Antiparkinsonian and anti-levodopa-induced dyskinesia effects obtained by stimulating the same site within the GPi in PD.
Explore the source record for details and available documents.
Antiparkinson Agents↗
Biomedical subjects
A Stefani
Publications and source records attributed to A Stefani.
Cardiac rhabdomyosarcoma: a clinicopathologic and electron microscopy study.
A 66-year-old woman was admitted to the hospital with a neurological syndrome characterized by ataxia and diplopia. Magnetic resonance of the brain documented an ischemic medullary lesion. Examination of the heart revealed a grade 2/6 systolic murmur at the left sternal border and apex that radiated towards the axilla. The echocardiography study showed a mild mitral regurgitation, and an abnormally enlarged posterior papillary muscle was found in the left ventricle. Two weeks after admission, the patient died suddenly due to a stroke. At autopsy, a recent vast swollen ischemic cerebral infraction was found. Furthermore, two old infarcts were observed in the spleen. A cardiac examination showed a white-gray ulcered mass in the left ventricle and histological analysis revealed a rhabdomyosarcoma.
Aged↗
A case of traumatic pericardiophrenic rupture.
An unusual case of traumatic pericardiophrenic rupture is presented. The defect was limited to the central tendon of the diaphragm, with herniation of the stomach into the pericardial sac. A correct preoperative diagnosis was not made because laparotomy was quickly performed for splenic rupture. Successful operative repair of the tear was performed, with interrupted reabsorbable sutures. The case is discussed and the management of patients with these rare lesions is reviewed.
Accidents, Traffic↗
Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies.
Among the several classes of drugs currently studied as neuroprotective agents, glutamate release blockers have been indicated as being rather effective. In particular, lamotrigine and riluzole have shown promise in the treatment of either acutely developing cellular damages (stroke, posttraumatic lesions) or slowly progressing neurodegenerative diseases as amyotrophic lateral sclerosis. These drugs are supposed to interfere with the release of endogenous glutamate in situ, yet the mechanisms underlying this effect are not fully defined. One possibility is that lamotrigine and riluzole act by inhibiting voltage-dependent inward conductances active in the soma and/or in the axon terminal region. Therefore, we have investigated the effects of lamotrigine and riluzole on the voltage-gated sodium and calcium currents of acutely isolated neurons from the adult rat neocortex. In addition, since phenytoin is a well-known blocker of the sodium channel, we have compared lamotrigine and riluzole responses with the peak current inhibition produced by phenytoin in the same cells. Lamotrigine produced a large reduction of the high-voltage-activated calcium currents and a smaller; use-dependent inhibition of the sodium conductance. Riluzole inhibited significantly the sodium current at surprisingly low concentrations (nanomolar range) and by up to 80% at saturating doses (1-10 microM). Furthermore, riluzole inhibited both high- and low-voltage-activated calcium currents in neocortical neurons isolated from adult and young animals. By contrast, phenytoin caused only a slight reduction of high-voltage-activated calcium currents even at supratherapeutic doses (by < 12% at 10 microM). Taken together, the different pharmacological profiles of the tested agents might indicate that glutamate release blockers do not represent a homogenous class of drugs. Conversely, our findings could support their selective utilization in different disease status.
Animals↗
Effects of increasing doses of apomorphine during stereotaxic neurosurgery in Parkinson's disease: clinical score and internal globus pallidus activity. Short communication.
We analysed the firing activity of internal globus pallidus cells in two Parkinson's disease patients undergoing stereotaxic surgery. Both patients showed an advanced rigid-akinetic syndrome with disabling levodopa induced dyskinesias. Apomorphine, intraoperatively administered at doses (1-2 mg) inducing a short but clear clinical improvement without involuntary movements, reduced the pallidal discharge rate by > 50% in both patients. An higher apomorphine dose (2.5 mg), tested in one hemisphere, blocked the firing activity with a time course independent from the occurrence of dyskinesias. These finding suggest that the reduction of internal pallidus excitability is one of the mechanisms underlying the efficacy of dopaminergic therapy, but also that changes in other basal ganglia stations are likely to be involved in dyskinesias.
