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Reverse homodigital dorsal radial flap of the thumb.

BACKGROUND: Reconstruction of extensive distal defects of the thumb with exposure of bone, tendon, or joint can be a difficult problem because immediate closure is of paramount importance for preserving function and avoiding complications. Surgical treatment includes the use of local, reverse flow, and free flaps. The authors describe a new reverse homodigital flap to repair distal defects of the thumb. This flap is raised from the dorsal radial side of the first metacarpal area. It is pedicled on the dorsal radial collateral artery, which is constant for course, caliber, and communication with the palmar circuit. METHODS: The flap is raised by means of distal to proximal dissection, the skin island is incised at the periphery, and the subcutaneous pedicle is separated from superficial and deep tissues, leaving a certain quantity of loose tissue to protect the vascular axis. The digital sensory radial nerve is enclosed in the pedicle. The dissection must stop near the middle point of the proximal phalanx, which constitutes the pivot point of the flap. The flap is distally transposed and sutured on the deficit site. RESULTS: The homodigital dorsal radial flap was used on 16 patients to repair distal losses of substance of the thumb. The final results were good for reliability and coverage and from the aesthetic point of view for both the reconstructed area and the donor site. In pulp reconstruction, there was a good recovery of sensitivity, without a neural anastomosis being performed (the mean value of static two-point discrimination was 9 cm in this series). CONCLUSION: Wider use of this flap has helped to improve knowledge of dorsal vascularization of the thumb and to give another option for the repair of distal losses of substance of the thumb.

Adolescent↗

Influence of an extracellular acidosis on excitatory synaptic transmission and long-term potentiation in the CA1 region of rat hippocampal slices.

The effects of extracellular acidification on the synaptic function and neuronal excitability were investigated on the hippocampal CA1 neurons. A decrease of extracellular pH from 7.4 to 6.7 did not alter either the resting membrane potential or the neuronal membrane input resistance. Extracellularly recorded field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) were significantly reduced by acidosis. Additionally, the amplitude of presynaptic fiber volley was also reduced. The sensitivity of postsynaptic neurons to N-methyl-D-aspartate, but not to alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, was depressed by acidosis. Lowering of extracellular pH did not significantly affect the magnitude of paired-pulse facilitation (PPF) of synaptic transmission. Acidosis also reversibly limited the sustained repetitive firing (RF) of Na(+)-dependent action potentials elicited by injection of depolarizing current pulses into the pyramidal cells. The limitation of RF by extracellular acidification was accompanied by the reduction of the maximal rate of rise (;V(max)) of the action potentials and the amplitude of afterhyperpolarization. Neither the Na (+)/H (+) antiporter blocker 5-(N -ethyl -N -isopropyl)-amiloride nor the selective adenosine A (1) receptor antagonist 1,3-dipropyl -8-cyclopentylxanthine, however, affected the acidosis -induced synaptic depression. It was also found that acidosis did not affect either the induction r maintenance of long -term potentiation (LTP) at Schaffer collateral -CA 1 synapses. These results suggest that the extracellular acidosis -induced synaptic depression is likely to result from an inhibition of presynaptic Na (+) conductance, thereby decreasing the amplitude of action potentials in individual afferent fibers or the number of afferent fiber activation to stimuli and then indirectly affecting the signaling processes contributing to trigger neurotransmitter release.

Acidosis↗

[Diagnosis of intra-articular fracture of the head of the tibia. A prospective comparative study].

Complete visualization of the joint surface is essential for correct assessment of tibial head fractures. Conventional tomography, computed tomography (CT), and magnetic resonance imaging (MRI) are compared in this prospective study. We examined 27 patients (19 suffering from B fractures and 8 from C fractures) from 1 January 1995 to 11 November 1998. Conventional tomography underestimated the fractures in 3 of the 19 cases of B fractures. Computed tomography underestimated two of these cases. MRI could not exactly depict the essential structures in three of the eight cases of C fractures because of edema and effusions. MRI identified complete cruciate ligament rupture in 6 of the 27 cases (18%) and 10 meniscal ruptures in 9 cases (33%: 6 medial meniscus, 4 lateral meniscus). Complete ruptures of the lateral collateral ligament were detected in five cases and medial collateral ligament ruptures in two cases. According to this, 63% of the patients suffered from relevant accompanying soft tissue injuries. The rate of soft tissue injuries increased up to 92% including the partial collateral ligament ruptures. Local hospital conditions permitting, X-ray-loaded conventional tomography should no longer be used in tibial head fractures. X-ray-free MRI is most efficient in cases of B fractures, which can in most cases be treated with a minimum of invasive techniques. Computed tomography is to be used in cases of C fractures that are regularly managed by open surgery accompanied by direct visualization of the inside of the knee joint.

