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Biomedical subjects

R Olivares

Publications and source records attributed to R Olivares.

At least 19 recordsLinked to original sources
PubMed2006

Delivery of a healthy baby following the transfer of embryos cryopreserved for 13 years.

Although embryos can theoretically be frozen for an unlimited period of time, there is still uncertainty about how long embryos can be cryopreserved without compromising pregnancy outcome. Following transfer of fresh embryos obtained after IVF, surplus embryos are usually frozen for personal use in later treatments. A 40-year-old woman was admitted to the centre's embryo adoption programme. She had a 7-year-old son, was diagnosed with ovarian factor infertility and her husband had secretory azoospermia. They underwent two cycles of IVF with donor spermatozoa and one cycle of donor intrauterine insemination that ended in spontaneous abortion. At this point, the couple was admitted to the embryo adoption programme. Six frozen embryos, obtained from a couple that had had a pregnancy through IVF at the centre and that had abandoned their surplus frozen embryos, were assigned to this patient. All six embryos were cryopreserved for 13 years. Of these, three were transferred and the patient became pregnant and delivered a healthy boy. Thanks to the embryo adoption programme, these embryos, rather than being left frozen for an indefinite period of time, were transferred to a couple that was willing to adopt them, resulting in the birth of a healthy newborn.

Adult↗
PubMed2005

In vitro cytotoxicity of amorphous carbon films.

Amorphous carbon (a-C), carbon nitride (a-CN) and titanium films were deposited on stainless steel substrates (SS) using a dc magnetron sputtering system attached to a high vacuum chamber. Films were deposited using a base pressure of 1.3x10(-4) Pa. For the carbon films a pure graphite target was eroded in an Argon plasma. For the case of the a-CN films, the Ar flux was substituted by 100% N2 gas. Titanium films were deposited in a different chamber, using a pure Ti target and an argon plasma. In vitro studies were carried out on the coated samples using human osteoblasts cells. Cytotoxicity of carbon films was assessed by cellular adhesion and proliferation, as determined by direct cellular counting using a spectroscopic technique and a well-defined standard curve. Osteoblasts cells were also grown on uncoated steel and prepared Petri dishes for comparison. The percentage of osteoblasts adhesion measured at 24 hrs attained maximum values for the a-C films. Similarly, cellular proliferation evaluated at three, five and seven days showed an outstanding increase of osteoblasts cells for the a-C and Ti coatings in contrast to the uncoated steel. The cell functionality was evaluated by the MTT test after incubation periods of 3, 5 and 7 days. The absorbance values obtained for a-C, a-CN and Ti surfaces resulted significantly higher with respect to the positive control, indicating that the surface did not induce any toxic effect. Preliminary bio-mineralization was evaluated by measuring the elemental composition of the mineral grown on the substrates after periods up to 14 days.

Bone Substitutes↗
PubMed2004

Mitochondrial calcium sequestration and protein kinase C cooperate in the regulation of cortical F-actin disassembly and secretion in bovine chromaffin cells.

Mitochondria play an important role in the homeostasis of intracellular Ca(2+) and regulate its availability for exocytosis. Inhibitors of mitochondria Ca(2+) uptake such as protonophore CCCP potentiate the secretory response to a depolarizing pulse of K(+). Exposure of cells to agents that directly (cytochalasin D, latrunculin B) or indirectly (PMA) disrupt cortical F-actin networks also potentiate the secretory response to high K(+). The effects of cytochalasin D and CCCP on secretion were additive whereas those of PMA and CCCP were not; this suggests different mechanisms for cytochalasin D and CCCP and a similar mechanism for PMA and CCCP. Mitochondria were the site of action of CCCP, because the potentiation of secretion by CCCP was observed even after depletion of Ca(2+) from the endoplasmic reticulum. CCCP induced a small increase in the cytosolic Ca(2+) concentration ([Ca(2+)](c)) that was not modified by the protein kinase C (PKC) inhibitor chelerythrine. Both CCCP and PMA induced cortical F-actin disassembly, an effect abolished by chelerythrine. In addition, rotenone and oligomycin A, two other mitochondrial inhibitors, also evoked cortical F-actin disassembly and potentiated secretion; again, these effects were blocked by chelerythrine. CCCP also enhanced the phosphorylation of PKC and myristoylated alanine-rich C kinase substance (MARCKS), and these were also inhibited by chelerythrine. The results suggest that the rapid sequestration of Ca(2+) by mitochondria would protect the cell from an enhanced PKC activation and cortical F-actin disassembly, thereby limiting the magnitude of the secretory response.

