Excitatory synaptic responses mediated by GABAA receptors in the hippocampus.

Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the cortex. Activation of postsynaptic GABAA receptors hyperpolarizes cells and inhibits neuronal activity. Synaptic responses mediated by GABAA receptors also strongly excited hippocampal neurons. This excitatory response was recorded in morphologically identified interneurons in the presence of 4-aminopyridine or after elevation of extracellular potassium concentrations. The synaptic excitation sustained by GABAA receptors synchronized the activity of inhibitory interneurons. This synchronized discharge of interneurons in turn elicited large-amplitude inhibitory postsynaptic potentials in pyramidal and granule cells. Excitatory synaptic responses mediated by GABAA receptors may thus provide a mechanism for the recruitment of GABAergic interneurons through their recurrent connections.

Psychological reactions in public melanoma screening.

Participants in public screening for malignant melanoma (n = 190) completed a questionnaire containing items regarding cognitive and emotional responses to skin examination on two occasions, before screening and 7 months later. The results suggest subjective susceptibility to melanoma in participants in public screening, especially in women. No increase in psychosomatic problems, anxiety or depressive symptoms or signs of "false security" were seen as an effect of the screening, neither in the total sample nor in those who at the screening were recommended further medical procedures.

Gap junctions synchronize the firing of inhibitory interneurons in guinea pig hippocampus.

The convulsant 4-aminopyridine (4AP) facilitates the synchronous firing of interneurons in the hippocampus, eliciting giant inhibitory postsynaptic potentials (IPSPs) in CA3 pyramidal cells. We used the gap junction blocker carbenoxolone to investigate the role of electrotonic coupling in both the initiation and the maintenance of 4AP-facilitated inhibitory circuit oscillations. Carbenoxolone abolished all synchronized IPSPs in CA3 cells elicited by 4AP in the presence of ionotropic glutamate receptor blockers. Carbenoxolone also blocked the isolated synchronized GABA(B) IPSPs generated in CA3 cells by a subpopulation of interneurons. These data confirm that: (1) the interneurons producing GABA(B) responses in CA3 cells are electrotonically coupled, and (2) gap junctions among interneurons are essential for initiating synchronized interneuron oscillatory firing in 4AP.

An ontogenetic study of kindling using rapidly recurring hippocampal seizures.

The present study investigated the acquisition and retention of kindling in immature rats. Postnatal (PN) 7-28-day-old rats were electrically kindled in the ventral hippocampus. Ten-second, 20-Hz stimulus trains were delivered every 5 min for 6 h on one day (short interval rapidly recurring hippocampal seizures, RRHS) or every 30 min for 9 h on each of two consecutive days (long interval RRHS). Afterdischarge durations (ADD) and behavioral seizure scores (BSS) were recorded following each stimulation. Animals of all ages kindled with both short and long interval RRHS, as manifested by lengthening of ADD and increasing BSS. With short interval RRHS, the course of kindling was erratic; with long interval RRHS, kindling proceeded smoothly over both test days. In PN 14-28 rats, the degree of kindling obtained on the first day of long interval RRHS was retained at the start of the second experimental day. In contrast, PN 7 rats showed a transient decrease in ADD and BSS from day 1 to day 2. Afterdischarge thresholds declined with maturation. Among the PN 14-28 animals, younger rats exhibited longer seizures at the outset of kindling and proceeded through kindling faster. Once established, kindled motor seizures also occurred with 2-s, 50-Hz stimulus trains. We conclude that rapid kindling occurs at all ages; however, PN 7 rats are less capable of retaining the kindling effect than are older rats.

Ontogeny of epileptogenesis in the rat hippocampus: a study of the influence of GABAergic inhibition.