Adult↗

Suppression of presynaptic calcium influx by metabotropic glutamate receptor agonists in neonatal rat hippocampus.

Mechanisms of presynaptic inhibition by metabotropic glutamate receptor (mGluR) agonists were investigated in neonatal rat hippocampal CA1 region using the optical recording technique recently developed. Following selective loading of presynaptic terminals with a fluorescent Ca2+ indicator dye rhod-2 AM, changes in Ca2+ signals and the corresponding field excitatory postsynaptic potentials (EPSPs) induced by single electrical stimuli to the Schaffer collateral-commissural (SCC) pathway were recorded simultaneously. Application of a mGluR agonist, 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 100 microM) or (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD; 100 microM), reversibly reduced both the field EPSP and the presynaptic Ca2+ transient, and the quantitative relationship between them was quite similar to that observed during application of Cd2+, a non-selective Ca2+ channel blocker, or in a Ca(2+)-free solution. Application of 4-aminopyridine (4-AP; 1 mM), a blocker of certain subtypes of voltage-dependent K+ channels, significantly inhibited the 1S,3R-ACPD effect. Application of DCG-IV, a novel mGluR2/mGluR3-selective agonist, suppressed field EPSPs only slightly even at a high dose (3 microM). These results suggest that activation of presynaptic mGluR different from mGluR2/mGluR3 suppresses the action potential-triggered Ca2+ influx, probably via 4-AP-sensitive mechanisms, and thereby reduces glutamate release in neonatal rat hippocampal CA1 region.

Animals↗

N-methyl-D-aspartate receptor-dependent long-term potentiation in CA1 region affects synaptic expression of glutamate receptor subunits and associated proteins in the whole hippocampus.

Long term potentiation in hippocampus, evoked by high-frequency stimulation, is mediated by two major glutamate receptor subtypes, alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptors and N-methyl-D-aspartate receptors. Receptor subunit composition and its interaction with cytoplasmic proteins constitute different pathways regulating synaptic plasticity. Here, we provide further evidence that N-methyl-D-aspartate receptor-mediated long term potentiation evoked at hippocampal CA1 region of rats induced by high-frequency stimulation of the Schaffer collateral-commissural pathway in vivo is not dependent on N-methyl-D-aspartate receptor subunit NR2B. Applying semi-quantitative immunoblotting, we found that in the whole tetanized hippocampus, synaptic expression of the N-methyl-D-aspartate and alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptor subunits (NR1, NR2A, glutamate receptor 1) and their associated partners, e.g. synaptic associated protein 97, postsynaptic density protein 95, alpha subunit of Ca2+/calmodulin-dependent protein kinase II, neuronal nitricoxide synthase, increased 180 min post-high-frequency stimulation. Moreover, phosphorylation of Ca2+/calmodulin-dependent protein kinase II at thr286 and glutamate receptor 1 at ser831 was increased 30 min post-high-frequency stimulation and blocked by N-methyl-D-aspartate receptor antagonists (AP-5 and MK-801). In sham group and controls, these changes were not observed. The expression of several other synaptic proteins (NR2B, glutamate receptors 2/3, N-ethylmaleimide sensitive factor) was not affected by long term potentiation induction. In hippocampal homogenates, the level of these proteins remained unchanged. These data indicate that N-methyl-D-aspartate receptor-dependent long term potentiation in CA1 region in vivo mainly affects the synaptic expression of glutamate receptor subunits and associated proteins in the whole hippocampus. The alteration of molecular aspects can play a role in regulating the long-lasting synaptic modification in hippocampal long term potentiation in vivo.

2-Amino-5-phosphonovalerate↗

Modulation of striatal neuronal activity by glutamate and GABA: iontophoresis in awake, unrestrained rats.