Antiparkinson Agents↗
Results of surgical resection in patients over the age of 70 years with non small-cell lung cancer.
METHODS: From January 1989 to October 1993, at the Department of Cardio-Thoracic Surgery of the University of Modena, 806 patients underwent thoracotomy and curative pulmonary resection for non small-cell lung cancer. Eighty five patients were 70 years old or older (mean 73.4 years, range 70-88). There were 78 males (91.7%) and 7 females (8.3%). This population was compared to 130 younger patients (under 70 years old), treated during the same period and with similar features with respect to the type of resection, sex, histology, grading and staging. Lobectomy was the procedure of preference in both groups. RESULTS: As regards postoperative mortality and overall complications, no significant differences were noted between the two groups of patients (two younger patients died and 43.8% had postoperative complications; one patient of the older group died and 55.2% had postoperative complications), but in the older ones a higher incidence of cardiovascular complications was found (P < 0.01). With respect to the long-term survival (follow-up 12-70 months), no significant difference was found between the two groups. CONCLUSION: Such findings show that pulmonary resection for bronchogenic cancer is feasible and justified in patients more than 70 years old, even if a higher incidence of cardiovascular complications may occur: a careful preoperative selection ought to be performed and lobectomy should be preferred.
Adult↗
Voltage-activated calcium channels: targets of antiepileptic drug therapy?
Voltage-gated calcium currents play important roles in controlling neuronal excitability. They also contribute to the epileptogenic discharge, including seizure maintenance and propagation. In the past decade, selective calcium channel blockers have been synthesized, aiding in the analysis of calcium channel subtypes by patch-clamp recordings. It is still a matter of debate whether whether any of the currently available antiepileptic drugs (AEDs) inhibit these conductances as part of their mechanism of action. We tested oxcarbazepine, lamotrigine, and felbamate and found that they consistently inhibited voltage-activated calcium currents in cortical and striatal neurons at clinically relevant concentrations. Low micromolar concentrations of GP 47779 (the active metabolite of oxcarbazepine) and lamotrigine reduced calcium conductances involved in the regulation of transmitter release. In contrast, felbamate blocked nifedipine-sensitive conductances at concentrations significantly lower than those required to modify N-methyl-D-aspartate (NMDA) responses or sodium currents. Aside from contributing to AED efficacy, this mechanism of action may have profound implications for preventing fast-developing cellular damage related to ischemic and traumatic brain injuries. Moreover, the effects of AEDs on voltage-gated calcium signals may lead to new therapeutic strategies for the treatment of neurodegenerative disorders.
Animals↗
Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications.
In pyramidal cortical cells, high-voltage-activated Ca2+ currents affect seizure propagation and the release of excitatory amino acids at the corticostriatal axon terminals. The new antiepileptic drug lamotrigine (Lamictal) produced a large and dose-dependent inhibition of high-voltage-activated Ca2+ currents (IC50 = 12.3 microM) in rat cortical neurons. This action was not blocked by the dihydropyridine receptor antagonist nifedipine; instead, the response was blocked by the concomitant application of the N-type Ca2+ channel blocker, omega-conotoxin GVIA (1-3 microM) and the P-type Ca2+ channel blocker, omega-agatoxin-IVA (20-100 nM). These findings demonstrate that lamotrigine, at therapeutic doses, is capable of modulating the Ca2+ conductances involved in excitatory amino acid release in the corticostriatal pathway, partially explaining lamotrigine usefulness in the therapy of epilepsy as well as in the treatment of excitatory amino acid-induced neurotoxicity.
Animals↗
L-AP4 inhibits high voltage-activated Ca2+ currents in pyramidal cortical neurones.