In vivo experiments were carried out to examine whether the period during which gamma-aminobutyric acid (GABA)ergic inhibition in the hippocampus matures is associated with a decrease in epileptogenesis. Seizures were elicited with bipolar electrodes stereotactically positioned in the hippocampus of urethane-anesthetized rat pups from postnatal (PN) 7 through 28 days of age. No clinical seizure activity was detected but electrographic seizures (afterdischarges) were induced at all ages. Afterdischarge thresholds (ADT) varied inversely with age. However, the durations of initial afterdischarges and the degree of lengthening of afterdischarges with the rapidly recurring hippocampal seizure (RRHS) protocol were not different for the various age animals studied. Paired pulse inhibition was assessed with a twin pulse paradigm that has been shown to monitor GABAergic inhibition. Measurements were made before and 60 min after a single seizure and again 60 min after the RRHS protocol. At no age was there a significant change in paired pulse inhibition after a single seizure. After RRHS there was a significant reduction of paired pulse inhibition only in the groups that had manifested adult levels of paired pulse inhibition in pre-seizure measurements (greater than or equal to PN 21). These studies indicate that heightened epileptogenesis in the young hippocampus cannot simply be explained on the basis of an immaturity of GABA-mediated inhibition.

An in vivo electrophysiological study of the ontogeny of excitatory and inhibitory processes in the rat hippocampus.

Although several studies have compared hippocampal slices from young vs adult rats, a systematic in vivo characterization of the ontogeny of electrophysiologic responses in this structure has not been done. The current report describes the postnatal development of excitatory and inhibitory responses in the CA1 region of the hippocampus in rats 7-65 days of age. Under urethane anesthesia, a recording electrode was placed in one CA1 region to measure extracellular population spikes elicited by stimulation of the contralateral CA3 region. Age-related changes in the maximal population spike amplitude, the voltage required to elicit a half-maximal amplitude spike, the width at half-maximal spike amplitude, and latency to onset of the population spike ('conduction velocity') were monitored as parameters describing excitatory processes in the hippocampus. A paired-pulse paradigm was used to quantify the ontogeny of inhibitory processes. In younger animals, population spikes were broader, smaller in amplitude, and required higher stimulus intensities to be elicited. After postnatal (PN) day 14, excitability (voltage to elicit half-maximal population spike) and spike width were at fully mature levels. Maximal spike amplitudes were also smaller in rats younger than PN14, but not thereafter. The conduction velocity parameter steadily increased during development. In contrast, no evidence of inhibition was found prior to PN18, after which it steadily increased to reach adult levels by PN28. These results indicate that, in the rat hippocampus, excitatory processes are well established or fully mature within 2 weeks following birth, whereas the maturation of inhibitory processes to adult levels is not achieved until several weeks later.

Evidence for a chronic loss of inhibition in the hippocampus after kindling: electrophysiological studies.

Rats were kindled with either of 2 protocols: (1) a rapidly recurring hippocampal seizure (RRHS) paradigm in which 10 sec stimulus trains were delivered every 5 min through hippocampal electrodes; and (2) a traditional approach in which 1 sec stimulus trains were given to the amygdala once daily. Three groups of kindled rats were prepared: (1) one of amygdala-kindled rats that had experienced 9-15 seizures; (2) one of RRHS-kindled rats that had experienced 96 seizures; and (3) one of RRHS-overkindled rats that had experienced 144-336 seizures. After a 1 month seizure-free period, the animals were anesthetized with urethane and measurements were made on the potency of paired pulse inhibition in the CA1 region of the hippocampus. All groups of kindled animals were found to have significantly less paired pulse inhibition than control rats. This decrement was confined to interpulse intervals less than or equal to 70 msec. The amount of inhibition lost correlated with the number of seizure that had occurred. The GABAergic agonist muscimol restored paired pulse inhibition in kindled animals for interpulse intervals less than or equal to 70 msec towards normal values. These results indicate that not only RRHS, but also other modes of kindling, reduced GABAergic inhibition in the CA1 region of the hippocampus and that this diminution was long-lasting, if not permanent.

Information to patients with malignant melanoma: a randomized group study.

An information programme for patients with cutaneous malignant melanoma, Stage 1, aiming at increasing satisfaction with information, was carried out at the Department of Oncology (Radiumhemmet). The programme consisted of a group meeting and a brochure. A total of 231 consecutive patients were included, and 149 (65%) reported interest in participation and were randomized to the Information group (n = 77) or to the Control group. A total of 67 patients (29%) were not interested (the NI-group). To evaluate the programme, the patients in the three groups completed questionnaires regarding satisfaction with information, knowledge of melanoma and psychological and psychosomatic variables before randomization and at the first visit for follow-up at Radiumhemmet. After the information programme, the Information group was significantly more satisfied with information, had a higher level of knowledge and a lower proportion requested further information as compared with the Control group. No differences were found on the psychological and psychosomatic variables.

