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Age-related alterations in noradrenergic input to the hippocampal formation: structural and functional studies in intraocular transplants.

Intrinsic versus extrinsic determinants of age-related alterations in hippocampal noradrenergic transmission were investigated using intraocular allografts in rats. Three groups of animals were examined: young hippocampal transplants in young hosts, old transplants in old hosts and young transplants in old hosts. Postsynaptic sensitivity to noradrenaline (NA) was measured by extracellular recordings of spontaneous activity and superfusion with known concentrations of catecholamines in the anterior chamber of the eye. Hill plots demonstrated that the dose-response relationships of NA-induced depressions were linear and parallel in the 3 groups. Aged hippocampal grafts displayed a highly significant subsensitivity to NA of one order of magnitude. The EC50 for this group was 203.1 microM as compared to 29.2 in young grafts. Young intraocular grafts in old hosts responded similarly to transplants in young hosts, with an EC50 of 32.4 microM for the depressant actions of NA. Collaterals of the host iris sympathetic ground plexus invaded the hippocampal grafts. The density of this noradrenergic innervation was estimated by immunohistochemistry for tyrosine hydroxylase. A slightly increased density and fluorescence intensity of the noradrenergic fibers were observed in the old transplants as compared to the young transplants in young and old hosts. This was correlated with a significantly (P less than 0.01) increased content of NA in old transplants, as measured with high performance liquid chromatography. The old transplants also contained a large number of autofluorescent lipofuchsin granules, which were absent in the young transplants, regardless of the recipient age. Taken together, these results suggest the existence of alterations in pre- as well as postsynaptic noradrenergic mechanisms in the aging hippocampus. These changes were dependent on transplant age rather than host age, thus suggesting an involvement of intrinsic rather than extrinsic determinants in this model system.

Action Potentials↗

Selective blockade of Ca2+ permeable AMPA receptors in CA1 area of rat hippocampus.

Using whole cell patch-clamp recording from pyramidal cells and interneurons in the CA1 area of hippocampal slices, the effect of IEM-1460, a selective channel blocker of Ca2+ permeable AMPA receptors (AMPARs), on postsynaptic currents (PSCs) was studied. Excitatory postsynaptic currents (EPSCs) were evoked by stimulation of Schaffer collaterals (SCs) in the presence of APV and bicuculline to pharmacologically isolate the EPSCs mediated by AMPAR activation. IEM-1460 (50 microM) did not affect the amplitude of EPSCs in CA1 pyramidal cells but reversibly decreased their amplitude in interneurons of pyramidal layer (15 cells), radiatum (37 cells) and border radiatum-lacunosum-moleculare (R-LM) (55 cells) layers. The ability of IEM-1460 to decrease EPSC amplitude correlated with EPSC rectification properties in CA1 interneurons, providing evidence for synaptic localization of Ca2+ permeable AMPARs at the SC synaptic input. Independent of their localization, the majority of interneurons studied exhibited only modest sensitivity to IEM-1460 (EPSC amplitude decreased by less than 30%), while in 15% of interneurons IEM-1460 induced more than 50% reduction in EPSC amplitude. To reveal possible afferent-specific localization of Ca2+ permeable AMPARs on R-LM interneurons, the effect of IEM-1460 on EPSCs evoked by stimulation of SC was compared with that of perforant path (PP). Although average sensitivities did not differ significantly, in 61% of R-LM layer interneurons, the SC-evoked EPSCs exhibited higher sensitivity to IEM-1460 than the PP-evoked EPSCs. Moreover, in 54% of R-LM layer interneurons the EPSCs evoked by SC stimulation were complex, having an initial peak followed by one or several late components. Kinetics, latency distribution and reversal potential of late components suggest di- and polysynaptic origin of the late components. Late EPSCs were strongly and reversibly inhibited by IEM-1460 indicating that Ca2+ permeable AMPARs are involved in the indirect excitation of R-LM layer interneurons. Despite the ability to decrease the excitatory synaptic input to interneurons, IEM-1460 did not affect interneuron-mediated inhibitory postsynaptic currents (IPSCs) evoked in pyramidal neurons by SC stimulation. These data suggest that interneurons with a synaptic input highly sensitive to IEM-1460 do not contribute specifically to the feed-forward inhibition of hippocampal pyramidal neurons.

Adamantane↗

Structure-function relationships in rat brain stem subnucleus interpolaris. IX. Inputs from subnucleus caudalis.