Actins↗
PubMed2001

Blockade by agmatine of catecholamine release from chromaffin cells is unrelated to imidazoline receptors.

The blockade of exocytosis induced by the putative endogenous ligand for imidazoline receptors, agmatine, was studied by using on-line measurement of catecholamine release in bovine adrenal medullary chromaffin cells. Agmatine inhibited the acetylcholine-evoked release of catecholamines in a concentration-dependent manner (IC(50)=366 microM); the K(+)-evoked release of catecholamines was unaffected. Clonidine (100 microM) and moxonidine (100 microM) also inhibited by 75% and 50%, respectively, the acetylcholine-evoked response. In cells voltage-clamped at -80 mV, the intermittent application of acetylcholine pulses elicited whole-cell inward currents (I(ACh)) that were blocked 63% by 1 mM agmatine. The onset of blockade was very fast (tau(on) = 31 ms); the recovery of the current after washout of agmatine also occurred very rapidly (tau(off = 39 ms). Efaroxan (10 microM) did not affect the inhibition of I(ACh) elicited by 1 mM agmatine. I(ACh) was blocked 90% by 100 microM clonidine and 50% by 100 microM moxonidine. The concentration-response curve for acetylcholine to elicit inward currents was shifted to the right in a non-parallel manner by 300 microM agmatine. The blockade of I(ACh) caused by agmatine (100 microM) was similar at various holding potentials, around 50%. When intracellularly applied, agmatine did not block I(ACh). At 1 mM, agmatine blocked I(Na) by 23%, I(Ba) by 14%, I(K(Ca)) by 16%, and I(K(VD)) by 18%. In conclusion, agmatine blocks exocytosis in chromaffin cells by blocking nicotinic acetylcholine receptor currents. In contrast to previous views, these effects seem to be unrelated to imidazoline receptors.

Acetylcholine↗
PubMed2001

Multicenter phase I-II trial of docetaxel, cisplatin, and fluorouracil induction chemotherapy for patients with locally advanced squamous cell cancer of the head and neck.

PURPOSE: We conducted a phase I-II, multi-institutional trial to determine the maximum-tolerated dose (MTD) of cisplatin in an induction chemotherapy regimen of docetaxel, cisplatin, and fluorouracil for squamous cell cancer of the head and neck (SCCHN) and to determine the safety, tolerability, and efficacy of the regimen at MTD. PATIENTS AND METHODS: A total of 43 patients with previously untreated, locally advanced, curable SCCHN were entered. Overall, 29 patients (67%) had N2 or N3 nodal disease and nine (21%) had T4 primary tumors. All patients received docetaxel 75 mg/m(2) on day 1; cisplatin at 75 (level I) or 100 (level II) mg/m(2) on day 1; and a continuous fluorouracil infusion at 1,000 mg/m(2)/d on days 1 through 4. Patients were treated with prophylactic antibiotics on days 5 through 15. Cycles were repeated every 21 days for a total of three cycles. Patients then received definitive therapy based on institutional preferences. RESULTS: Thirteen patients were treated at level I, and 30 patients were treated at level II. All 43 patients were assessable for toxicity. There were no major differences in toxicity between level I and level II. Cisplatin-associated grade 3 or 4 hypomagnesemia or hypocalcemia occurred in 13 (30%) and hearing loss in two patients (5%). Grade 3 or 4 neutropenia was observed in 41 patients (95%) and febrile neutropenia occurred in eight (19%). There was one serious infection (2%). There were 17 (40% [95% confidence interval [CI], 25% to 56%]) clinical complete responders (CR), 23 (54% [95% CI, 39% to 69%]) partial responders (PR), one (2%) with no change, and two (5%) unassessable patients. Major responses (CR, PR) were observed in 40 (93% [95% CI, 81% to 99%]) patients. Primary site CR was documented in 24 (54%) of patients. Postchemotherapy primary site biopsies were performed in 25 patients (58%) and pathologically negative biopsy was obtained in 11 (92%) of 12 primary site clinical CRs and seven (54%) of 13 with PR or no change. Overall, negative biopsies were obtained in 18 patients (72%). CONCLUSION: TPF induction chemotherapy can be delivered safely with a cisplatin dose of 100 mg/m(2) in previously untreated patients with SCCHN. The regimen is associated with a high rate of primary site clinical and pathologic CRs. Phase III comparison with cisplatinum and fluorouracil chemotherapy is warranted.