Six-month follow-up of effects of an information programme for patients with malignant melanoma.

Using a randomized design, the effects of an information programme for melanoma patients were studied. The programme consisted of a group meeting and a brochure. The present study reports on the six-month follow-up of the effects of the programme. A total of 128 patients participated in the programme, 55 before and 73 after the first medical control visit. Questionnaires regarding knowledge about melanoma, psychological and psychosomatic variables were completed at the first medical control visit and six months later by mail. A questionnaire concerning patients attitudes to the programme was included after six months. Knowledge about melanoma increased and a majority of patients were satisfied with the information brochure, the group meeting and the group leader, but 40% considered that too few participants attended in their group meeting. No effects on psychological or psychosomatic variables were found. Men and women participated to the same extent.

Repair of rupture of the distal tendon of the biceps brachii. Review of the literature and report of three cases treated with a single anterior incision and suture anchors.

Operative repair of distal biceps tendon ruptures is recommended for active individuals desiring maximum return of elbow supination and flexion power and endurance. Traditional two-incision repair methods are highly successful, but they carry the risk of radioulnar synostosis formation if the ulna is exposed. Repair via an anterior incision through bone drill holes requires more dissection and potential risk to the posterior interosseous nerve. The authors present a method of repair of distal biceps tendon ruptures via a single anterior incision using suture anchors. This technique has been used in 3 patients with excellent functional results and is recommended for use as an alternative to the two-incision method.

Multiple chronic health problems are negatively associated with health related quality of life (HRQoL) irrespective of age.

PURPOSE: To examine HRQoL measured by EORTC QLQ-C30 with respect to an increasing number of self-reported chronic health problems in the general Swedish population and to study the association between HRQoL, chronic health problems and age, gender, income, marital status and employment status. METHOD: A postal survey among a large random sample of 4000 adults aged 18-79 years. The study material contained EORTC QLQ-C30 core questionnaire supplemented by a sociodemographic questionnaire including questions about 13 chronic health problems of which four categories, 'No', 'Few', 'Some' or 'A lot of chronic health problems were constructed. RESULTS: Multiple chronic health problems were significantly associated with reduced HRQoL. The increased number of chronic health problems was also associated with age. When the number of chronic health problems was accounted for, the influence of age diminished. Low income and unemployment were associated with greater decline in HRQoL with respect to increasing number of problems among the respondents in working age. CONCLUSION: The impact of increased number of chronic health problems had varying consequences in different age groups. Moreover, sociodemographic and economic factors showed to interact differently with chronic health problems and HRQoL in various age groups. It appears from our results that an assessment and a careful consideration of these factors will be valuable in order to facilitate the interpretation of the effects of cancer and treatment on long-term HRQoL of cancer patients.

Synchronization of inhibitory neurones in the guinea-pig hippocampus in vitro.