To examine the effects of glutamate (GLU) and gamma-aminobutyric acid (GABA) and their interactions in the striatum under behaviorally relevant conditions, single-unit recording was combined with microiontophoresis in awake, unrestrained rats. Iontophoretically applied GLU (0-40 nA, 20 s) excited all spontaneously active neurons in dorsal (caudate-putamen) and ventral (accumbens, core) striatum; phasic GLU-induced excitations (mean threshold 19.7 nA) were dose-dependent, inversely correlated with rate of basal activity (excitation limit approximately 65 imp/s), and highly stable during repeated GLU applications. GLU also excited silent and sporadically active units, which greatly outnumbered spontaneously active cells, and enhanced neuronal excitations associated with movement. Both spontaneously active and GLU-stimulated striatal neurons were highly sensitive to GABA (0-40 nA, 20 s); most showed short-latency inhibitions during GABA diffusion from the pipette (0 nA) and the response quickly progressed to complete silence with a small increase in current. The GABA-induced inhibition was current-dependent, equally strong on spontaneously active and GLU-stimulated units, and independent of neuronal discharge rate, but less stable than the GLU-induced excitation during repeated drug applications. Prolonged GABA application (0-20 nA, 2-4 min) reduced basal impulse activity, but was less effective in attenuating the neuronal excitations induced by GLU or associated with movement. Our data support the role of GLU afferents in the phasic activation of striatal neurons and suggest that the effects of GLU strongly depend on the level of ongoing neuronal activity. The ability of GABA to modulate both basal and GLU-evoked activity suggests that GABA, released from efferent collaterals and interneurons, plays a critical role in regulating neuronal activity and responsiveness to phasic changes in excitatory input.

Action Potentials↗

Analysis of PTCA-induced ischemia using an ECG inverse solution or the wavelet transform.

In patients without significant collaterals, percutaneous transluminal coronary angioplasty (PTCA) produces acute transient ischemia that is detectable in both standard electrocardiograms (ECG) and body surface potential maps (BSPMs). Control recordings made before or between inflations provide personalized baselines, which isolate the effects of ischemia from interpatient differences, such as torso shape and electrode location. In this study, two methods of evaluating PTCA-induced ischemia from BSPM recordings are presented. In the first method, an ECG inverse solution that estimates epicardial potentials from body surface signals using a realistic model of torso geometry is applied. The strength of this method lies in its potential ability to localize areas of cardiac ischemia on the epicardial surface. In the second approach, wavelet transforms were used to perform a multiresolution decomposition of the BSPM data into different frequency bands. The basis functions of the wavelet transform are time-limited and narrow band and hence can be expected to be sensitive to features of the BSPM that originate in discrete electrophysiologic events, such as intrusion of the activation front onto regions of ischemia or arrhythmias due to local conduction abnormalities. The method also offers a means of temporal and frequency localization of cardiac events related to the initiation of injury currents and abnormal conduction due to PTCA-induced ischemia. The inverse solution and the wavelet transform each offer new views of the spatial and temporal courses of acute ischemia potentially leading to new diagnostic insights in ECG patient examination.

Angioplasty, Balloon, Coronary↗

T-cell immune responses in the brain and their relevance for cerebral malignancies.

In order that cellular immune responses afford protection without risk to sensitive normal tissue, they must be adapted to individual tissues of the body. Nowhere is this more critical than for the brain, where various passive and active mechanisms maintain a state of immune privilege that can limit high magnitude immune responses. Nevertheless, it is now clear that immune responses are induced to antigens in the brain, including those expressed by cerebral malignancies. We discuss hypotheses of how this can occur, although details such as which antigen presenting cells are involved remain to be clarified. Antitumor responses induced spontaneously are insufficient to eradicate malignant astrocytomas; many studies suggest that this can be explained by a combination of low level immune response induction and tumor mediated immunosuppression. A clinical objective currently pursued is to use immunotherapy to ameliorate antitumour immunity. This will necessitate a high level immune response to ensure sufficient effector cells reach the tumor bed, focused cytotoxicity to eradicate malignant cells with little collateral damage to critical normal cells, and minimal inflammation. To achieve these aims, priority should be given to identifying more target antigens in astrocytoma and defining those cells present in the brain parenchyma that are essential to maintain antitumour effector function without exacerbating inflammation. If we are armed with better understanding of immune interactions with brain tumor cells, we can realistically envisage that immunotherapy will one day offer hope to patients with currently untreatable neoplastic diseases of the CNS.