Adult↗
PubMed2001

Control of secretion by mitochondria depends on the size of the local [Ca2+] after chromaffin cell stimulation.

In chromaffin cells, plasma membrane calcium (Ca2+) channels and mitochondria constitute defined functional units controlling the availability of Ca2+ nearby exocytotic sites. We show here that, when L-/N-type Ca2+ channels were inhibited with nisoldipine and omega-conotoxin GVIA, cytosolic [Ca2+] ([Ca2+]c) peaks measured in fura-4F-loaded cells were reduced by 36%; however, mitochondrial Ca2+ uptake was unaffected and secretion was potentiated by protonophores as in control cells. By contrast, when non L-type Ca2+ channels were inhibited with omega-conotoxin MVIIC, [Ca2+]c peaks induced by high K+ were reduced by 73%, mitochondrial Ca2+ uptake was abolished, and secretion was not modified by protonophores. However, if Ca2+ entered only through L-type channels activated by FPL64176, high K+ stimulation induced fast mitochondrial Ca2+ uptake and catecholamine secretion was strongly increased and potentiated by protonophores. These results confirm the close association of catecholamine secretion to mitochondrial Ca2+ uptake, and indicate the sharp threshold of local [Ca2+]c (about 5 microM) required for triggering fast mitochondrial Ca2+ uptake that is able to modulate secretion. The entry of Ca2+ through L-type channels generated local [Ca2+]c increases just below that, inducing little mitochondrial Ca2+ uptake unless FPL64176 was present. By contrast, Ca2+ entry through P/Q-type channels fully activated mitochondrial Ca2+ uptake. Control of secretion by mitochondria therefore depends critically on the ability of the stimulus to create large local [Ca2+]c microdomains.

Adrenal Medulla↗
PubMed2001

Species differences and similarities in the fine structure of the mammalian corpus callosum.

A cross-species ultrastructural study of the corpus callosum was performed in six domestic species: the rat, the rabbit, the cat, the dog, the horse and the cow. The results indicate cross-species conservatism in callosal fiber composition with a good interspecies relation between fiber number and brain size. Across species, increases in both brain size and callosal area indicate more callosal fibers, although less than expected from the estimated increase in cortical cell number. Within each species, the correlation between fiber number and brain weight tends to disappear, although in most cases a larger callosum implies a larger number of callosal fibers. The median fiber diameter was conservative across species (0.11-0.2 microm), indicating the maintenance of conduction velocity of most callosal fibers regardless of interhemispheric distance. Nevertheless, the maximal fiber diameters tended to be higher in species with larger brains. Therefore, there is a population of coarse-diameter fibers that tend to increase their diameter and conduction velocity with increasing brain size. However, allometric calculations suggest that the associated increase in velocity in these large fibers may not be sufficient to maintain a constant interhemispheric transmission time in different species.

Animals↗
PubMed2000

A multicenter, randomized, phase III study of docetaxel plus best supportive care versus best supportive care in chemotherapy-naive patients with metastatic or non-resectable localized non-small cell lung cancer (NSCLC).

This was an open-label randomized Phase III study of 207 patients with either unresectable or metastatic non-small cell lung cancer (NSCLC) who were treated with docetaxel plus best supportive care (BSC) or best supportive care alone. Patients in the chemotherapy arm of the study received docetaxel 100 mg/m(2) as a 1 h intravenous infusion every 21 days until they showed evidence of progressive disease, or estimated maximum benefit obtained or unacceptable side effects. Patients who received docetaxel were pretreated with oral dexamethasone. Patients in the BSC arm should not receive chemotherapy or anticancer therapy except for palliative radiotherapy. Overall survival obtained in the docetaxel arm was significantly longer than in the BSC arm (P=0.026). Two-year survival in the docetaxel arm was 12%, whereas none of the BSC patients survived after 20 months. The response rate was 13.1% (95% CI, 7.5-18.8%). There was a significantly longer time to progression in the docetaxel versus the BSC arm (P<0.001), and statistically significant improvement of clinical symptoms with docetaxel compared to BSC. The quality-of-life descriptors were in favor of docetaxel, and the difference was significant for pain, dyspnea and emotional functioning. The safety profile of docetaxel for this study was similar to that already reported in this patient population.

