Latency Of Appearance Research Articles

Primary somatosensory cortex sensitivity may increase upon completion of a motor task

ObjectivesThe electroencephalogram and magnetic field primary somatosensory cortex (S1)-derived components are attenuated before and during motor tasks compared to the resting state, a phenomenon called gating; however, the S1 response after a motor task has not been well studied. We aimed to investigate sensory information processing immediately after motor tasks using magnetoencephalography. Materials and methodsWe investigated sensory information processing immediately after finger movement using magnetoencephalography in 14 healthy adults. Volunteers performed a simple reaction task where they were required to press a button when they received a cue. In parallel, electrical stimulation to the right index finger was applied at regular intervals to detect the magnetic brain field changes. The end of the motor task timing was defined using the event-related synchronization (ERS) appearance latency in the brain magnetic field’s beta band around the primary motor cortex. The ERS appearance latency and the sensory stimuli timing applied every 500 ms were synchronized over the experimental system timeline. We examined whether there was a difference in the S1 somatosensory evoked field responses between the ERS emergence and ERS disappearance phase, focusing on the N20m-P35m peak-to-peak amplitude (N20m-P35m amplitude) value. A control experiment was also conducted in which only sensory stimulation was applied with no motor task. ResultsThe N20m-P35m mean amplitude value was significantly higher in the ERS emergence phase (15.81 nAm; standard deviation [SD], 6.54 nAm) than in the ERS disappearance phase (13.54 nAm; SD, 5.12 nAm) (p < 0.05) and the control (12.08 nAm, SD 5.61 nAm) (p = 0.013). No statistically significant differences were identified between the ERS disappearance phase and the control (p = 0.281). ConclusionsThe S1 sensitivity may increase rapidly after exiting from the gating influence in S1 (after completing a motor task).

Synergistic Antinociceptive, Anti-inflammatory Interaction between Vitamin B12 and Ketorolac in Long Evans Rats

In certain painful disorders, B12 vitamins have been documented to be clinically useful alone or paired with non-steroidal anti-inflammatory drugs (NSAIDs). However, it has not been identified to equate these effects with related effects of ketorolac tromethamine (KT) and their combination. To test and compare the effects of vitamin B12 on pain with those of the combination of vitamin B12 with KT in rat models. This experimental research was performed at the Department of Physiology, BSMMU. The control (A, A1 with 5 ml/kg normal saline) and experimental (B1, B1a with 15 mg/kg B12; B2, B2a with 10 mg/kg KT; B3, B3a with B12+KT) groups of 5 rats in each group were divided into 40 (forty) long Evans rats (215±35 gm) of either sex. Both medications and vitamins were administered intraperitoneally in a single dose just one hour prior to the writhing and paw edema test caused by formalin. The statistical study was carried out by ANOVA, followed by the post-hoc Bonferroni test. In the interpretation of outcomes, p≤0.05 was regarded as significant. B12 lowered only the writhing count and KT lowered both writhing appearance latency time and writhing count significantly (p≤0.001) in the writhing test. However, the combination of B12 and KT significantly (p≤0.001) lowered both the study variables in the writhing test. In addition, KT lowered edema volume significantly (p≤0.01) in the paw edema test. The combination of B12 and KT, on the other hand, substantially (p≤0.001) decreased the amount of edema in the paw edema test. It can be concluded that vitamin B12 has analgesic and anti-inflammatory effects, and that the combination of B12 with KT is more effective than when administered individually.

Anticonvulsant effect of acute curcumin nanoparticle on pentylenetetrazole-induced seizures in mice: non-involvement of JNK restoration