Animals↗

Effects of exogenous creatine on population spike amplitude and on postanoxic hyperexcitability in brain slices.

In in vitro rat hippocampal slices, a short period of transient anoxia caused a lasting increase in the amplitude of the compound action potential (population spike, PS) that was evoked in CA1 by stimulation of the Schaffer collaterals. No such increase was seen over a comparable period of time in slices that were not subjected to anoxia. The appearance of such an increase was dependent on the duration of anoxia. Anoxia of 1 min duration did not cause any increase, anoxia lasting 2 min caused a nonsignificant increase, while 3 min of anoxia caused a lasting and statistically significant increase in PS amplitude. Addition of creatine, a compound that is known to afford protection against severe neuronal damage from longer periods of anoxia, prevented PS potentiation at a concentration of 10 mM, but not at a concentration of 1 mM. In addition, while 1 mM creatine by itself did not show any effect on PS amplitude of control slices, 10 mM creatine decreased PS amplitude also in such control slices, that had not been exposed to anoxia. These data demonstrate that this postanoxic hyperexcitability is caused by mechanisms that are little sensitive to the protection that in other contexts is provided by creatine. We suggest that understanding the mechanisms of postanoxic hyperexcitability may help understand the pathophysiology of the epileptic seizures that sometimes occur at the time of an ischemic stroke.

Action Potentials↗

Collateral methotrexate resistance in cultured human head and neck carcinoma cells selected for resistance to cis-diamminedichloroplatinum(II).

A human head and neck squamous cell carcinoma line (SCC25) derived from a patient with no prior history of radiotherapy or chemotherapy was made resistant to cis-diamminedichloroplatinum(II) (CDDP) by continuous escalation of weekly 30-min pulses of the CDDP from 0 to 0.2 mM over 20 months and then cloned and pulsed weekly with 0.2 mM CDDP for another 20 months. This afforded a resistant subline, SCC25/CP[1], with an IC50 for CDDP 12-fold higher than that of the parental cells. The SCC25/CP[1] cells unexpectedly proved to be cross-resistant to methotrexate (MTX) (24-fold for 30-min treatment and 8-fold for continuous treatment). Resistance was associated with a modest (about 2-fold) increase in the dihydrofolate reductase (DHFR) content according to radioligand-binding assay, and in the rate of cell division. In addition there was a 4-fold decrease in the fraction of long-chain MTX polyglutamates MTX(G4-6) in the cell after 24 h exposure to either 0.2 or 2.0 microM MTX. When the SCC25/CP[1] cells were kept out of CDDP for 8-9 months and 12 months to give the sublines SCC25/CP[2] and SCC25/CP[3], respectively, MTX sensitivity to continuous exposure returned to normal. The SCC25/CP[3] cells still exhibited a slightly elevated DHFR level, but their generation time became shorter than that of the parental SCC25 line. In addition the SCC25/CP[3] cells had an initial uptake velocity (V0) for MTX that was 9-fold greater than the V0 of the SCC25 or SCC25/CP[1] cells, while its ability to form MTX(G4-6) was comparable to that of the SCC25 cells. When SCC25/CP[2] cells were rechallenged with weekly 0.2 mM CDDP pulses for 4-6 months, a MTX-resistant line, SCC25/CP[4], was produced. The SCC25/CP[4] cells retained a slightly elevated DHFR content and a high proliferation rate, but the V0 for MTX influx was intermediate between SCC25 and SCC25/CP[3] cells. The ability to form the longer-chain polyglutamates MTX(G4-6) was again impaired. Thus, MTX cross-resistance can develop in cultured head and neck carcinoma cells when CDDP is used as the selecting agent for primary resistance. MTX resistance is multifactorial, as it is when MTX itself is used as the selecting agent, and appears to involve various combinations of altered growth rate, DHFR content, MTX uptake, and ability to form noneffluxing long-chain MTX polyglutamate species. These results are potentially of clinical relevance, since CDDP and MTX are often used in combination with other drugs or with radiation to treat patients with squamous cell carcinoma of the head and neck.

Biological Transport↗

Comparison of ultrasound, CT, and MR imaging in the evaluation of candidates for TIPS.