We tested the ability of L-AP4 to modulate high voltage-activated (HVA) calcium (Ca2+) currents in pyramidal neurones acutely isolated from the adult rat (4-8 weeks). Whole cell recordings, with barium (Ba2+) ions as the charge carrier, were performed. L-AP4 reduced HVA Ca2+ conductances in 86% of the recorded cells. Saturating concentrations of L-AP4 inhibited about 21% of the current (+/- 8.3%, n = 8), although great variability was observed. Interestingly, low micromolar concentrations of (1S,3R)-1-aminocyclo-pentane-1,3-dicarboxylic acid (1S,3R-ACPD) and (2S,3S,4R)-alpha-(carboxy-cyclopropyl)-glycine (1-CCGI) had weaker effects than L-AP4. MAP4 fully antagonized the L-AP4-mediated reduction of HVA Ca2+ currents. These findings suggest the involvement of the AP4-sensitive receptor in the control of both cellular excitability and transmitter release in rat neocortical neurones.
Amino Acids, Dicarboxylic↗
The modulation of calcium currents by the activation of mGluRs. Functional implications.
Glutamatergic transmission in the central nervous system (CNS) is mediated by ionotropic, ligand-gated receptors (iGluRs), and metabotropic receptors (mGluRs). mGluRs are coupled to GTP-binding regulatory proteins (G-proteins) and modulate different second messenger pathways. Multiple effects have been described following their activation; among others, regulation of fast synaptic transmission, changes in synaptic plasticity, and modification of the threshold for seizure generation. Some of the major roles played by the activation of mGluRs might depend on the modulation of high-voltage-activated (HVA) calcium (Ca2+) currents. Some HVA Ca2+ channels (N-, P-, and Q-type channels) are signaling components at most presynaptic active zones. Their mGluR-mediated inhibition reduces synaptic transmission. The interference, by agonists at mGluRs, on L-type channels might affect the repetitive neuronal firing behavior and the integration of complex events at the somatic level. In addition, the mGluR-mediated effects on voltage-gated Ca2+ signals have been suggested to strongly influence neurotoxicity. Rather different coupling mechanisms underlie the relation between mGluRs and Ca2+ currents: Together with a fast, membrane-delimited mechanism of action, much slower responses, involving intracellular second messengers, have also been postulated. In the recent past, the relative paucity of selective agonists and antagonists for the different subclasses of mGluRs had hampered the clear definition of the roles of mGluRs in brain function. However, the recent availability of new pharmacological tools is promising to provide a better understanding of the neuronal functions related to different mGluR subtypes. The analysis of the mGluR-mediated modulation of Ca2+ conductances will probably offer new insights into the characterization of synaptic transmission and the development of neuroprotective agents.
Animals↗
Primary right atrial fibrosarcoma diagnosed by endocardial biopsy.
Explore the source record for details and available documents.
Biopsy↗
Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study.
1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors.
Animals↗
A field potential analysis on the effects of lamotrigine, GP 47779, and felbamate in neocortical slices.
We studied the action of the new antiepileptic drugs lamotrigine (LTG), GP 47779 (the active metabolite of oxcarbazepine), and felbamate (FBM) on stimulus-evoked field potentials recorded from rat prefrontal and frontal cortical slices. In the presence of physiologic concentrations of extracellular magnesium (1.2 mM) the field potential amplitude was not affected by the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, 2-amino-5-phosphonovalerate (APV), while it was blocked by the non-NMDA glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). When magnesium was removed from the bathing medium, there was a significant NMDA-mediated component of the field potential. LTG and GP 47779 decreased, in a dose-dependent manner, the field potential amplitude under both experimental conditions. FBM caused a dose-related decrease of the field potential amplitude only in the absence of external magnesium, suggesting a selective interaction with an NMDA-mediated component of this potential. These findings indicate that the reduction of cortical excitatory transmission might represent a common target for new antiepileptic drugs.
Animals↗
Felbamate inhibits dihydropyridine-sensitive calcium channels in central neurons.