1. In an accompanying paper, Jacquin et al. (1990) described the effects of cortical ablation on the receptive-field (RF) properties of neurons in spinal trigeminal (SpV) subnucleus interpolaris (SpVi). A similar ablation paradigm was used here to clarify the role of an additional source of SpVi RF modulation, the extensive projection from caudally adjacent subnucleus caudalis (SpVc). 2. Intra- and extracellular recording, electrical stimulation, and RF mapping techniques were used to study the responses and projections of 356 SpVi cells in 11 rats 58-141 days after surgical isolation of SpVc from SpVi. This was achieved by a transverse knife cut through the lateral one-half of the left medulla just caudal to the obex. Because this lesion severs trigeminal (V) primary afferents caudal to SpVi, as well as postsynaptic intersubnuclear axons traversing to and from SpVi, kainic acid was used in other animals to selectively lesion SpVc inputs to SpVi. Seven rats received kainic acid injections into SpVc 5-28 days before providing similar electrophysiological data on 300 SpVi cells. Results were compared with that of 330 cells from 9 normal adult rats. 3. Knife-cut or kainic-acid lesions did not alter the topography of SpVi cells or the RF properties of 71 ipsilateral V primary afferents. However, both types of lesions produced the same profound changes in the response character of SpVi cells. Statistically reliable increases were found in the relative percentages of cells that 1) expressed convergence from multiple receptor organs, 2) were unresponsive to mechanical stimulation of orofacial regions, 3) responded tonically to a maintained peripheral stimulus, 4) were spontaneously active, 5) were directionally sensitive, 6) responded to stimulation of body surfaces innervated by cervical primary afferents, and 7) had split RFs. 4. RFs were also reliably larger for whisker-activated local circuit and projection neurons after both types of lesions. Over one-third of this local circuit group responded to more than one whisker in both experimental groups, whereas in normals all responded to one whisker. 5. All other SpVi response indices were unchanged by SpVc lesions. The most notable negative result was a normally low percentage of cells that were responsive to nociceptive stimuli. 6. To assess whether these RF changes reflected altered collateral morphology of V primary afferents in SpVi, whisker (n = 11) and guard-hair- (n = 7) activated axons were stained with horseradish peroxidase rostral to knife-cut or kainic-acid lesions.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

The coeruleospinal noradrenergic neurons: anatomical and electrophysiological studies in the rat.

The neuranatomical location and pharmacological sensitivity of coeruleospinal neurons were studied with a combination of retrograde tracing experiments and single unit recording. Coeruleospinal neurons were multipolar, medium-sized cells and were found in the ventral division of the locus coeruleus and in the locus subcoeruleus. In the locus coeruleus proper, they presumably corresponded to the large cells of the ventral division defined in previous Golgi studies. Coeruleospinal cells were identified by antidromic stimulation from the cervical spinal cord. Their firing rate was slow and regular, their conduction velocity characteristic of unmyelinated fibers (0.65 m/sec). The method of antidromic stimulation also revealed that coeruleospinal neurones possess an anteriorly directed collateral traveling in the midbrain reticular formation outside the main noradrenergic dorsal bundle. These neurones were strongly inhibited by the iontophoretic application of morphine, noradrenaline, clonidine, GABA and excited by ACh. Although the coeruleo- and subcoeruleospinal neurones are clearly a group of cells distinct from the coeruleocortical projection, their electrophysiological and pharmacological properties are essentially identical.

Animals↗

Transient increase of cytoplasmic calcium concentration in the rat hippocampus after kindling-induced seizures. An ultrastructural study with the oxalate-pyro-antimonate technique.

Kindling stimulations were applied to the Schaffer collateral/commissural fibers in the CA1 area of the dorsal rat hippocampus. In fully kindled animals the ultrastructural distribution of calcium was studied at different time intervals after an induced generalized seizure, using the oxalate-pyro-antimonate technique. Semi-quantitative analysis of the amount of precipitate revealed no change in the investigated structures analysed after 2 h or 24 h: boutons and spines of the Schaffer-collateral/pyramidal-dendrite synaptic contacts, cytoplasm and mitochondria of terminals on pyramidal cell bodies and smooth dendrites. The major change was found 15 min after a seizure, when calcium precipitate in boutons and spines of stratum radiatum was strongly increased, precipitate in somata terminals only slightly, while smooth dendrites were not affected. These results imply a seizure-related increase of the intracellular calcium concentration. The transient character suggests that the investigated cellular compartments in kindled tissue are still capable of maintaining calcium homeostasis. The observed increase in precipitate density for at least 15 min may initiate the neurochemical mechanisms leading to an enhanced seizure sensitivity in the kindling model of epilepsy.