To compare ultrasound (US), CT, and MRI in the evaluation of hepatic vascular anatomy, portal and splenic venous flow, and collateral pathways (varices and spontaneous shunts) in candidates for transjugular intrahepatic portosystemic shunting (TIPS), 17 patients with history of refractory variceal bleeding or intractable ascites underwent duplex US, contrast-enhanced CT, and MRI before TIPS. The appearance of portal and hepatic anatomy was graded from 1 (not visible) to 4 (excellent visualization) independently by four radiologists. Presence and direction of portal and splenic venous flow, and presence and location of varices and spontaneous portosystemic shunts were also assessed. Results and effects of interobserver variation were assessed for significance using Friedman's ANOVA and Wilcoxon's signed-rank test. MRI yielded higher scores than CT or US for hepatic veins (P < .0001) and inferior vena cava (P < .0001). MRI and CT scored better than US for portal vein branches (P = .012) and splenic vein (P = .0038). All tests demonstrated the main portal vein well, with no statistically significant difference. US and MRI were more sensitive than CT for detecting portal vein flow and direction (US 76%, CT 0%, MRI 82%). MRI was most sensitive for splenic vein flow and direction (US 41%, CT 0%, MRI 76%). CT and MRI were more sensitive than US in detecting varices (US 5%, CT 50%, MRI 58%) and spontaneous shunts (US 13%, CT 75%, MRI 75%). Interobserver variation did not influence results significantly P = .3691). MRI provides the most useful information and may be the preferred single imaging test prior to TIPS.

Adolescent↗

Do electrocardiographic changes with adenosine myocardial perfusion imaging predict ischaemia in patients with left ventricular hypertrophy?

BACKGROUND: Electrocardiographic (ECG) changes during adenosine myocardial perfusion imaging (MPI) correlate with severe coronary artery disease and the presence of collaterals. However, the significance of these changes during adenosine MPI in patients with left ventricular hypertrophy (LVH) on baseline electrocardiogram is less well understood. OBJECTIVE: To evaluate whether ECG changes on adenosine MPI predict ischaemia in patients with LVH. METHODS: We reviewed retrospectively 454 consecutive patients who had undergone adenosine MPI at our institution. The baseline electrocardiogram was reviewed to determine whether or not LVH was present. All patients were administered adenosine at 140 microg x kg x min for a total of 6 min and Tc-sestamibi was injected at 3 min into the protocol. None of the patients underwent any form of exercise during the stress test. RESULTS: Of the 146 patients with LVH, 10 had stress ECG changes suggestive of ischaemia and 40 had evidence of ischaemia on MPI. Similarly, of the 308 patients without LVH, 43 had stress ECG changes suggestive of ischaemia and 68 had ischaemia on MPI. The sensitivity and specificity of stress ECG changes in predicting ischaemia on perfusion in patients with LVH were 12.5% and 95.3%, respectively, with a positive predictive value of 50% and a negative predictive value of 74.3%. CONCLUSION: ECG changes suggestive of ischaemia in patients with LVH are very specific for ischaemia on MPI, and their significance is similar to that in patients without LVH.

Adenosine↗

Synaptic transmission and synchronous activity is disrupted in hippocampal slices taken from aged TAS10 mice.

Synaptic transmission was studied in hippocampal slices from aged (12-14 months of age) TAS10 mice overexpressing the human form of the amyloid precursor protein harboring the Swedish mutation. A significant deficit in the input-output relationship of glutamatergic synapses in the CA3-CA1 Schaffer collateral pathway was observed, while synaptic transmission in the medial perforant pathway of the dentate gyrus was comparatively preserved. Despite this deficit, relative levels of short- and long-term synaptic plasticity in the CA1 region were similar to those observed in wildtype slices. Specifically, paired pulse facilitation, frequency facilitation (at frequencies of 1, 5, and 10 Hz), and long-term potentiation induced by a theta burst stimulation paradigm were all normal in the CA3-CA1 synapses of TAS10 hippocampal slices. However, synchronized network activity induced by bath application of 4-aminopyridine (4-AP) was compromised. Thus, the frequency of synchronous events induced by 100 microM 4-AP was significantly lower in TAS10 hippocampal slices (inter-event interval: WT, 2.4+/-0.6 s; TAS10, 6.9+/-1.7 s). To study gamma-aminobutyric acid (GABA)ergic synaptic transmission NBQX (20 microM) and D-AP5 (50 microM) were added in order to isolate bicuculline-sensitive GABA-mediated synchronous network activity. The GABAergic network activity was not significantly different from wildtype in terms of frequency. This study suggests that the deficit in glutamatergic synaptic transmission observed in the TAS10 hippocampal slices, may be coupled with alterations in synchronous network activity, which in turn would lead to deficient information processing.