Adult↗
PubMed2000

Phase II study of docetaxel in the treatment of patients with advanced non-small cell lung cancer in routine daily practice.

The purpose of this study was to evaluate the efficacy and safety of docetaxel as first- and second-line chemotherapy for advanced non-small cell lung cancer (NSCLC) under routine clinical conditions. Two hundred and three patients with advanced NSCLC received docetaxel 100 mg/m2 (1-h intravenous infusion) every 3 weeks, with oral corticosteroid pre-medication, of whom 173 were eligible. Median age was 60 (29-78) years and median Karnofsky performance status was 80% (60-100). A total of 77% of patients had metastatic disease, 33% had bone metastases and 18% had liver metastases. The treatment was second-line or more for 72 patients (35%). Overall response rates in the eligible population were 19.7% [95% CI, 12.5-23.0] for both treatments, 22.6% for first-line treatment and 13.8% for second-line treatment. Median survival was 8.3 months and 1-year survival was 35% for the overall population (8.7 months and 38%, respectively, for patients receiving first-line treatment and 7.2 months and 27%, respectively, for patients receiving second-line treatment). Neutropenia, grade 3 and 4, occurred in 57% of the cycles and 5% of patients experienced febrile neutropenia. Alopecia (62% of patients), neuro-sensory symptoms (32%), asthenia (28%), diarrhea (22%), nausea (22%) and nail disorders (20%) were the most common non-hematological adverse effects. A total of 33% of patients suffered fluid retention, despite the use of corticosteroid pre-medication, but this was only severe in 1.5% of patients. It was possible to confirm the efficacy of docetaxel as a single agent for first- and second-line chemotherapy in a large patient population treated in a community setting.

Adult↗
PubMed2000

Clinical trial simulation of docetaxel in patients with cancer as a tool for dosage optimization.

BACKGROUND: Pharmacokinetic and pharmacodynamic analyses conducted during the development of docetaxel showed that patients with non-small-cell lung cancer with high baseline alpha1-acid glycoprotein levels had shorter time to progression and time to death. To assess whether such patients might benefit from dose intensification, we initiated a series of clinical trial simulations. METHODS: Pharmacokinetic and pharmacodynamic models for time to progression, death, and drop-out were developed and validated with the use of phase II data from 151 patients with non-small-cell lung cancer. The simulation process, in which these models were combined with a previously reported model for safety, was evaluated by comparison of the original phase II data with the predicted results. Simulations were undertaken for the evaluation of whether a trial (phase III) of 125 mg/m2 of docetaxel versus 100 mg/m2 of docetaxel in patients with high alpha1-acid glycoprotein levels would show improved survival. RESULTS: The hazard models showed that lower alpha1-acid glycoprotein levels, fewer number of organs involved, and higher docetaxel cumulative area under plasma concentration-time curve were significantly associated with enhanced time to progression and time to death. The simulation process produced data patterns similar to actual patterns. In the simulated phase III trial, although median survival was slightly longer in the 125 mg/m2 docetaxel group than in the 100 mg/m2 group (5.49 months versus 5.31 months, respectively), the difference was significant in only 6 of 100 trials. CONCLUSIONS: The low power to detect a difference due to dose intensification was the basis for the decision not to perform such a trial. The simulation exercise yielded valuable insight into how pharmacokinetic- and pharmacodynamic-based simulation of clinical trials may have an impact on decision making in drug development.

Adult↗
PubMed2000

Phase II study of docetaxel alternating with cisplatin in chemotherapy-naïve patients with advanced non-small cell lung cancer.

The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and 100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.

Adult↗
PubMed2000

Cross-species and intraspecies morphometric analysis of the corpus callosum.

A cross-species morphometric study of the corpus callosum was performed in the rat, rabbit, cat, dog, horse, cow and human. Across species, the results indicate a strong, although less than linear, dependency of callosal size on brain weight. This relation tends to lose significance within species. This is consistent with other morphometric studies indicating a tendency to decrease the correlations between morphometric variables in within-species analyses as compared to between-species analyses. There are species differences in the relative size of some callosal segments particularly in the posterior third, which is larger in frontally-looking species than in laterally-looking species. No sex differences in callosal size were detected in any of the species examined. These findings are discussed in the light of possible developmental and functional correlates of the variability observed.