1. Intracellular recordings were obtained from pyramidal, granule and hilar cells in transverse slices of guinea-pig hippocampus to examine synaptic interactions between GABAergic neurones. 2. In the presence of the convulsant compound 4-aminopyridine (4-AP), after fast excitatory amino acid (EAA) neurotransmission was blocked pharmacologically, large amplitude inhibitory postsynaptic potentials (IPSPs) occurred rhythmically (every 4-8 s) and synchronously in all principal cell populations (triphasic synchronized IPSPs). In the presence of the GABAA receptor blocker picrotoxin (PTX), a large amplitude IPSP continued to occur spontaneously in all principal cells simultaneously (monophasic synchronized IPSP). 3. Burst firing occurred simultaneously in a group of hilar neurones (synchronized bursting neurones) coincident with triphasic synchronized IPSPs in principal cells. After PTX was added, the bursts and the underlying depolarizing synaptic potentials were completely suppressed in some of the synchronized bursting neurones (type I hilar neurones), while others (type II hilar neurones) continued to fire in bursts coincident with monophasic synchronized IPSPs in principal cells. Intense hyperpolarization blocked burst firing and revealed underlying attenuated spikes of less than 10 mV, but did not uncover any underlying depolarizing synaptic potentials. 4. In type II hilar neurones, during sufficient hyperpolarization, spontaneous activity consisted of attenuated spikes. With depolarization, the small spikes began to trigger full size action potentials. These data suggest the presence of electrotonically remote spike initiation sites. 5. The morphology of synchronized bursting neurones was revealed by intracellular injection of the fluorescent dye Lucifer Yellow. Attempts to inject dye into one type II hilar neurone often resulted in the labelling of two to four cells (dye coupling). Dye coupling was not observed in type I hilar neurones. 6. These findings indicate that excitatory interactions synchronizing the firing of GABAergic neurones can occur in the absence of fast EAA neurotransmission. GABAergic neurones can become synchronized via their recurrent collaterals through the depolarizing action of synaptically activated GABAA receptors. In addition, a subpopulation of GABAergic neurones can become synchronized by a mechanism probably involving electrotonic coupling.

Alterations in beta-adrenergic receptor binding in partially and fully amygdala-kindled juvenile and adult rats.

Twenty-eight-day-old (juvenile) rats were kindled with hourly stimulations to partial or fully kindled status. Adult rats were stimulated with hourly or daily stimulations. Alterations in [3H]dihydroalprenolol binding were determined 3 weeks after the last stimulation. We found that partially kindled, hourly stimulated juvenile rats showed a significant increase in the dissociation constant (Kd), with no change in maximal binding values. Fully kindled juvenile rats showed no change in Kd or Bmax. Partially kindled, hourly stimulated adult rats showed a significant decrease in Kd, with no change in Bmax. There was no change in Kd or Bmax values in fully kindled, hourly stimulated adult rats. Fully kindled, daily stimulated adult rats showed a decrease in maximal binding, with no change in Kd values. These findings indicate that kindling-induced beta-adrenergic receptor alterations were influenced by the age of the animal and the kindling parameters used, as well as the extent to which the animals were kindled.

Novel glutamate- and GABA-independent synaptic depolarization in granule cells of guinea-pig hippocampus.

1. Dual intracellular recordings of granule cells, hilar interneurons and CA3 pyramidal cells were performed in transverse slices of guinea-pig hippocampus. At resting membrane potential, in the presence of 4-aminopyridine, ionotropic glutamate receptor antagonists and the GABAA receptor antagonist bicuculline, granule cells showed spontaneous, large amplitude depolarizations correlated with synchronous bursting activity of interneurons. 2. Under these conditions, pyramidal cells exhibited large amplitude monophasic GABAB inhibitory postsynaptic potentials (IPSPs) synchronous with the GABAergic interneuron burst discharges. The granule cells also received a GABAB input, which was evident only when the neurons were depolarized by DC injection. The GABAB receptor antagonist CGP 55,845A (CGP) blocked the GABAB IPSPs in both pyramidal cells and granule cells; however, the depolarizing potential in granule cells was unaffected by the drug. 3. The granule cells depolarization in the presence of CGP was monophasic and exhibited linear voltage dependence with a reversal potential around -40 mV, suggesting that it was generated by a synaptic input activating a mixed cationic current. 4. The granule cell depolarization was abolished following the addition of tetrodotoxin to the bath. In addition, perfusing the slice with a low Ca(2+)-containing solution (0.5 mM Ca(2+)-10 mM Mg2+) also abolished the granule cell depolarization, confirming the synaptic origin of the event. 5. (S)-Methyl-4-carboxyphenylglycine, L-(+)-2-amino-3-phosphonopropionic acid, propranolol and atropine did not affect the granule cell depolarization, indicating that metabotropic glutamate receptors, beta-adrenergic receptors and muscarinic cholinergic receptors were not involved in generating the granule cell depolarizing synaptic response. 6. These findings indicate that, in the absence of both glutamatergic and GABAergic inputs, synchronous interneuronal activity can produce a depolarizing synaptic response in granule cells. The neurochemical responsible for the depolarization is currently under investigation.