Introduction: Although several animal studies have indicated the antiepileptic effect for curcumin, there are reports stating the null antiepileptic effect of this substance. This inconsistency might be due to the low bioavailability of curcumin. Therefore, the current study aimed to assess the effect of oral bovine serum albumin (BSA)-based nanocurcumin on seizure caused by pentylenetetrazol (PTZ) in mice. Furthermore, due to the suggested involvement of JNK signaling in seizure pathology, the hippocampal pattern of JNK phosphorylation (activation) was evaluated. Methods: BSA based nanocurcumin was administered at doses of 50 and 100mg/kg oral gavage to male NMRI mice, one hour before PTZ administration. Intravenous PTZ paradigm was used to determine the threshold dose of PTZ to induce clonic seizures, while the intraperitoneal PTZ paradigm was applied to evaluate the latency for appearance of generalized clonus. Upon completion of intraperitoneal PTZ paradigm experiments, the hippocampi were removed and Western blot analysis was performed to determine the phosphorylated and total forms of JNK. Results: The results indicated that BSA-based nanocurcumin at the doses of 50 and 100mg/kg could significantly increase the threshold and latency of clonic seizure, which was a significant superior effect compared to natural curcumin. PTZ significantly increased the level of hippocampal JNK phosphorylation, but pretreatment of nanocurcumin did not modify this effect. Conclusion: The present study shows that converting curcumin to BSA-based nanocurcumin can increase its antiepileptic effect. Furthermore, the antiepileptic effect of nanocurcumin was not associated with a modification in PTZ-induced hippocampal JNK hyper activation.

Radiation myelitis after pembrolizumab administration, with favorable clinical evolution and safe rechallenge: a case report and review of the literature

BackgroundNeurologic complications as myelitis are very rare but extremely deleterious adverse effects of both immunotherapy and radiotherapy. Many recent studies have focused on the possible synergy of these two treatment modalities due to their potential to enhance each other’s immunomodulatory actions, with promising results and a safe tolerance profile.Case presentationWe report here the case of a 68-year-old man with metastatic non-small-cell lung cancer (NSCLC) who developed myelitis after T12-L2 vertebral radiotherapy, with motor deficit and sphincter dysfunction, while on treatment with pembrolizumab (an immune checkpoint inhibitor). The spinal abnormalities detected by magnetic resonance imaging (MRI), suggestive of myelitis, faithfully matched the area previously irradiated with 30 Gy in 10 fractions, six and a half months earlier. After immunotherapy discontinuation and steroid treatment, the patient rapidly and completely recovered. On progression, pembrolizumab was rechallenged and, after 8 cycles, the patient is on response and there are no signs of myelitis relapse.ConclusionThe confinement within the radiation field and the latency of appearance are suggestive of delayed radiation myelopathy. Nevertheless, the relatively low dose of radiation received and the full recovery after pembrolizumab discontinuation and steroid therapy plead for the contribution of both radiotherapy and immunotherapy in the causality of this complication, as an enhanced inflammatory reaction on a focal post-radiation chronic inflammatory state. In the three previously described cases of myelopathy occurring after radiotherapy and immunotherapy, a complete recovery had not been obtained and the immunotherapy was not rechallenged. The occurrence of a radiation recall phenomenon, in this case, can not be excluded, and radiation recall myelitis has already been described with chemotherapy and targeted therapy. Safe rechallenges with the incriminated drug, even immunotherapy, have been reported after radiation recall, but we describe it for the first time after myelitis.

Effect of free-ranging dogs and cats on medium-sized wild mammal assemblages in urban protected areas of a Mexican city

Abstract ContextUrban protected areas (PAs) are the habitat of several Neotropical medium-sized wild mammal (MSWM) species. However, this richness is seriously threatened by the growing populations of free-ranging dogs and cats in these areas. AimsThe aim of the present study was to evaluate the effect of free-ranging dogs and cats on the assemblage structure of MSWM in PAs of Xalapa city, Veracruz, Mexico. MethodsCamera traps were used to assess the effect of abundance and activity of dogs and cats on richness, abundance, dominance and activity of MSWM across two urban and three peri-urban PAs. The effect of plant diversity, vegetation structure and PA on mammal richness, activity and abundance were also evaluated. Key resultsThe dominance of MSWM was higher in peri-urban areas than urban areas, and the activity of dogs and cats from peri-urban and urban PAs was similar with wildest MSWM. Only inside urban areas did the size of the area and the dogs’ activity have a negative effect on the richness, activity and abundance of MSWM. Moreover, the activity and abundance of cats also had a negative effect on the activity of MSWM in urban PAs. The presence of dogs affected the latency of appearance of MSWM. ConclusionsThe presence of free-ranging dogs and cats in urban PAs affects MSWM assemblages and their appearance latency. ImplicationsThe potential harm of free-ranging dogs and cats on the community of MSWM in urban areas is clear, as is the need for increased scientific research to aid in the control of these exotic species in urban landscapes.

Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H4 receptor inhibitor SENS-111 using a modified caloric test in healthy subjects.

