25.6). These changes may reflect changes in the relative contribution of the five different pathways transmitting information from the cortex to the substantia nigra. In all cases the cortico-striato-nigral pathway is largely intact.(ABSTRACT TRUNCATED AT 250 WORDS)

Subthalamic nucleus lesion regularizes firing patterns in globus pallidus and substantia nigra pars reticulata neurons in rats.

Subthalamic nucleus lesion altered the statistical properties of the firing patterns of globus pallidus and substantia nigra pars reticulata neurons recorded in urethane anesthetized rats by increasing the proportion of cells in both structures that fired with a very highly regular pattern (from approximately 25% to approximately 50%). In all cases, the most regularly firing neurons fired at a higher mean rate than did more slowly firing neurons. In contrast, globus pallidus lesion shifted the pattern of substantia nigra neurons towards more irregular firing and induced a bursty pattern in two neurons.

Alteration of neuronal responses in the subthalamic nucleus following globus pallidus and neostriatal lesions in rats.

Kainic acid (2-4 days) or ibotenic acid (7-9 days) lesions of the globus pallidus or neostriatum altered the responsiveness of subthalamic nucleus neurons to electrical stimulation of the agranular frontal cortex. Three changes in responsiveness were seen following pallidal lesion: a) An increase in the proportion of responding cells as compared to controls (approximately 90% vs. 60%); b) an increase in the total duration of the evoked response (62.5 ms vs. 28.6 ms); 3) an increase in magnitude of response (9.76 spikes per stimulus vs. 3.24). Both an increase in firing rate (17.94 spikes/s vs. 8.23) and a change to a bursty spontaneous firing pattern were seen. Lesion of the neostriatum had fewer but opposite effects including decreased firing rate (7.21 spikes/s) and decreased total response duration (18.9 ms). These results suggest that the normal tonic inhibition of the subthalamic nucleus by the globus pallidus may play an important role in controlling subthalamic neuronal spontaneous activity and responsiveness. The neostriatum may influence the subthalamic nucleus via the globus pallidus. Globus pallidus lesions may have important consequences on the specificity of cortical control of the subthalamic nucleus and may alter subthalamic influence on basal ganglia output.

Auto- and cross-correlation analysis of subthalamic nucleus neuronal activity in neostriatal- and globus pallidal-lesioned rats.

Statistical analyses (autocorrelation and first-order interstimulus interval) were conducted on the spontaneous activity of over 420 subthalamic neurons recorded in 5 groups (control, large globus pallidus kainic acid lesion, partial globus pallidus kainic acid lesion, partial globus pallidus ibotenic acid lesion and neostriatal lesion) of anesthetized rats. Cross-correlation and peristimulus time histogram (to frontal motor cortex stimulation at 0.7 mA) analyses were conducted on pairs (n = 58) of subthalamic neurons recorded simultaneously on a single microelectrode. Lesion of the globus pallidus increased spontaneous firing rate as compared to controls and shifted the pattern of spontaneous activity from either a regular or irregular pattern to a markedly bursting pattern. Neostriatal lesion reduced firing rate and reduced the likelihood of highly regular firing. In control, neostriatal and partial lesioned animals, approximately 1 in 3 pairs of neurons showed correlated firing. The correlations were joint increased probabilities of firing over intervals of 200-400 ms, suggesting a shared excitatory input. No short-interval (less than 10 ms) correlations were seen. Large globus pallidus lesion increased the likelihood of correlated firing (12 of 16 pairs). In all groups of animals the peristimulus time histograms (PSTHs) to motor cortex stimulation were more similar than would be expected by chance and pairs of neurons showed the same increases in response following globus pallidus lesion. Thus adjacent neurons share common cortical inputs and responsiveness to those inputs. These changes indicate that the globus pallidus influences the spontaneous firing rate and pattern of subthalamic neurons as well as the degree of correlated firing of adjacent neurons.

The role of the subthalamic nucleus in the response of globus pallidus neurons to stimulation of the prelimbic and agranular frontal cortices in rats.

We investigated how the cerebral cortex can influence the globus pallidus by two routes: the larger, net inhibitory route through the neostriatum and the separate, smaller, net excitatory route through the subthalamic nucleus. Stimulation (0.3 and 0.7 mA) of two regions of frontal agranular (motor) cortex and of the medial orbitofrontal cortex centered in the prelimbic cortex typically elicited one or more of the following extracellularly recorded responses in over 50% of tested cells: an initial excitation (approximately 6 ms latency), a short inhibition (15 ms latency) and a late excitation (29 ms latency). Some other cells responded with an excitatory response only (18 ms latency). The excitatory responses largely arise from the subthalamic route. Kainic acid or electrolytic lesion of the subthalamic nucleus eliminated most excitatory responses and greatly prolonged the duration (16 vs 50 ms) of the inhibition. Subthalamic neurons typically showed one or more of the following responses to cortical stimulation: an early excitatory response (4 ms latency), an inhibitory period (9 ms) and a late excitatory response (16 ms). The early response was seen after motor cortex but not prelimbic stimulation. The timing of the globus pallidus and subthalamic responses suggest the operation of a reciprocal inhibitory/excitatory pathway. Two reciprocal interactions were indicated. First, pallidal inhibition may disinhibit the subthalamus and, via a feedback pathway onto the same pallidal cells, act to terminate the neostriatal-induced inhibition. Second, there may be a feedforward pathway from pallidal cells to subthalamic neurons to a different group of pallidal cells. This pathway could act to suppress competing responses. Thus the subthalamus may have three actions: 1) an early direct cortical and 2,3) later reciprocal feedforward and feedback excitatory antagonism of the neostriatal mediated inhibition of globus pallidus.

