Influence of the simultaneous calibration of multiple ring dosimeters on the individual absorbed dose.

Ring dosimeters for personal dosimetry are calibrated in accredited laboratories following ISO 4037-3 guidelines. The simultaneous irradiation of multiple dosimeters would save time, but has to be carefully studied, since the scattering conditions could change and influence the absorbed dose in nearby dosimeters. Monte Carlo simulations using PENELOPE-2014 were performed to explore the need to increase the uncertainty ofHp0.07in the simultaneous irradiation of three and five DXT-RAD 707H-2 (Thermo Scientific) ring dosimeters with beam qualities: N-30, N-80 and N-300. Results show that the absorbed dose in each dosimeter is compatible with each of the others and with the reference simulation (a single dosimeter), with a coverage probability of 95% (k= 2). Comparison with experimental data yielded consistent results with the same coverage probability. Therefore, five ring dosimeters can be simultaneously irradiated with beam qualities ranging, at least, between N-30 and N-300 with a negligible impact on the uncertainty ofHp0.07.

Correlation between eye lens doses and over apron doses in interventional procedures.

Measurements of eye lens dose using over apron dosimeters with a geometric correction factor is an international accepted practice. However, further knowledge regarding geometric correction factors in different contexts is required. The authors studied the correlation between eye lens dose and over apron dosimetry for different medical specialties in eleven hospitals, using a standardized protocol, two independent over apron dosimeters (worn at chest and at neck levels) and a dedicated calibration procedure. The results show good correlation between subjects working on the same medical specialty for 5 specialties: Interventional Radiology, Vascular Surgery, Vascular Radiology, Hemodynamics and Neuroradiology. The geometric correction factors resulting from this study could be used to estimate eye lens dose using over apron dosimeters, which are more comfortable than eye lens dosimeters, as reported by the study subjects, as long as the increased uncertainty of the over apron dosimetry compared to the dedicated eye lens dosimetry is acceptable.

Calibration of a thermoluminescent dosimeter worn over lead aprons in fluoroscopy guided procedures.

Fluoroscopy guided interventional procedures provide remarkable benefits to patients. However, medical staff working near the scattered radiation field may be exposed to high cumulative equivalent doses, thus requiring shielding devices such as lead aprons and thyroid collars. In this situation, it remains an acceptable practice to derive equivalent doses to the eye lenses or other unprotected soft tissues with a dosimeter placed above these protective devices. Nevertheless, the radiation backscattered by the lead shield differs from that generated during dosimeter calibration with a water phantom. In this study, a passive personal thermoluminescent dosimeter (TLD) was modelled by means of the Monte Carlo (MC) code Penelope. The results obtained were validated against measurements performed in reference conditions in a secondary standard dosimetry laboratory. Next, the MC model was used to evaluate the backscatter correction factor needed for the case where the dosimeter is worn over a lead shield to estimate the personal equivalent dose H p (0.07) to unprotected soft tissues. For this purpose, the TLD was irradiated over a water slab phantom with a photon beam representative of the result of a fluoroscopy beam scattered by a patient. Incident beam angles of 0° and 60°, and lead thicknesses between the TLD and phantom of 0.25 and 0.5 mm Pb were considered. A backscatter correction factor of 1.23 (independent of lead thickness) was calculated comparing the results with those faced in reference conditions (i.e., without lead shield and with an angular incidence of 0°). The corrected dose algorithm was validated in laboratory conditions with dosimeters irradiated over a thyroid collar and angular incidences of 0°, 40° and 60°, as well as with dosimeters worn by interventional radiologists and cardiologists. The corrected dose algorithm provides a better approach to estimate the equivalent dose to unprotected soft tissues such as eye lenses. Dosimeters that are not shielded from backscatter radiation might underestimate personal equivalent doses when worn over a lead apron and, therefore, should be specifically characterized for this purpose.

Strong induction of iodothyronine deiodinases by chemotherapeutic selenocompounds.

The biological activity of thyroid hormones (TH) is regulated by selenoenzymes of the iodothyronine deiodinase (DIO) family catalysing TH activating and inactivating reactions. Besides TH metabolism, several studies indicate an important role of DIO isoenzymes in tumorigenesis and cancer growth. It is therefore of therapeutic importance to identify modulators of DIO expression. We have synthesized and studied a series of selenocompounds containing a methyl- or benzyl-imidoselenocarbamate backbone. One of these novel compounds had chemotherapeutic activities in a murine xenograft tumour model by an unknown mechanism. Therefore, we tested their effects on DIO expression in vitro. In HepG2 hepatocarcinoma cells, DIO1 activity was strongly (up to 10-fold) increased by the methyl- but not by the corresponding benzyl-imidoselenocarbamates. Steady-state mRNA levels remained unaltered under these conditions indicating a post-transcriptional mode of action. The effects were further characterized in HEK293 cells stably expressing DIO1, DIO2 or DIO3. Even within the artificial genetic context of the expression vectors, all three DIO isoenzymes were up-regulated by the methyl- and to a lesser extent by the benzyl-imidoselenocarbamates. Consistent stimulating effects were observed with methyl-N,N'-di(quinolin-3-ylcarbonyl)-imidoselenocarbamate (EI201), a selenocompound known for its anti-tumour activity. DIO inducing effects were unrelated to the intracellular accumulation of selenium, yet the precise mode of action remains elusive. Collectively, our data highlight that these selenocompounds may constitute interesting pharmacological compounds for modifying DIO expression potentially affecting the balance between cell differentiation and proliferation.