A Phase 1 study was performed to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the selective histamine H4 receptor antagonist SENS-111, an oral small molecule. One hundred healthy subjects were randomized in a placebo-controlled, double-blind study evaluating single-ascending doses (SAD; 100-500mg) and multiple-ascending doses (MAD; 50-150mgday-1 , 4 days; 200-250mgday-1 , 7 days). Effects of SENS-111 on nystagmus and vertigo induced by modified caloric tests were measured in the MAD studies. Population PK and PK/PD models were developed using a nonlinear mixed-effects approach. SENS-111 was well tolerated with mild to moderate events. No sedation was reported. A maximal tolerated dose was not reached. Dose-proportional increases in concentrations were seen up to 200mg and more than dose-proportional thereafter, with mean half-life between 24 and 56h. The caloric test induced mild but measurable vertigo and nystagmus with large intra/inter-individual variation for all parameters. SENS-111 did not significantly impact nystagmus but significantly improved latency of vertigo appearance/disappearance, duration and European Evaluation of Vertigo questionnaire parameters vs. baseline. A two-compartment model with first-order absorption, distribution and elimination best fit the data. PK/PD indirect modelling applied to vertigo duration and latency of appearance indicated maximum activity between 100 and 500ngml-1 plasma concentrations, corresponding to 100 and 200mgday-1 , which are appropriate for clinical efficacy evaluations in vestibular diseases. SENS-111 is a well-tolerated first-in-class H4 receptor antagonist with acceptable PK for oral daily dosing. PK/PD modelling determined plasma concentrations and doses for efficacy studies in patients with vertigo symptoms.

Analgesic Effects of Thiamine in Male Long Evans Rats

Background: The concept of analgesic effects of thiamine along with other B vitamins has been supported since long by various clinical and experimental evidences, though effects of individual thiamine on pain are yet to be clearly demonstrated.Objective: To assess the effects of increasing doses of thiamine supplementation on pain.Methods: Forty-eight (48) male Long Evans rats (200±20 gm) were given thiamine (100, 200, 250, mg/kg/day; experimental) or normal saline (5 ml/kg/day; control) intraperitonealy (i.p) for 7 consecutive days. The analgesic activity was evaluated by three experimental pain models, hot (52±0.50C) water tail immersion test, the interphase (6th-15th minutes) of formalin (50?l, 2.5%, subcutaneous) test and acetic acid (2%, i.p) induced writhing test. Statistical analysis was done by ANOVA followed by Bonferroni post hoc test and p?0.05 was considered as significant.Results: In tail immersion test, %MPE significantly increased after 200 (p?0.05) and 250 (p?0.001) mg/kg of thiamine. In the formalin test, thiamine significantly lowered the jerking frequency (p?0.05, p?0.001, p?0.001, respectively) and duration of flexing and licking (p?0.001, in all doses), compared to control. In addition, in writhing test, significant increment in latency of appearance of 1st writhe (p?0.001, in higher 2 doses) and significant decrement in frequency of writhes (p?0.01, p?0.001, p?0.001, respectively, in all doses) were observed.Conclusion: The results of this study conclude that, repetitive administration of thiamine may cause alleviation of pain through central as well as peripheral inhibitory mechanisms, which is dose dependent as well.Bangladesh Soc Physiol. 2017, June; 12(1): 1-9

Abstract 15280: Comparisons of Action Potentials and Ionic Currents Between Neonatal Rat Ventricular Myocytes and Adult Zebrafish Ventricular Myocytes