[Retraction of lower limbs in a female with hyperthyroidism]. / Retracción de miembros inferiores en un paciente con hipertiroidismo.

We report a 47 years old woman with hyperthyroidism that had a severe tendinous retraction of hips and knees that subsided with propylthiouracil treatment. Electrodiagnosis showed myopathic alterations and muscle strength was moderately reduced. The authors did not find references of a similar condition in patients with hyperthyroidism.

Synaptic connectivity of distinct hilar interneuron subpopulations.

Dual intracellular recordings of hilar interneurons and CA3 pyramidal cells were performed in transverse slices of guinea pig hippocampus in the presence of the convulsant compound 4-aminopyridine (4-AP) and ionotropic glutamate receptor antagonists. Under these conditions, interneurons burst fire synchronously, producing synchronized inhibitory postsynaptic potentials (sIPSPs) in pyramidal cells. Three different hilar interneuron subpopulations that contributed to the sIPSP were identified based on their projection properties and morphology. These three types were pyramidal-like stellate interneurons, spheroid interneurons, and oviform interneurons. Physiologically, pyramidal-like stellate interneurons could be differentiated from the other interneuron subpopulations because they generated short synchronized bursts of action potentials coincident with the hyperpolarizing and depolarizing gamma-aminobutyric acid-A (GABAA)-mediated inhibitory postsynaptic potentials (IPSPs) recorded in pyramidal cells. The bursts in pyramidal-like stellate cells were abolished by theGABAA-receptor blocker, bicuculline. In contrast, spheroid interneurons of the dentate-hilus (D-H) border and oviform hilar interneurons exhibited prolonged bicuculline-resistant bursts that occurred coincident with the GABAB pyramidal cell sIPSPs. Pyramidal-like stellate interneurons likely did not contribute to the generation of synchronized GABAB responses in hippocampal pyramidal cells. Spheroid interneurons were unique among these subpopulations of interneurons in that the bicuculline-resistant bursts in spheroid interneurons were sustained by a synaptic depolarization that persisted in the presence of antagonists of ionotropic glutamate, GABAA and GABAB receptors [6-cyano-7-nitroquinoxaline-2,3-dione, 20 microM; 3-3(2-carboxipiperazine-4-yl)propyl-1-phosphonate, 20 microM; bicuculline, 10-15 microM; CGP 55845A, 20 microM]. This novel depolarizing potential reversed between -30 and 0 mV. No noticeable synaptic depolarization sustaining burst firing could be isolated in oviform interneurons, suggesting that firing in this interneuron subpopulation was synchronized by nonsynaptic mechanisms. The results of the present study indicate that the hilar inhibitory circuit is composed of at least three different subpopulations of interneurons, distinguishable by their morphological characteristics and synaptic inputs and outputs. These findings give further support to the hypothesis that there are distinct populations of interneurons producing GABAA and GABAB responses with defined functional roles within the hippocampal inhibitory circuit. Notably, we found that spheroid interneurons were unique among the hilar interneurons studied, in that the synchronized bursts observed in these cells are sustained by a novel ionotropic glutamate and GABA receptor-independent synaptic depolarization.

Amygdala kindling in juvenile rats following neonatal administration of 6-hydroxydopamine.

The role of catecholamines in mediating the acquisition of amygdala-kindled seizures was investigated in juvenile rats administered intracisternal injections of 6-hydroxydopamine (6-OHDA) on postnatal days 1 and 2. Amygdala kindling was initiated on day 28, using stimulations delivered each hour through two consecutive stage V seizures. The 6-OHDA treatment resulted in a 53% increase in the overall rate of kindling in juvenile rats. This acceleration was confined primarily to the early phases of kindling in that the 6-OHDA-treated rats skipped the early kindling stages, and the later stages of kindling were unaffected. These findings support evidence from adult rats that catecholamines play a role in initially limiting the spread of seizure activity during kindled seizure acquisition; however, when the seizures have begun to generalize, the ability of catecholaminergic systems to inhibit seizure spread diminishes.