IMRT: preliminary results in a series of advanced head-and-neck cancer patients

PURPOSE: To determine retrospectively 2-3 year local and regional control (LRC), free-of-disease survival (FDS) and overall survival (OS), as well as summarized toxicities in a group of 31 advanced head-and-neck cancer patients, treated at our institution between 2004 and 2011 with definitive IMRT low-dose concomitant boost, the majority of them with concurrent chemotherapy based on cisplatin. The results are also shown in the sub-group of nasopharyngeal cancer patients (NPC: 15 cases). PATIENTS AND METHODS: Radiological basal and contrasted CT series, MR-CT or PET/CT fused images in the setup position with immobilization mask were registered in simulation therapy patients. Planed doses were: 70 Gy in primary tumor and positive nodes >1 cm; 63 Gy in high-risk areas of microscopic diseases +10 mm safety margin; and 56 Gy in low risk of diseases regional lymph nodes. Treatment was delivered using a Varian 2100 Clinac with sliding windows IMRT. Spinal cord doses were limited to a strict maximum of 45 Gy, and optimization aimed for mean doses in parotid glands below 26 Gy, especially in the contralateral parotid gland. Online DRR-portal X-ray comparison images were taken every day with a deviation module tolerance ≤3 mm. RESULTS: The mean follow-up since IMRT was 34 months (interval: 8-89; median 31 months). Median follow-up in living patients was 22 months. The 2-year rate for global LRC was 64 %, for FDS 61 % and OS 77 %. For the NPC group after 2 years, LRC was 73 %, FDS 73 % and OS 93 %. The 3-year rates were similar. Seven patients died as a consequence of local and/or regional progression (mean time 10 months). Relapses were observed in eight patients (26 %), but only seven could be confirmed by biopsy (22.6 %; mean time to relapse: 8.6 months). Global acute mucositis was 61 % and chronic mucositis was shown in six cases which developed xerostomia (19 %) in the first control after IMRT, but 1 year later it was reduced to only four patients, two Grade 2 and two Grade 1. CONCLUSIONS: No excessive, unwarranted toxicities were observed using concomitant low doses boost in IMRT. High rates of compliance to concurrent chemotherapy were achieved. Late xerostomia associated with this regime decreased 1 year after conclusion of treatment. The implementation of IMRT requires advances in imaging for better tumor delineation; otherwise the physician loses the advantage of dose modulation or faces a risk of geographical miss (AU)

Innovative lead compounds and formulation strategies as newer kinetoplastid therapies.

The protozoan diseases leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease (CD) are responsible for substantial global morbidity and mortality in tropical and subtropical regions. Environmental changes, drug resistance and immunosuppression are contributing to the emergence and spread of these diseases. In the absence of safe and efficient vaccines, chemotherapy, together with vector control, remains the most important measure to control kinetoplastid diseases. Nevertheless, the current chemotherapeutic treatments are clearly inadequate because of their toxic effects, generation of resistances as well as route and schedules of administration not adapted to the field-conditions. This review overlooks the strategies that can be addressed to meet immediately the patient needs such as the reconsideration of current regimens of administration and the rational combination of drugs in use. In the medium-long term, due to new methodologies of medicinal-chemistry, the screening from natural products and the identification of new therapeutic targets, new lead compounds have great chance to advance through the drug development pipeline to clinic. Modern pharmaceutical formulation strategies and nanomedicines also merit a place in view of the benefits of a single dose of liposomal Amphotericin B (AmBisome®) against visceral leishmaniasis. BBB-targeted nanodevices could be suited for selective delivery of drugs against HAT encephalitic phase. Bioadhesive nanoparticles can be proposed to enhance the bioavailability of drugs after oral administration by reason of improving the drug solubility, and permeability across the intestinal epithelia.

The quinoline imidoselenocarbamate EI201 blocks the AKT/mTOR pathway and targets cancer stem cells leading to a strong antitumor activity.