The effect of the antiepileptic drug felbamate (FBM) on high-voltage-activated Ca++ currents was studied in cortical and neostriatal neurons acutely isolated from adult rats. Patch-clamp recordings in the whole-cell configuration were performed. Ba++ ions as the charge carrier for Ca++ channels were used. In pyramidal cortical cells, FBM dose-dependently reduced high-voltage-activated Ca++ currents in all the tested neurons. At concentrations of 30 to 100 nM, FBM already produced a significant inhibition of high-voltage-activated Ca++ currents (-6/-15%). At saturating concentrations (1-3 microM), FBM-mediated inhibition averaged 44%. The responses were fully reversible. The dose-response curves revealed IC50 of 504 nM. In striatal neurons, FBM decreased the same conductances by about 28%; the threshold dose was 1 to 2 microM, with an IC50 of 18.7 microM. In both structures, the observed inhibitions were unaffected by omega-conotoxin GVIA and omega-agatoxin IVA, suggesting that N-like channels and P-Like channels were not involved in the FBM-mediated responses. In addition, when omega-conotoxin GVIA and omega-agatoxin IVA (100 nM) were coapplied, the FBM-mediated inhibition on the remaining Ca++ currents averaged 87%. The FBM responses were occluded by micromolar concentrations of nifedipine, supporting a direct interference with dihydropyridine-sensitive channels. It is concluded that the described effect of FBM might represent an efficacious mechanism for either controlling spike discharge from epileptic foci or protecting neurons from excessive Ca++ loading. In both cases, FBM would act as a broad spectrum neuroprotective agent.
Animals↗
Ethylene-oxide and steam-sterilised polysulfone membrane in dialysis patients with eosinophilia.
Eosinophilia and some acute dialysis side-effects, such as itching, flushing and bronchospasm, are often associated with the presence of ethylene oxide (ETO) as dialyzer sterilizing agent. This study evaluated the effects of two different polysulfone (PS) hollow-fiber dialysers sterilized with ETO and steam in 31 chronic dialysis patients with eosinophilia. Clinical symptoms, metabolic and biochemical parameters, complement (C3a and C5a) activation and production were evaluated in each patient dialysed for two months at a time with Cuprophan dialyser, ETO-PS dialyser and steam-PS dialyser. The steam-sterilizer agent does not alter the purifying capacity of the PS membrane which maintains its superiority over Cuprophan in terms of biocompatibility. Using steam-PS, intradialytic eosinophil kinetics seems to improve. In some patients with high serum levels of ETO-specific IgE these levels tend to diminish. Generic intradialytic symptoms do not differ between the two sterilization methods, although some hypersensitivity symptoms during the first dialysis hour are considerably lower in some patients when steam-sterilized PS is used.
Adult↗
Vulnerability of medium spiny striatal neurons to glutamate: role of Na+/K+ ATPase.
In Huntington's disease neuronal degeneration mainly involves medium-sized spiny neurons. It has been postulated that both excitotoxic mechanisms and energy metabolism failure are implicated in the neuronal degeneration observed in Huntington's disease. In central neurons, > 40% of the energy released by respiration is used by Na+/K+ ATPase to maintain ionic gradients. Considering that impairment of Na+/K+ ATPase activity might alter postsynaptic responsivity to excitatory amino acids (EAAs), we investigated the effects of the Na+/K+ ATPase inhibitors, ouabain and strophanthidin, on the responses to different agonists of EAA receptors in identified medium-sized spiny neurons electrophysiologically recorded in the current- and voltage-clamp modes. In most of the cells both ouabain and strophanthidin (1-3 microM) did not cause significant change in the membrane properties of the recorded neurons. Higher doses of either ouabain (30 microM) or strophanthidin (30 microM) induced, per se, an irreversible inward current coupled to an increase in conductance, leading to cell deterioration. Moreover, both ouabain (1-10 microM) and strophanthidin (1-10 microM) dramatically increased the membrane depolarization and the inward current produced by subcritical concentrations of glutamate, AMPA and NMDA. These concentrations of Na+/K+ ATPase inhibitors also increased the membrane responses induced by repetitive cortical activation. In addition, since it had previously been proposed that dopamine mimics the effects of Na+/K+ ATPase inhibitors and that dopamine agonists differentially regulate the postsynaptic responses to EAAs, we tested the possible modulation of EAA-induced membrane depolarization and inward current by dopamine agonists. Neither dopamine nor selective dopamine agonists or antagonists affected the postsynaptic responses to EAAs. Our experiments show that impairment of the activity of Na+/K+ ATPase may render striatal neurons more sensitive to the action of glutamate, lowering the threshold for the excitotoxic events. Our data support neither the role of dopamine as an ouabain-like agent nor the differential modulatory action of dopamine receptors on the EAA-induced responses in the striatum.