Animals↗

Depolarization-induced long-term depression at hippocampal mossy fiber-CA3 pyramidal neuron synapses.

Hippocampal CA3 pyramidal neurons receive two types of excitatory afferent innervation: mossy fibers (MFs) from granule cells of the dentate gyrus and recurrent collateral fibers (CFs) from other CA3 pyramidal neurons. At CF-CA3 pyramidal neuron synapses, membrane depolarization paired with low (0.33 Hz) presynaptic stimulation generated a heterogeneous response that ranged from long-term potentiation (LTP), long-term depression (LTD), to no alteration of synaptic strength. However, the same induction paradigm applied at MF-CA3 pyramidal neuron synapses consistently induced LTD. This novel form of LTD was independent of NMDARs, mGluRs, cannabinoid receptors, opioid receptors, or coincident synaptic activity, but was dependent on postsynaptic Ca2+ elevation through L-type Ca2+ channels and release from inositol 1,4,5-trisphosphate receptor-sensitive intracellular stores. Ca2+ imaging of both proximal and distal CA3 pyramidal neuron dendrites demonstrated that the depolarizing induction paradigm differentially elevated intracellular Ca2+ levels. L-type Ca2+ channel activation was observed only at the most proximal locations where mossy fibers make synapses. Depolarization-induced LTD did not occlude the conventional 1 Hz-induced LTD or vice versa, suggesting independent mechanisms underlie each form of plasticity. The paired-pulse ratio and coefficient of variation of synaptic transmission were unchanged after LTD induction, suggesting that the expression locus of LTD is postsynaptic. Moreover, peak-scaled nonstationary variance analysis indicated that depolarization-induced LTD correlated with a reduction in postsynaptic AMPA receptor numbers without a change in AMPA receptor conductance. Our results suggest that this novel form of LTD is selectively expressed at proximal dendritic locations closely associated with L-type Ca2+ channels.

Animals↗

Postnatal development of alpha-adrenoceptor-mediated autoinhibition in the locus coeruleus.

Rats, from birth to postnatal day 34, were anesthetized with urethane and a neuropharmacological study was carried out of the autoreceptors located on the somadendritic membranes of locus coeruleus (LC) neurons. Iontophoretic application of noradrenaline (NA) caused inhibition of LC cell firing at all developmental stages, and such inhibition was totally blocked by the alpha 2-antagonist piperoxane. The sensitivity of LC neurons to iontophoretically applied NA appeared to become reduced with age. In LC neurons from birth to postnatal day (PD) 8, the prolonged period of suppressed firing after antidromic activation by stimulation of the dorsal noradrenergic bundle was not shortened by piperoxane. After PD 9, the proportion of LC neurons in which piperoxane could antagonize the postactivation inhibition increased with age. These results indicated that although LC neurons, even at birth, had alpha 2-adrenoceptors on the somadendritic membranes which were responsible for the NA-induced inhibition, inhibition of LC cell firing caused by NA released from the terminals of axon collaterals and/or possibly from dendrodendritic synapses did not occur until PD 9.

Action Potentials↗

Spatial memory deficits in patients with lesions to the right hippocampus and to the right parahippocampal cortex.

Spatial memory tasks, performance of which is known to be sensitive to hippocampal lesions in the rat, or to medial temporal lesions in the human, were administered in order to investigate the effects of selective damage to medial temporal lobe structures of the human brain. The patients had undergone thermo-coagulation with a single electrode along the amygdalo-hippocampal axis in an attempt to alleviate their epilepsy. With this surgical technique, lesions to single medial temporal lobe structures can be carried out. The locations of the lesions were assessed by means of digital high-resolution magnetic resonance imaging and software allowing a 3-D reconstruction of the brain. A break in the collateral sulcus, dividing it into the anterior collateral sulcus and the posterior collateral sulcus is reported. This division may correspond to the end of the entorhinal/perirhinal cortex and the start of the parahippocampal cortex. The results confirmed the role of the right hippocampus in visuo-spatial memory tasks (object location, Rey-Osterrieth Figure with and without delay) and the left for verbal memory tasks (Rey Auditory Verbal Learning Task with delay). However, patients with lesions either to the right or to the left hippocampus were unimpaired on several memory tasks, including a spatial one, with a 30 min delay, designed to be analogous to the Morris water maze. Patients with lesions to the right parahippocampal cortex were impaired on this task with a 30 min delay, suggesting that the parahippocampal cortex itself may play an important role in spatial memory.