Introduction: Zebrafish heart is established as a model to investigate cardiac electrical abnormalities. However, electrical properties of adult zebrafish cardiomyocytes are not sufficiently characterized. Hypothesis: In this study, by comparing the electrical properties between neonatal rat ventricular myocytes (NRVMs) and adult zebrafish ventricular myocytes (AZVMs), we intended to characterize the action potential (AP), action current (AC) and the properties of Na + current ( I Na ) in AZVMs. Methods: We used patch-clamp technique to characterize the electrical properties, including AP, AC and I Na , in cultured NRVMs and freshly isolated AZVMs. Results: NVRMs showed larger AP amplitude (119±6 vs. 79±4mV, p&lt;.05) but shorter AP duration (APD 90 , 136±11 vs. 213±19 ms, p&lt;.05) than those of AZVMs. The AP duration exhibited marked frequency-dependent alterations in AZVMs. Under the slow pacing rate, early after-depolarizations (EAD) emerged under slow pacing rate with 0.05 Hz. In cell-attached voltage-clamp recordings made from AZVMs, ACs could be elicited by +10 mV steps. As the depolarization step increased to +70 mV, the latency for appearance of ACs was progressively reduced from &gt;123 ms to 9.8 ms. The presence of spontaneous ACs was monitored in spontaneously beating NRVMs and AZVMs. The AC amplitude in NRVMs was larger compared to that in AZVMs (17.3±2.1 vs. 11.6±1.1 pA, p&lt;.05), although firing frequency of AC in NRVMs is higher than in AZVMs (1.13±0.09 vs. 0.38±0.03 Hz, p&lt;.05). The lowering effect of ranolazine, a I Na antagonist, on firing frequency was significantly larger in NRVMs (1.13±0.09 to 0.31±0.02 Hz, p&lt;.05) than in AZVMs (0.38±0.03 to 0.27±0.02 Hz). There was a hyperpolarizing shift of peak I Na in AZVM compared to NRVM. Conclusions: Our results demonstrated major differences in the cellular electrical behavior between AZVMs and NRVMs.

Orthographic priming also depends on the emotional valence of the neighbor and prime duration: An ERP study

Abstract Event-related brain potentials (ERPs) were recorded in two experiments to examine whether the time course of the orthographic priming effect depends on the emotional valence of the orthographic neighbor and on prime duration. Neutral target words ( e.g. , GICLER [squirt] , TINTER [ring] ) had only one higher-frequency orthographic neighbor. This orthographic neighbor was negative for half of the targets ( e.g. , gifler [slap] ) and neutral for the other half ( e.g. , tenter [tempt] ). Target words were presented in a primed lexical decision task, preceded either by their orthographic neighbor or by a non-alphabetic control prime. Two prime durations of 66 ms (Experiment 1) and 166 ms (Experiment 2) were used. In Experiment 1, results showed an orthographic priming effect on three ERP components (P150, N200 and N400) that was modulated by the negative emotional valence of orthographic neighbors. In Experiment 2, the same components were influenced by the orthographic priming effect, although their appearance latency was brought forward and their amplitude increased. However, the emotional valence of the neighbor no longer influenced the time course of the orthographic priming effect. The results are discussed in terms of early activation of the emotional content of the orthographic neighbor during word processing.

Inhibitory effect of fluoxetine on lymphoma growth through the modulation of antitumor T-cell response by serotonin-dependent and independent mechanisms

Fluoxetine, a selective serotonin reuptake inhibitor, is widely used for the treatment of depressive symptoms of cancer patients. However, there are contradictory evidences about its effects on immunity and cancer. Thus, we studied the effects of fluoxetine on tumor growth and on antitumoral T-cell-mediated immunity. In vivo chronic fluoxetine treatment inhibited tumor growth, and increased latency of appearance of solid tumors and survival of mice. Fluoxetine administration also increased mitogen-induced T-cell proliferation and Tumor Necrosis Factor-α (TNF-α) and Interferon-γ (IFN-γ) expression, without altering CD4 +/CD8 + ratio. In vitro, fluoxetine did not affect tumor cells proliferation, but it exerted a direct effect on T lymphocytes. Both fluoxetine and serotonin stimulated proliferation induced by a suboptimal mitogen concentration but inhibited proliferation at the optimal one. When both drugs were combined the results indicated that the effects of fluoxetine are in part independent of its ability to elevate serotonin extracellular levels. Finally, continue fluoxetine administration in nude mice – devoid of T lymphocytes – did not modify tumor progression, thus supporting the hypothesis of an immuno-modulatory effect of this drug on T cells that drives tumor growth control. These findings indicate, for the first time, that fluoxetine inhibits tumor growth through modulation of T-cell-mediated immunity by the already known serotonin-dependent pathway and by a novel independent mechanism.