Methylimidoselenocarbamates have previously proven to display potent antitumor activities. In the present study we show that these compounds act as multikinase inhibitors. We found that the most effective compound, quinoline imidoselenocarbamate EI201, inhibits the PI3K/AKT/mTOR pathway, which is persistently activated and contributes to malignant progression in various cancers. EI201 blocked the phosphorylation of AKT, mTOR and several of its downstream regulators (p70S6K and 4E-BP1) and ERK1/2 in PC-3, HT-29 and MCF-7 cells in vitro, inducing both autophagy and apoptosis. EI201 also contributes to the loss of maintenance of the selfrenewal and tumorigenic capacity of cancer stem cells (CSCs). 0.1 µmol/L EI201 triggered a reduction in size and number of tumorspheres in PC-3, HT-29 and MCF-7 cells and 4 µmol/L induced the elimination of almost all the tumorspheres in the three studied cell lines. In addition, EI201 suppressed almost 80% prostate tumor growth in vivo (p < 0.01) compared to controls at a relatively low dose (10 mg/kg) in a mouse xenograft model. There was a significant decrease in the subcutaneous primary tumor [18F]-FDG uptake (76.5% reduction, p < 0.05) and in the total tumor burden (76.8% reduction, p < 0.05) after EI201 treatment compared to vehicle control, without causing toxicity in mice. Taken together, our results support further development of EI201 as a novel multi-kinase inhibitor that may be useful against cancers with aberrant upregulation of PI3K/AKT and MAPK signaling pathways.

Selenium and clinical trials: new therapeutic evidence for multiple diseases.

The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use. Selenium is used by people in the prevention and/or treatment of different disorders including cardiovascular disease, osteoarthritis, rheumatoid arthritis, hypothyroidism, stroke, atherosclerosis, cancer susceptibility and treatment, HIV, AIDS, neuronal diseases such as Alzheimer or amyotrophic lateral sclerosis, pancreatitis, depression, and diabetes amongst others. Several mechanisms have been suggested to mediate the biological effects of Se and these include antioxidant defence systems, synthesis and stability of metabolites that act as intermediates implicated in diverse selenoproteins expression pathways oxidative metabolism, immune system modulation, DNA intercalators, kinase regulation, enzymatic cofactor, and gene expression. A number of clinical trials in recent years have provided convincing evidence of the central role of this element, either alone or in combination with other micronutrients or antioxidants, in the prevention and treatment of multiple diseases. Based on these studies this review focuses on the advances made so far in the study of mechanisms and applications of selenium compounds that could be suitable for chronic diseases.

Differences in exhaled breath condensate pH measurements between samples obtained with two commercial devices.

BACKGROUND: The objective of this study was to determine differences in EBC pH between samples obtained by RTube and EcoScreen, and to identify the effect of storage at -80 degrees C on the pH values. METHODS: Twenty-three nonsmoking subjects with asthma or allergic rhinitis or without respiratory disease performed two sequential exhaled breath condensate (EBC) collections, using the RTube collection system and the EcoScreen condenser. EBC pH was measured immediately after collection and after storage at -80 degrees C for 8 weeks, without deaeration and repeated following deaeration with Argon. RESULTS: In EBC samples without deaeration, the EcoScreen pH values were significantly higher than the RTube pH values (mean difference, 0.32; 95% CI, 0.21-0.44, P < 0.0001). In deaerated EBC samples, the EcoScreen pH values were also significantly higher than the RTube pH values (mean difference, 0.12; 95% CI, 0.01-0.25, P=0.04). For both EBC collection systems, storage for 8 weeks had a significant influence on pH of nondeaerated samples. CONCLUSIONS: The present study demonstrates that EBC pH value is dependent on the collection device used and that the storage for 8 weeks had a significant influence on the pH of samples analyzed without deaeration.

[Usefulness of transcutaneous carbon dioxide pressure monitoring to measure blood gases in adults hospitalized for respiratory disease]. / Utilidad de la presión transcutánea del anhídrido carbónico en la valoración gasométrica de adultos hospitalizados con enfermedad respiratoria.

OBJECTIVE: To evaluate the usefulness of transcutaneous carbon dioxide pressure (TcPCO2) monitoring in patients hospitalized for respiratory disease. PATIENTS AND METHODS: We used a SenTec TcPCO2 monitor that also determines transcutaneous oxygen saturation (SpO2) by means of a sensor placed behind the ear lobe at a temperature of 42 degrees C. We compared arterial blood gas measurements--PaCO2 and arterial oxygen saturation (SaO2)--with transcutaneous measurements and analyzed the correlation, regression line, and agreement between the 2 methods. RESULTS: Thirty patients (20 men and 10 women) with various respiratory diseases and a mean (SD) age of 71 (13) years were included in the study. The median TcPCO2 was 43.25 mm Hg and the median PaCO2 was 42.6 mm Hg with no significant differences between the 2 measurements. The correlation was significant (rho=0.979; P< .0001) and the corresponding regression equation was TcPCO2=-2.475+1.058 PaCO2. The mean difference was 0.16 mm Hg (95% confidence interval [CI], --0.74 to 1.06). The lower limit of agreement (mean -1.96 SD) was -4.64 mm Hg, and the upper limit (mean +1.96 SD) was 4.96 mm Hg. For SaO2, the median was 94% and for SpO2, 95%. The difference between the 2 medians was significant (P< .004). The correlation was also significant (rho=0.822; P< .0001) with SpO2=4.427+0.97 SaO2. The mean difference was 1.14% (95% CI, 0.381% to 1.899%). The lower limit of agreement (mean -1.96 SD) was --2.93% and the upper limit (mean +1.96 SD) was 5.21% CONCLUSIONS: Transcutaneous determination of carbon dioxide pressure and oxygen saturation is useful for patients hospitalized for respiratory disease in view of its good correlation and agreement, although SpO2 does tend to overestimate SaO2.