Adolescent↗

The effects of cyanide on neural and synaptic function in hippocampal slices.

Transverse slices from guinea pig hippocampi were exposed to micromolar concentrations of sodium cyanide while neural and synaptic function were monitored in the CA1 region. Cyanide concentrations between 10 and 200 microM rapidly depressed synaptic transmission between Schaffer collateral-commissural fibers and CA1 pyramidal cells. Analysis of input/output curves revealed that the suppression had two components, a decrease in EPSP generation and an increase in action potential threshold. Direct electrical excitability of axons was not affected. At concentrations to 500 microM, cyanide had no effect on antidromic activation of pyramidal cells. At 1000 microM, cyanide caused a moderate depression of the antidromic response in one slice while having no effect in one other. In some experiments, postsynaptic responses in the gyrus dentatus (GD), evoked by perforant path stimulation, were recorded simultaneously with CA1 responses during cyanide application. GD was found to be less sensitive to cyanide than CA1. All cyanide effects reversed rapidly and completely upon washout. These findings suggest that cyanide has a direct effect on neurons not mediated by its inhibition of metabolism.

Action Potentials↗

Differential sensitivity of human visual cortex to faces, letterstrings, and textures: a functional magnetic resonance imaging study.

Twelve normal subjects viewed alternating sequences of unfamiliar faces, unpronounceable nonword letterstrings, and textures while echoplanar functional magnetic resonance images were acquired in seven slices extending from the posterior margin of the splenium to near the occipital pole. These stimuli were chosen to elicit initial category-specific processing in extrastriate cortex while minimizing semantic processing. Overall, faces evoked more activation than did letterstrings. Comparing hemispheres, faces evoked greater activation in the right than the left hemisphere, whereas letterstrings evoked greater activation in the left than the right hemisphere. Faces primarily activated the fusiform gyrus bilaterally, and also activated the right occipitotemporal and inferior occipital sulci and a region of lateral cortex centered in the middle temporal gyrus. Letterstrings primarily activated the left occipitotemporal and inferior occipital sulci. Textures primarily activated portions of the collateral sulcus. In the left hemisphere, 9 of the 12 subjects showed a characteristic pattern in which faces activated a discrete region of the lateral fusiform gyrus, whereas letterstrings activated a nearby region of cortex within the occipitotemporal and inferior occipital sulci. These results suggest that different regions of ventral extrastriate cortex are specialized for processing the perceptual features of faces and letterstrings, and that these regions are intermediate between earlier processing in striate and peristriate cortex, and later lexical, semantic, and associative processing in downstream cortical regions.

Adult↗

Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistance-associated protein 1 and provokes high levels of cross-resistance to glucocorticoids.

OBJECTIVE: To explore the onset and molecular mechanism of resistance to the antimalarial disease-modifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells. METHODS: Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ. RESULTS: Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor alpha) and chemokines (interleukin-8). CONCLUSION: Induction of overexpression of the multidrug resistance efflux transporter MRP-1 can emerge after long-term exposure to CQ and results in CQ resistance and collateral resistance to dexamethasone. These findings warrant further detailed investigations into the possible role of MRP-1 and other members of the superfamily of drug efflux pumps in diminishing the efficacy of DMARDs in rheumatoid arthritis treatment.

Antirheumatic Agents↗

[Skier's thumb. Sonographic clarification of retracted ruptures].

Rupture of the ulnar collateral ligament (LCU) is the result of traumatic abduction of the metacarpophalangeal joint of the thumb ("skier's thumb"). If the ligament becomes retracted superficially to the adductor aponeurosis, surgical treatment is advocated, non-displaced tears can be treated by immobilization. Differentiation between displaced and non-displaced tears by radiography is not possible. We examined 45 patients to assess whether sonography was of help in this respect. The retracted LCU appeared as a hypoechogenic, mostly round structure medial to the metacarpal head. Using this criterion, 86% of retracted ruptures could be diagnosed correctly. Although intact LCU and nondisplaced tear cannot be differentiated consistently by sonography, high sensitivity in diagnosis of retracted ruptures seems promising, as it enables specific planning of therapeutic decisions.