Sarcomes radio-induits après cancer du sein : expérience de l'institut Curie et revue de la littérature

Adjuvant radiotherapy to the breast plays a significant role in preventing local failure in women treated for early stage breast cancer. This fact is supported by multiple clinical trials demonstrating that adjuvant radiotherapy decreases the risk of local recurrence and increases the rate of breast preservation, and actually the rules of adjuvant breast irradiation are clearly established. Sarcomas are a rare but recognized complication of radiation therapy for breast carcinoma, and are associated with poor prognosis. The first case of a bone sarcoma after radiation therapy of breast cancer was described by Beck in 1922. In 1948, Cahan et al. defined the criteria for diagnosis of radiation-induced sarcoma. Since then, some studies have reported the incidence of radiation-induced sarcoma after radiotherapy for different cancers. This article reports and discusses the incidence, management and treatment outcome of radiation-induced sarcomas occurring after radiotherapy for breast cancer in our institute. The incidence, histology, latency of appearance, genesis, their treatment and the prognostic factors of these rare tumors are discussed and the literature is reviewed.

Anisakis simplex only provokes allergic symptoms when the worm parasitises the gastrointestinal tract.

We analysed patients with allergic or digestive symptoms after seafood ingestion in order to assess a correct diet in Anisakis simplex sensitised individuals. A total of 120 patients who suffered allergic and/or digestive symptoms after marine food ingestion were studied. We performed skin prick tests for A. simplex and seafood, total serum and specific serum immunoglobulin E to A. simplex in the acute stage and 1 month later. A gastroscopy was carried out to find larvae in those patients with persistent abdominal pain. A challenge with non-infective larvae was performed to assess a correct diet. Some 96 patients were sensitised to A. simplex. Gastroscopy was performed in 47 and we detected larvae in 24. We compared symptoms, skin tests, total and specific IgE and the latency of appearance of symptoms in patients positive for Anisakis larvae, patients without larvae at gastroscopy and patients without digestive symptoms. There was no difference among the groups. We challenged 22 patients with frozen A. simplex larvae. After allowing deep-frozen seafood in the diet for more than 2 years, no patient suffered a reaction. At this time, we allowed all our patients well-frozen seafood without any allergic reaction occurring. Allergic symptoms are the most frequent manifestation of A. simplex parasitism. We could not find any patient allergic to the thermostable proteins of parasite.

Codon 12 and codon 13 mutations at the K-ras gene induce different soft tissue sarcoma types in nude mice.

K-ras codon 12 mutation is more oncogenic in in vitro and in vivo experimental systems than K-ras codon 13 mutation. Moreover, human colorectal tumors bearing a codon 12 mutation are more aggressive, invasive, and metastatic than the same tumor types carrying a codon 13 mutation. However, despite the association between specific sarcoma types and codon 12 or codon 13 mutations, the relationship between the position of the mutated codon at ras genes and tumor aggressiveness has not been studied in this tumor type. Here, we used a nude mice model to evaluate the tumorogenic capacity of stable transfectants of NIH3T3 fibroblasts, expressing K-ras mutated at codon 12 (K12) or 13 (K13), and morphologically, functionally, and molecularly compared these tumors. We found histopathological differences between them, K12-derived tumors showing fibrosarcoma-like features, whereas K13-derived tumors resembled malignant fibrous histiocytomas. Moreover, K12 tumors showed shorter latency of appearance, lower apoptotic and mitotic rates, and higher expression of markers for sarcoma aggressiveness (Ki67, p53 and c-myc) than K13 tumors. They also showed differences in the expression or activation of Ras, Ras downstream pathways [c-Jun N-terminal kinase (JNK), MAPK and AKT], and apoptotic [AKT, Bcl-2, Focal adhesion kinase (FAK)] and mitotic (cyclin B1) regulators, which could explain their functional differences. Most remarkably, the significantly diminished apoptotic rate observed in K12-derived tumors was associated with enhanced antiapoptotic signaling through the AKT pathway. These morphological, functional, and molecular differences demonstrate that codon 12 and codon 13 mutations in the K-ras oncogene can induce two different soft tissue sarcoma types in our in vivo model.

Effect of red peppers ( Capsicum frutescens) intake during gestation on thermonociceptive response of rat offspring

Oral administration of aqueous red pepper ( Capsicum frutescens, Cf) solution and low capsaicin (8-methyl- N-vanillyl-6-nonenamide) doses during gestation produces an increase in the latency of the thermonociceptive escape response of rat offspring. The present work shows that different amounts of Cf (10%, 25% and 50%) incorporated to normal food of gestating rats modify in a dose-dependent manner the flexion reflex latency ( R), as well as the latency of appearance of antialgesic behaviours expressed as paw lick (P) and escape response ( E) using the hot plate test (53°C ± 0.5°C). The latency of the same parameters was tested in the same subjects 55 days later to determine the persistence of this effect. Results show an increase in latency of the three parameters R, P and E in all experimental groups with respect to controls. Animals (Cf, 25% group) tested 55 days after the first test exhibited latencies similar to controls, which suggests that the process is reversible.