Histological and ultrastructural evidence that D-amphetamine causes degeneration in neostriatum and frontal cortex of rats.

D-Amphetamine sulfate, continuously administered for 3 days subcutaneously via an implanted minipump, induced neural degeneration in Long-Evans and Sprague-Dawley rats at doses between 20 and 60 mg/kg/day. Using Fink-Heimer silver staining, axonal degeneration was detected in the neostriatum and the dorsal agranular insular cortex and degenerating pyramidal cells were observed in portions of the somatosensory neocortex in both strains. In contrast, dense axonal degeneration largely confined to layers 2 and 3 of frontal motor areas (Fr1, Fr2 and Fr3 of Zilles36) with occasional degenerating cells was seen reliably in Long-Evans rats but rarely in Sprague-Dawley rats. In the electron microscope, cortical degeneration consisted mainly of disrupted cell bodies and dark processes, including axons making asymmetric synapses. Damage in all cortical areas represents damage to non-monoamine neurons and processes since tyrosine hydroxylase and serotonin immunolabeling were normal. In contrast, the damage in neostriatum probably includes damage to dopamine axonal terminals since tyrosine hydroxylase immunolabeling was patchy with many swollen and distorted labeled axons. Serotonin and Leu-enkephalin labeling were normal. Electron microscopy confirmed that the neostriatum contained many tyrosine hydroxylase-labeled axons that were swollen and disrupted, although other labeled processes made normal symmetric synapses onto spines and dendrites. Additional degeneration found only in amphetamine-treated rats included many dark, shrunken profiles. Some of these appeared to be astrocytic processes and a few were myelinated axons, suggesting that some non-monoamine, possibly cortical afferents, are also degenerating in the neostriatum. Since similar degrees of behavioral activation, weight loss and lethality were seen in both strains, a genetic predisposition constrain amphetamine-induced motor cortex damage but not neostriatal damage.

Multisite recording of brain field potentials and unit activity in freely moving rats.

A technique has been developed to record from 16 different brain sites of the freely moving rat using subminiature MOSFET preamplifiers. The high input impedance, small size, durability and light weight of the amplifiers and connecting cable allows high quality multisite recording of field potentials and unit activity. In addition, a movable headstage for positioning multiple microelectrodes is described. The compact recording system permits one to construct neocortical EEG maps, instant depth profiles of evoked and spontaneous field data, and to study neuronal synchrony of distant cell populations.

Antidromically identified striatonigral projection neurons in the chronically implanted behaving rat: relations of cell firing to amphetamine-induced behaviors.

The effects of systematically administered amphetamine (0.25-5.0 mg/kg, sc) on neostriatal neurons recorded in chronically implanted behaving rats were studied. Projection neurons, identified by antidromic activation from the substantia nigra, fired very infrequently during most predrug behaviors (e.g., median rate, 0.02 spikes per second during locomotion; 17 of 18 fired less than 1 spike per second during all rated behaviors). Nonantidromic cells also tended to fire slowly (median rate, 0.02 spikes per second during locomotion; 20 of 24 cells fired less than 1 spike per second). Cells of both type showed up to 10-fold variations in firing rate across behaviors. For most neurons, amphetamine caused a reduction in the firing rate during related pre- and postdrug behaviors. For instance, the firing rate of 28 of 42 neurons was reduced during the initial amphetamine-induced locomotion as compared with the rate during predrug locomotion. Moreover, with the higher doses of amphetamine, there was a further reduction in firing rate corresponding to the transition from locomotion to stereotypies. In contrast to previous studies, which suggest that amphetamine generally increases neostriatal firing rate in behaving animals, these results suggest that amphetamine inhibits the numerous slowly firing neostriatal neurons, many of which were identified as projection neurons. Thus amphetamine alters the magnitude and pattern of neostriatal control of its neural targets.

Dopamine D1 heteroreceptors on striatonigral axons are not stimulated by endogeneous dopamine either tonically or after amphetamine: evidence from terminal excitability.

The role of dopamine D1 heteroreceptors located on the axon terminals of striatonigral neurons was investigated. Local infusion of the direct acting, specific dopamine D1 agonist, R-SKF 38393, into the substantia nigra terminal field of antidromically identified neostriatal projection neurons decreased the electrical excitability of these axons. This effect was dose-dependent and could be partially reversed by subsequent infusion of the specific D1 antagonist, R-SCH 23390. In contrast, excitability was not affected by the systemic administration of SCH-23390 (0.3 and 0.6 mg/kg, iv), or the non-specific antagonist haloperidol (0.2 mg/kg, iv). Since activation of the D1 heterorecptors by R-SKF 38393 decreased excitability, the inability of these antagonists to modify excitability indicates that endogenous dopamine does not tonically activate these receptors. Systemic administration of the indirect acting agonist, amphetamine (1.0 and 5.0 mg/kg, iv) also failed to change terminal excitability suggesting that, even when unnaturally high levels of dopamine are released in the substantia nigra, endogenous dopamine does not affect neostriatal axons terminating in the substantia nigra. Thus it is unlikely that endogeneous dopamine modulates neostriatal control of the substantia nigra through these presynaptic terminal D1 heteroreceptors.