Adolescent↗

Loss of the insular ribbon: another early CT sign of acute middle cerebral artery infarction.

Although computed tomography (CT) remains the most frequently used imaging examination in acute cerebral infarction, its sensitivity for early detection of strokes remains limited. In middle cerebral artery (MCA) strokes less than 6 hours old, loss of definition of the gray-white interface in the lateral margins of the insula ("insular ribbon") was observed. The acute and subacute CT findings in 11 retrospective and 16 prospective patients are presented. Loss of the insular ribbon was detected in 12 of the prospective cases and in all 11 retrospective cases. The insular ribbon is supplied by the insular segment of the MCA and its claustral branches. With cessation of MCA flow, the insular ribbon becomes the region most distal from the anterior and posterior cerebral collateral circulations. Consequently, the insular ribbon effectively becomes a watershed arterial zone. Loss of the insular ribbon is thus a reflection of acute edema due to infarction. Loss of the insular ribbon appears to be another frequent and reliable finding in acute MCA stroke.

Aged↗

Pharmacological characterization of extracellular pH transients evoked by selective synaptic and exogenous activation of AMPA, NMDA, and GABAA receptors in the rat hippocampal slice.

1. Inhibitors of extracellular carbonic anhydrase (CAo) offer much promise as diagnostic tools in the study of the synaptic basis of activity-induced alkaline transients in the brain. However, most of the present information related to the effects of CAo blockers in nervous tissue comes from experiments that involve simultaneous synaptic activation of various types of postsynaptic receptor channels. In the present work, double-barreled H(+)-selective microelectrodes were used to study alkaline shifts in extracellular pH (pHo) evoked by selective synaptic and pharmacological activation of glutamate and gamma-aminobutyric acid (GABA) receptors in the CA1 cell body layer in rat hippocampal slices. Inhibition of CAo was achieved with the use of the poorly permeant carbonic anhydrase inhibitor, benzolamide (10 microM; applied in the bath solution) or the impermeant macromolecular inhibitor, prontosil-dextran 5000 (PD 5000; applied in microdrops). 2. Alkaline transients that were exclusively attributable to synaptic activation of glutamate receptors were induced by stimulation of Schaffer collaterals in the presence of picrotoxin (PiTX, 100 microM). An enhancement by the CAo inhibitors of these alkaline transients took place at all stimulus frequencies (5-200 Hz) and stimulus train durations (0.5-20 s) examined. 3. Inhibition of CAo enhanced the alkaline transients evoked by selective synaptic activation of alpha-amino-3-hydroxy-5-methyli-oxazolate- 4-propionic acid (AMPA)/kainate receptors in experiments involving stimulation of Schaffer collaterals in the simultaneous presence of PiTX and D-2-amino-5-phosphonopentoate (AP5, 40-80 microM). 4. Alkaline shifts evoked by selective synaptic activation of N-methyl-D-aspartate (NMDA) receptors were enhanced after inhibition of CAo as seen in experiments where Schaffer collaterals were stimulated in the simultaneous presence of PiTX and 6-cyano-2,3-dihydroxy-7-nitroquinoxaline (CNQX, 20-40 microM) in an Mg(2+)-free solution. 5. Benzolamide and PD 5000 also enhanced the alkaline shifts seen upon pressure injection of glutamate, AMPA, or NMDA. The glutamate-induced alkaline shifts were inhibited by AP5+CNQX, suggesting that uptake of glutamate did not significantly contribute to their generation. 6. Stimuli applied at 5-10 Hz in stratum radiatum close (within 0.5 mm) to the recording site evoked alkaline shifts that were blocked by CNQX plus AP5. In the continuous presence of the two glutamate antagonists, PiTX-sensitive alkaline transients were observed in response to brief high-frequency (20-100 Hz) trains consisting of 100 stimuli. Upon application of pentobarbital sodium (100 microM), these apparently monosynaptically evoked GABAA receptor-mediated alkaline transients were evident also at low stimulation frequencies (5-10 Hz).(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Morphology of globus pallidus neurons: its correlation with electrophysiology in guinea pig brain slices.