Adult↗
PubMed2000

Ontogenetic changes in the fractal geometry of the bronchial tree in Rattus norvegicus.

Respiration and metabolism change dramatically over the course of the development of vertebrates. In mammals these changes may be ascribed to organogenesis and differentiation of structures involved in gas exchange and transport and the increase in size. Since young as well as mature individuals must be well-designed if the species is to survive, the physiological changes during the development should be matched with geometrical or structural adjustments of the respiratory system. The aim of this study was to evaluate changes in the fractal geometry of the bronchial tree during the postnatal development of the rat. The average fractal dimension of the bronchial tree of the rats was 1.587, but that of juveniles was larger than that of the adults. We found a significant negative correlation between age and fractal dimension. This correlation could be considered be misleading because of the difficulty of separating age/body size effects. Nevertheless, because fractal dimensions of the bronchial tree of rabbits and humans are known to be similar, 1.58 and 1.57 respectively, the body size effect may be nil. To our knowledge, this is the first report of ontogenetic changes in the fractal dimension of the bronchial tree in mammals.

Animals↗
PubMed1999

Voltage inactivation of Ca2+ entry and secretion associated with N- and P/Q-type but not L-type Ca2+ channels of bovine chromaffin cells.

1. In this study we pose the question of why the bovine adrenal medullary chromaffin cell needs various subtypes (L, N, P, Q) of the neuronal high-voltage activated Ca2+ channels to control a given physiological function, i.e. the exocytotic release of catecholamines. One plausible hypothesis is that Ca2+ channel subtypes undergo different patterns of inactivation during cell depolarization. 2. The net Ca2+ uptake (measured using 45Ca2+) into hyperpolarized cells (bathed in a nominally Ca2+-free solution containing 1.2 mM K+) after application of a Ca2+ pulse (5 s exposure to 100 mM K+ and 2 mM Ca2+), amounted to 0.65 +/- 0.02 fmol cell-1; in depolarized cells (bathed in nominally Ca2+-free solution containing 100 mM K+) the net Ca2+ uptake was 0.16 +/- 0.01 fmol cell-1. 3. This was paralleled by a dramatic reduction of the increase in the cytosolic Ca2+ concentration, [Ca2+]i, caused by Ca2+ pulses applied to fura-2-loaded single cells, from 1181 +/- 104 nM in hyperpolarized cells to 115 +/- 9 nM in depolarized cells. 4. A similar decrease was observed when studying catecholamine release. Secretion was decreased when K+ concentration was increased from 1.2 to 100 mM; the Ca2+ pulse caused, when comparing the extreme conditions, the secretion of 807 +/- 35 nA of catecholamines in hyperpolarized cells and 220 +/- 19 nA in depolarized cells. 5. The inactivation by depolarization of Ca2+ entry and secretion occluded the blocking effects of combined omega-conotoxin GVIA (1 microM) and omega-agatoxin IVA (2 microM), thus suggesting that depolarization caused a selective inactivation of the N- and P/Q-type Ca2+ channels. 6. This was strengthened by two additional findings: (i) nifedipine (3 microM), an L-type Ca2+ channel blocker, suppressed the fraction of Ca2+ entry (24 %) and secretion (27 %) left unblocked by depolarization; (ii) FPL64176 (3 microM), an L-type Ca2+ channel 'activator', dramatically enhanced the entry of Ca2+ and the secretory response in depolarized cells. 7. In voltage-clamped cells, switching the holding potential from -80 to -40 mV promoted the loss of 80 % of the whole-cell inward Ca2+ channel current carried by 10 mM Ba2+ (IBa). The residual current was blocked by 80 % upon addition of 3 microM nifedipine and dramatically enhanced by 3 microM FPL64176. 8. Thus, it seems that the N- and P/Q-subtypes of calcium channels are more prone to inactivation at depolarizing voltages than the L-subtype. We propose that this different inactivation might occur physiologically during different patterns of action potential firing, triggered by endogenously released acetylcholine under various stressful conditions.

Adrenal Medulla↗
PubMed1998

Unmasking the functions of the chromaffin cell alpha7 nicotinic receptor by using short pulses of acetylcholine and selective blockers.