4-Aminopyridine↗

Predicting aneurysm enlargement in patients with persistent type II endoleaks.

OBJECTIVE: The clinical significance of type II endoleaks is not well understood. Some evidence, however, indicates that some type II endoleaks might result in aneurysm enlargement and rupture. To identify factors that might contribute to aneurysm expansion, we analyzed the influence of several variables on aneurysm growth in patients with persistent type II endoleaks after endovascular aortic aneurysm repair (EVAR). METHODS: In a series of 348 EVARs performed during a 10-year period, 32 patients (9.2%) developed type II endoleaks that persisted for more than 6 months. Variables analyzed included those defined by the reporting standards for EVAR (SVS/AAVS) as well as other endoleak characteristics. Univariate, receiver operating characteristic curve, and Cox regression analyses were used to determine the association between variables and aneurysm enlargement. RESULTS: The median follow-up period was 26.5 months (range, 6-88 months). Thirteen patients (41%) had aneurysm enlargement by 5 mm or more (median increase in diameter, 10 mm), whereas 19 (59%) had stable or shrinking aneurysm diameter. Univariate and Cox regression analyses identified the maximum diameter of the endoleak cavity, ie, the size of the nidus as defined on contrast computed tomography scan, as a significant predictor for aneurysm enlargement (relative risk, 1.12; 95% confidence interval, 1.04-1.19; P =.001). The median size of the nidus was 23 mm (range, 13-40 mm) in patients with aneurysm enlargement and 8 mm (range, 5-25 mm) in those without expansion (Mann-Whitney U test, P <.001). Moreover, receiver operating characteristic curve and Cox regression analyses showed that a maximum nidus diameter greater than 15 mm was particularly associated with an increased risk of aneurysm enlargement (relative risk, 11.1; 95% confidence interval, 1.4-85.8; P =.02). Other risk factors including gender, smoking history, hypertension, need of anticoagulation, aneurysm diameter, type of endograft used, and number or type of collateral vessels were not significant predictors of aneurysm enlargement. CONCLUSIONS: In patients with persistent type II endoleaks after EVAR, the maximum diameter of the endoleak cavity or nidus is an important predictor of aneurysm growth and might indicate the need for more aggressive surveillance as well as earlier treatment.

Aged↗

Regulation of coronary blood flow.

Coronary blood flow is dependent upon arterial pressure, diastolic time, and small vessel resistance. The system is regulated to achieve a low flow high oxygen extraction and low myocardial Po(2). This setting is sensitive to change in oxygen needs. Regulation of blood flow occurs primarily through local intrinsic regulation, most likely through production of vasodilating metabolites in response to minimal degrees of ischaemia. Local regulation appears to dominate over remote regulation in most circumstances. Blood flow distribution to the myocardium is depth dependent as well as regional in variation. Both types of distribution of blood flow are profoundly disturbed in the presence of obstructive coronary atherosclerosis. This results in either concentric myocardial shells or patchy transmural zones of selective ischaemia with clear-cut but local abnormalities in metabolism and performance.

Arteriosclerosis↗

Age-dependent, steroid-specific effects of oestrogen on long-term potentiation in rat hippocampal slices.

1. Long-term potentiation (LTP) of hippocampal population spike responses and excitatory postsynaptic potentials (EPSPs) from area CA1 stratum pyramidale was induced in slices of rat hippocampus maintained in vitro following brief high-frequency stimulation (HFS) of the Schaffer collateral-commissural pathway. When administered to slices prior to HFS, 17beta-oestradiol (OE2), at a concentration as low as 0.1 nM, suppressed the magnitude of the resultant HFS-induced potentiation in slices from prepubertal animals (3 and 4 weeks old) of both sexes. 2. OE2 did not suppress the induction of LTP in slices taken from the hippocampus of adult animals of either sex. 3. There was no similar suppressant effect of 17alpha-oestradiol (OE1), progesterone (PRG) or testosterone (TST) on LTP in the young animals, even at a concentration 100 times greater than was effective for OE2. 4. The anti-oestrogen compound tamoxifen (TMX; 1.0 and 10.0 microM), which acts principally at intracellular binding sites within the nucleus, was without effect in diminishing the suppressant effect of OE2 on LTP in slices from young animals. 5. The LTP observed in slices from both 3-week-old and adult rats was AP5 sensitive and thus was shown to be dependent on activation of NMDA receptors. Results from whole-cell recording experiments suggested that OE2 caused the LTP-suppressant effect through an action on NMDA-mediated currents. 6. These data suggest an age-dependent and possibly a surface membrane receptor-mediated role for oestrogens in modulating the efficacy of input-output properties of CA1 neurones produced by HFS during a critical period in development.