Animals↗
Properties of the hyperpolarization-activated cation current Ih in rat midbrain dopaminergic neurons.
Intracellular electrophysiological recordings in current- and voltage-clamp mode were obtained from dopaminergic neurons of the rat mesencephalon in an in vitro slice preparation. In current-clamp mode, a time-dependent anomalous rectification (TDR) of the membrane was observed in response to hyperpolarizing current pulses. In single-electrode voltage-clamp mode, a slowly developing inward current (Ih) underlying the TDR was studied by hyperpolarizing voltage commands from a holding potential of -50 to -60 mV. Ih started to be activated at approximately -69 mV, was fully activated at -129 to -141 mV, with half-maximal activation at -87 mV, and showed no inactivation with time. The time course of development of Ih followed a single exponential, and its time constant was voltage-dependent. At -81 mV, Ih activated with a time constant of 379 +/- 47.6 ms, whereas at -129 mV Ih activated with a time constant of 65 +/- 2.2 ms. Its estimated reversal potential was -35 +/- 4 mV. Raising the extracellular concentration of K+ from 2.5 to 6.5 and to 12.5 mM increased the amplitude of Ih while reducing the extracellular concentration of Na+ from 153.2 to 27.2 mM caused a reduction in amplitude of Ih. Bath application of caesium (1-5 mM) reversibly reduced or blocked the TDR/Ih. Perfusion of tetrodotoxin (0.5-1 microM), tetraethylammonium (10-20 mM) or barium (0.3-2 mM) did not significantly affect Ih. Ih was also present in cells impaled with CsCl-filled electrodes.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Outward potassium currents activated by depolarization in rat globus pallidus.
Voltage-dependent potassium currents play a key role in shaping the firing pattern of central neurons. Their pharmacological and physiological identification is rather important in the structures which are involved in the filtering of input/output messages. In this regard, globus pallidus external segment (GPe) is indicated as a crucial station in the well-known indirect pathway of the basal ganglia. Among the potassium conductances which have been indicated to condition the firing behavior and the neuronal integrative properties in many central neurons, we analysed the depolarization-activated ones by means of patch-clamp recordings in the whole-cell configuration. Two main families of calcium-independent outward potassium currents are activated by depolarization in GPe neurons acutely isolated from the adult rat. From depolarized holding potentials (-50/-45 mV), a slowly-activating, sustained current is evoked; it manifests very little inactivation and it is available at rather depolarized potentials (-30 mV/-20 mV). This current is relatively resistant to 4-aminopyridine (4-AP) but it is blocked by tetraethilammonium ions (TEA) and consequently it resembles delayed rectifier current (Ik). From negative holding potentials (-80/-100 mV), on the other hand, A-like conductances are activated. Together with a fast-inactivating transient current, another component is observed in a significant proportion of recordings (45%). This current shows half-inactivation voltage around -90 mV, peculiar sensitivity to micromolar doses of 4-AP and a slow rate of recovery from inactivation. The presence and the modulation of these A-like currents may be a very critical aspect in the membrane physiology of pallidal neurons.
4-Aminopyridine↗