Photoparoxysmal response elicited by flickering dot pattern stimulation to the center and periphery

Objective: We performed this study to elucidate the roles of stimulus spatial frequency and visual field in eliciting generalized photoparoxysmal response (PPR) by flickering dot pattern (FDP) stimulation. Methods: We studied 20 photosensitive epilepsy patients, aged 7–48 years (means±SD, 21.4±11.7 years), producing a 20 Hz FDP stimulation with a strobo-filter. Using dot patterns (0.5, 1, 2, 4 and 6 mm in diameter), we gave FDP stimulation to the center (11×11°) and periphery (11–30×11–30°) of subjects with eyes open, and analyzed each PPR appearance latency. Results: Significant results were: latency by 1 (2.1 c/deg) and 0.5 mm (4.9 c/deg) FDP stimulation to the center was shorter than that to the periphery; latency by 4 mm (0.8 c/deg) FDP stimulation to the periphery was shorter than that to the center. As for 2 (1.5 c/deg) and 6 mm (0.5 c/deg) FDP stimuli, no significant difference could be observed. Conclusions: A higher spatial frequency FDP stimulation to the center elicits PPR more strongly than that to the periphery, whereas a lower spatial frequency FDP stimulation showed the opposite result, with peripheral stimulation being more effective than central stimulation.

Neuroprotection by 21-aminosteroids: insights from latencies of anoxic terminal negativity in hippocampus slices of guinea pig

The protection of neuronal function by 21-aminosteroids against a hypoxic challenge was tested in guinea pig hippocampal slices. 21-aminosteroidswhich apart from a protective mechanism against membrane lipid peroxidation, provide direct membrane stabilizing effects, are reported. We tested whether the 21- aminosteroid U-74389G delays the anoxic terminal negativity (ATN) of the DC-potential during hypoxia. Hippocampal slices were placed at the interface of artificial cerebrospinal fluid (aCSF) and gaseous phase (normoxic: 95% 02/ 5% CO2; hypoxic: 95% N2, 5% CO2). Population spikes obtained by stimulation of Schaffer-collaterals as well as the DC-Potential were recorded in the CA1 region. The latency of appearance of ATN after oxygen deprivation was determined. In control experiments the latency of ATN was 12.6 ±3.1 min (n = 6, mean±SEM). With application of U-74389G, the ATN-latency was 8.8 ± 3.2 min (n - 6). We conclude that the cerebroprotective effect of the 21-aminosteroid is not mediated via direct membrane stabilization. [Neurol Res 1999; 21: 305-308]

Effects of Muscimol or Homotaurine on Sleep–Wake States in Alcohol-Dependent Rats During Withdrawal

Sleep–wake states were studied following withdrawal in 36 adult male wistar alcohol-dependent rats, after chronic administration of ethanol (10 g/kg/24 h) for 13 days. In the light phase of the withdrawal day, 12 alcohol-dependent rats received muscimol (0.25 mg/kg), 12 received homotaurine (140 mg/kg), and 12 received 0.9% physiological saline (10 ml/kg). The results have been compared with a control group of 36 rats that received water during the treatement phase of the experiment, and the 14th day received intraperitoneal muscimol or homotaurine. Muscimol significantly improves the alterations of sleep–wake states in alcohol-withdrawn rats, decreasing the percentage of active wakefulness and increasing the percentage of REMS, but without any action on the latency of appearance of REMS, which remains shortened. The effects of homotaurine are less important on the wakefulness, but it also increases the percentage of REMS without influencing its latency of appearance. The influence of these GABA A agonists is not identical during the whole period of survey in the light phase, as there are important differences in the temporal sequences for each of them. We conclude that the stimulation of GABA A receptors, of which the activity is decreased during alcohol withdrawal, significantly improves the disturbances in the sleep–wake states in the alcohol-dependent rats, in a time-related manner, and there are significant pharmacodynamic differences between muscimol and homotaurine.