Aging↗

Different anticonvulsive effects of hesperidin and its aglycone hesperetin on electrical activity in the rat hippocampus in-vitro.

This study investigated the possibility that hesperidin or hesperetin might interact directly with brain matter in a physiological manner. The effects of both compounds were followed in the in-vitro hippocampus preparation by continuous superfusion in a concentration-dependent manner in the presence of single stimuli and theta-burst stimulation of the Schaffer Collaterals. Hesperidin increased the population spike response at a concentration up to 10 microM, especially after induction of long-term potentiation, but attenuated it significantly at higher concentrations of up to 60 microM. Hesperetin only attenuated the response within the same concentration range. Modulation of the pyramidal cell response in the presence of tetraethylammonium (TEA) and pentylentetrazol on one hand and 4-aminopyridine (4-AP) and bicuculline on the other was influenced in a different way. Whereas hesperidin attenuated the response to 4-AP and bicuculline but not to TEA or pentylentetrazol, hesperetin was able to attenuate the response to TEA and pentylentetrazol, but not to 4AP or bicuculline. This feature was reproduced and confirmed ex-vivo after repetitive administration of hesperidin and hesperetin in-vivo for one week (500 mg kg(-1) orally) before in-vitro testing against the challenging effects of 4-AP and TEA. Since the action of hesperidin was sensitive to the presence of iberiotoxin, the involvement of a large conductance calcium-dependent potassium channel might be assumed. In summary, the results provide the possibility for use of both compounds to control pathophysiological disturbances of brain excitability in drug abuse, migraine and epilepsy.

4-Aminopyridine↗

Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat.

We have investigated the co-involvement of endogenous NGF and impulses in the collateral sprouting of cutaneous sensory nerves in adult rats, specifically the A delta-axons involved in mechanonociception and the C-fibers that mediate heat nociception. Their collateral sprouting was measured by the progressive expansion, respectively, of the behaviorally defined "pinch" and "heat" fields into surrounding denervated skin (the light-touch A alpha-fibers do not sprout in adult mammals). The expansions of such "isolated" fields were totally prevented in animals injected daily with anti-NGF serum, but developed normally after treatment was discontinued. Light microscopic and EM examination of the skin confirmed that the effect of the anti-NGF treatment was attributable to its prevention of collateral sprouting. Initiation of treatment would also rapidly halt sprouting already in progress. Finally, intradermal injections of purified NGF protein would not only increase the rate of nociceptive fiber sprouting, but also evoke sprouting de novo within normally innervated skin (again, A alpha-axons were unaffected). We conclude that the collateral sprouting of intact nociceptive nerves following partial denervation of skin is entirely dependent on endogenous NGF. The observed latency of this sprouting was 10-12 d; we estimate, however, that at least 2 d of field expansion is required for its reliable detection. Thus, about 8-10 d are required for NGF levels in the skin to rise to effective levels, and for the neurons to respond and initiate sprouting. From indirect findings, the NGF component of this sprouting latency appears to be about 2 d. In accord with earlier findings, the remaining "initiation time" was reduced by 5-6 d if the neurons were briefly excited, even 2 d prior to the isolation of their fields. Unexpectedly, this phenomenon of "precocious sprouting" requires that endogenous NGF be available; the sprouting latency reverted to normal values when the conditioning impulses were evoked during a 2 d anti-NGF "umbrella." In contrast to the impulse-sensitive neuronal mechanisms involved in the initiation of sprouting, those underlying the sprouting rate were unaffected by nerve activity and were entirely dependent on the level of endogenous NGF. We suggest that interactions like that revealed in these studies between a sprouting agent and impulses that seem to prime the neuron's response to it contribute to plasticity within the nervous system.

Animals↗