Methyllycaconitine (MLA), alpha-conotoxin ImI, and alpha-bungarotoxin inhibited the release of catecholamines triggered by brief pulses of acetylcholine (ACh) (100 microM, 5 s) applied to fast-superfused bovine adrenal chromaffin cells, with IC50s of 100 nM for MLA and 300 nM for alpha-conotoxin ImI and alpha-bungarotoxin. MLA (100 nM), alpha-conotoxin ImI (1 microM), and alpha-bungarotoxin (1 microM) halved the entry of 45Ca2+ stimulated by 5-s pulses of 300 microM ACh applied to incubated cells. These supramaximal concentrations of alpha7 nicotinic receptor blockers depressed by 30% (MLA), 25% (alpha-bungarotoxin), and 50% (alpha-conotoxin ImI) the inward current generated by 1-s pulses of 100 microM ACh, applied to voltage-clamped chromaffin cells. In Xenopus oocytes expressing rat brain alpha7 neuronal nicotinic receptor for acetylcholine nAChR, the current generated by 1-s pulses of ACh was blocked by MLA, alpha-conotoxin ImI, and alpha-bungarotoxin with IC50s of 0.1 nM, 100 nM, and 1.6 nM, respectively; the current through alpha3 beta4 nAChR was unaffected by alpha-conotoxin ImI and alpha-bungarotoxin, and weakly blocked by MLA (IC50 = 1 microM). The functions of controlling the electrical activity, the entry of Ca2+, and the ensuing exocytotic response of chromaffin cells were until now exclusively attributed to alpha3 beta4 nAChR; the present results constitute the first evidence to support a prominent role of alpha7 nAChR in controlling such functions, specially under the more physiological conditions used here to stimulate chromaffin cells with brief pulses of ACh.

Acetylcholine↗
PubMed1997

'Wide-spectrum Ca2+ channel antagonists': lipophilicity, inhibition, and recovery of secretion in chromaffin cells.

Repetitive application of short depolarizing K+ pulses (70 mM K+, 2 mM Ca2+ Krebs-HEPES solution, for 10 s every 5 min) produced reproducible catecholamine secretory responses from superfused bovine chromaffin cells. At 10 microM for 15 min, the piperazine derivatives dotarizine, flunarizine and lidoflazine inhibited secretion by around 90%; cinnarizine halved the secretory response. Recovery of secretion after 30-min washout with Krebs-HEPES solution amounted to 75% in the case of dotarizine, 8% for flunarizine, 46% for lidoflazine and 21% for cinnarizine. The benzothiazol derivatives (10 microM) (+)-S-lubeluzole and R91154 (the (-)-R-enantiomer of lubeluzole) blocked the response by 75%; sabeluzole inhibited secretion by only 34% and R56865 (N-[1-(4-(4-fluorophenoxy)butyl]-4-piperidinyl-N-methyl-2-benzo-thiaz olamine) by 61%. Recoveries were around 70% in the case of these four benzothiazol derivatives. The diphenylbutyl-piperazine derivatives fluspirilene and penfluridol inhibited secretion by over 80%; no recovery was produced after 30-min washout. The inhibition of secretion was time dependent, as the recovery of the response was. Blockade of secretion by dotarizine and flunarizine occurred even in the absence of intermittent K+ stimulations of the cells. No obvious correlation was seen between the octanol/water partition coefficients of the ten compounds tested (that ranged between 6 and 4.61), the rate and extent of blockade of secretion, and the recovery of the secretory response upon washout. Rather than non-specific actions on ion channels (and secretion) due to their high lipophilicity, we believe that blockade of various Ca2+ channels relates to their binding properties to specific channel micro and macrodomains, as the case might be for 'narrow' (omega-conotoxin GVIA) and 'wide-spectrum' (omega-conotoxin MVIIC) peptide toxins.

Animals↗
PubMed1996

Age-related changes in fibre composition of the human corpus callosum: sex differences.

We found positive correlations between the number of myelinated callosal fibres > 1 micron in diameter and age in humans. The relatively abundant axons with diameters between 1 and 3 microns correlated with age only in females, while the scarce fibres > 3 microns in diameter correlated significantly with age only in males. When analysing different callosal segments, it was found that in the midbody (but not in the splenium) of females the number of fibres > 3 microns also increased with age. In males, the relationship between these large diameter fibres and age disappeared after dividing the callosum into distinct segments. There may, therefore, be sex differences in the course of callosal fibre growth and myelination during the normal lifespan.

Adult↗