Calcium Concentration and Movement in the Ventricular Cardiac Cell during an Excitation-Contraction Cycle

This paper extends the model for Ca movement in the cardiac ventricular cell from the diadic cleft space to the entire sarcomere. The model predicts the following: 1) Shortly after SR release there is a [Ca] gradient >3 orders of magnitude from cleft center to M-line which, 50 ms after release, is still >30. Outside the cleft, 40 ms after cessation of release, the axial gradient from Z to M-line is >3. 2) At the end of SR release, >50% of the total Ca released is bound to low-affinity inner sarcolemmal phospholipid binding sites within the cleft. 3) Halving the SR release almost doubles the fraction of release removed from the cell via Na/Ca exchange and reduces average sarcomeric free [Ca] by 70%. 4) Adding 100 μM fluo-3, which doubles the buffering capacity of the cytoplasm, reduces peak average sarcomeric [Ca] by >50% and increases the initial half-time for [Ca] decrease by approximately twofold. 5) A typical Ca “spark” can be generated by an SR release 20% of maximum (4 × 10 −20 moles) over 2 ms. Fluo-3 (100 μM) significantly “shrinks” the spark. 6) The “spark” is a consequence of elementary events within the diadic cleft space. For example, removal of cleft binding sites would cause average sarcomeric Ca to increase by >10 fold, fall 10 times more rapidly, decrease latency for appearance of the spark by >20 times, and reduce spark duration by 85%. 7) Dividing SR Ca release between cleft and corbular SR produces a secondary [Ca] peak and a “flattening” of the sarcomeric [Ca] transient. These changes probably could not be resolved with current confocal microscopic techniques.

Prenatal cocaine: Seizure susceptibility in rat offspring

Proconvulsant and convulsant effects of cocaine have been described in various experimental models of epilepsy. We have studied the susceptibility to bicuculline and pentylenetetrazol-induced seizures in developing 10-, 20- and 30-day old rats, gestationally exposed to cocaine. Incidence and latency of appearance of the epileptic manifestations, their evolution toward status epilepticus and successive recovery or death, have been evaluated and compared to the same parameters obtained in control animals of the same ages. Results have demonstrated that 10-day-old rats that had been exposed to cocaine are significantly less sensitive than control animals to the convulsant action of both bicuculline and pentylenetetrazole while no substantial differences between the two groups have been found at the successive ages. It is possible that modifications of various neurotransmitter systems caused by prenatal cocaine exposure modify neuronal excitability at least at early stages of development.

Guanosine 5'-[beta-thio]triphosphate selectively activates calcium signaling in mast cells.

In rat peritoneal mast cells, the activation of GTP-binding proteins (G proteins) by guanosine 5'-[gamma-thio]triphosphate GTP[gamma S] has been found to induce a transient rise in intracellular calcium as well as degranulation. A G protein that couples to phospholipase C (Gp) is thought to mediate the calcium response, whereas degranulation is mediated by a different G protein, termed Ge. In an attempt to activate mast-cell G proteins more selectively, the GTP analogues guanosine 5'-[alpha-thio]triphosphate (GTP[alpha S]) and guanosine 5'-[beta-thio]triphosphate (GTP[beta S]) (RP and SP diastereomers) were introduced into mast cells by means of patch pipettes. Degranulation and free intracellular calcium were monitored by cell capacitance and fura-2 measurements, respectively. It was found that RP-GTP[alpha S], like GTP[gamma S], induced both calcium release and exocytosis. In contrast, RP-GTP[beta S] induced repetitive calcium spikes that were not regularly accompanied by exocytosis. These results suggest that RP-GTP[beta S] selectively activates calcium signaling in mast cells. The RP-GTP[beta S]-induced oscillations were independent of extracellular calcium. They were absent in the presence of heparin or high concentrations of inositol 1,4,5-trisphosphate and modulated by compound 48/80, suggesting the involvement of the inositol phospholipid signaling pathway. Latency of appearance and spiking frequency were markedly modulated by varying the intracellular ATP concentration. The differential activation of intracellular calcium signaling and exocytosis by GTP[beta S] confirms the presence of independent signal-transduction pathways for the two cell responses. RP-GTP[beta S] may prove helpful in the biochemical and molecular characterization of Gp, the as-yet-unidentified G protein that couples receptors to intracellular calcium release.