Intracellular recordings obtained from globus pallidus neurons in guinea pig revealed, on the basis of their membrane properties, the existence of at least two major (types I and II) and one minor (type III) groups of neurons. Type I neurons were silent at the resting membrane level and generated a burst of spikes with strong accommodation to depolarizing current injection. Type II neurons fired at the resting membrane level or with small membrane depolarization, and their repetitive firing (< or = 200 Hz) was very sensitive to the amplitude of injected current and showed weak accommodation. Type III neurons did not fire spontaneously at the resting membrane level. The neurons were morphologically characterized by intracellular injection of biocytin following the electrophysiological recordings. Among the major groups, the soma size of type I neurons (40 x 23 microns) was larger than that of type II neurons (29 x 17 microns). Both types of neurons had three to six primary dendrites. Dendritic spines were very sparse. Occasionally, dendrites exhibited varicosities, especially in their terminal branches. Dendritic fields were disc-like in shape and were perpendicular to striopallidal fibers. Most of the axons had intranuclear collaterals. Main axonal branches projected rostrally or caudally, and in some neurons one axonal branch could be followed caudally, and another rostrally, into the striatum. These two types were major neurons in the globus pallidus and were considered to be projection neurons. Type III neurons were small (18 x 12 microns), and their dendrites were covered with numerous spines. They were considered to be interneurons.

Animals↗

Mathematical performance and behavior of children with hyperactivity with and without coexisting aggression.

An analysis was made of a basic skill deficit and collateral behavior that could differentiate youth with hyperactivity from children with both hyperactivity and aggression. A total of 92 boys (with hyperactivity, with hyperactivity and aggression, and without disorders) were assessed for their timed performance and accuracy of computer-generated math operations. Response time differences documented between disordered and nondisordered groups, and between the diagnostic groups, were not explained by the group differences that were also observed in behavior or motor response speed (typing). Conclusions derived from these findings, and from prior work, indicated that speed of addition may be a marker of academic and social dysfunction. The overall importance of this assessment is related to the potential sensitivity of math fluency data for assessment and treatment monitoring.

Aggression↗

Electrical stimulation of the stratum radiatum increases the release and neosynthesis of aspartate, glutamate, and gamma-aminobutyric acid in rat hippocampal slices.

The release of endogenous aspartic, glutamic, and gamma-aminobutyric acids (Asp, Glu, GABA, respectively) was measured in the effluent from superfused hippocampal slices using a new and sensitive mass spectrometric method. The stimulation of the stratum radiatum of the rat dorsal hippocampus caused a Ca2+-dependent increase in the release of these amino acids. This release was accompanied by an increase in the incorporation of [13C2] from [13C]glucose into Asp, Glu, and GABA, suggesting an increase in their neosynthesis. The removal of Ca2+ from the superfusion fluid brought about a marked decrease in Asp and Glu release at rest, and prevented their stimulation-evoked release and the appearance of population spikes. The results support the hypothesis that Asp and Glu are excitatory neurotransmitters in intrinsic hippocampal circuits and are possibly released from the Schaffer collaterals and commissural fibres. The increase in GABA release and neosynthesis during stimulation of the stratum radiatum could be related to recurrent inhibition evoked by transsynaptic stimulation of the pyramidal cells.

Animals↗

Cardiac resynchronization therapy with special focus on patency of coronary sinus and its branches: conceptual viewpoint and semi-theoretical considerations on lead-induced obstruction.

Cardiac resynchronization therapy appears to be useful for patients with severe chronic congestive heart failure. However, many questions still arise concerning the effectiveness of this kind of therapy since hemodynamic improvement is not observed in all patients. Heterogeneity of conclusions reported by several multicenter clinical trials and prominent experts demonstrates that many uncertainties related to cardiac resynchronization therapy still exist. We tried to reveal some inadequacies in clinical results by focusing on cardiac venous blood return which is likely complicated by the presence of lead inside the coronary sinus and its branches. Downstream traversing lead may occlude (partially or completely) the ostia of minor tributaries and target vein of lead final positioning. Thrombosis may also be incited within the coronary sinus itself. Remaining lumen predetermined by the lead body and subsequent thrombosis may be insufficient to provide adequate blood flow. Resulting detrimental venous return presumably may slightly depress myocardial contractility which may be significant in very sensitive group of patients assigned to the New York Heart Association class III or IV. Cardiac venous blood pumping conditions (or venous drainage) are likely also complicated by abnormal activation of left ventricle. The contributory role of these two subtle causes unfavorably influencing venous drainage is still unknown. It may be treated as a hypothetical attempt to find the clue and needs future studies for verification.

Cardiac Pacing, Artificial↗