Utilidad de la presión transcutánea del anhídrido carbónico en la valoración gasométrica de adultos hospitalizados con enfermedad respiratoria / Usefulness of transcutaneous carbon dioxide pressure monitoring to measure blood gases in adults hospitalized for respiratory disease

Objetivo: Estudiar la utilidad de la medida de la presión transcutánea de anhídrido carbónico (PtcCO2) en pacientes con enfermedad respiratoria hospitalizados. Pacientes y métodos: Utilizamos el analizador de PtcCO2 SenTec®, que también determina la saturación transcutánea de oxígeno (SpO2), mediante un sensor colocado en el lóbulo de la oreja a una temperatura de 42 °C. Se compararon los valores gasométricos ­--presión arterial de anhídrido carbónico (PaCO2) y saturación arterial de oxígeno (SaO2)--­ con los transcutáneos, analizando la correlación, recta de regresión y la concordancia entre ambos métodos. Resultados: Se incluyó a 30 pacientes (20 varones y 10 mujeres) con diversas enfermedades respiratorias, con una media (± desviación estándar [DE]) de edad de 71 ± 13 años. La mediana de la PtcCO2 era de 43,25 mmHg, y la de la PaCO2 de 42,6 mmHg, sin existir diferencias entre ellas. La correlación era significativa (ρ = 0,979; p < 0,0001), siendo la PtcCO2 = -­2,475 + 1,058 PaCO2. La media de las diferencias fue de 0,16 mmHg (intervalo de confianza del 95%, de ­-0,74 a 1,06); la media de las diferencias menos 1,96 DE fue de ­-4,64 mmHg, y más 1,96 DE, de 4,96 mmHg. En cuanto a la SaO2, la mediana era del 94%, y la de la SpO2 del 95%, con diferencias entre ambas (p < 0,004). La correlación fue significativa (ρ = 0,822; p < 0,0001), con SpO2 = 4,427 + 0,97 SaO2. La media de la concordancia era del 1,14% (intervalo de confianza del 95%, 0,381-1,899%); la media menos 1,96 DE era del ­-2,93%, y más 1,96 DE, del 5,21%. Conclusiones: La determinación transcutánea de anhídrido carbónico y de la SaO2 es de utilidad en pacientes con enfermedad respiratoria hospitalizados, dada su buena correlación y concordancia, aunque la SpO2 tiende a sobrevalorar la SaO2

Objective: To evaluate the usefulness of transcutaneous carbon dioxide pressure (TcPCO2) monitoring in patients hospitalized for respiratory disease. Patients and methods: We used a SenTec TcPCO2 monitor that also determines transcutaneous oxygen saturation (SpO2) by means of a sensor placed behind the ear lobe at a temperature of 42ºC. We compared arterial blood gas measurements--PaCO2 and arterial oxygen saturation (SaO2)--with transcutaneous measurements and analyzed the correlation, regression line, and agreement between the 2 methods. Results: Thirty patients (20 men and 10 women) with various respiratory diseases and a mean (SD) age of 71 (13) years were included in the study. The median TcPCO2 was 43.25 mm Hg and the median PaCO2 was 42.6 mm Hg with no significant differences between the 2 measurements. The correlation was significant (ρ=0.979; P<.0001) and the corresponding regression equation was TcPCO2=­-2.475+1.058 PaCO2. The mean difference was 0.16 mm Hg (95% confidence interval [CI], ­-0.74 to 1.06). The lower limit of agreement (mean ­-1.96 SD) was ­-4.64 mm Hg, and the upper limit (mean +1.96 SD) was 4.96 mm Hg. For SaO2, the median was 94% and for SpO2, 95%. The difference between the 2 medians was significant (P<.004). The correlation was also significant (ρ=0.822; P<.0001) with SpO2=4.427+0.97 SaO2. The mean difference was 1.14% (95% CI, 0.381% to 1.899%). The lower limit of agreement (mean ­1.96 SD) was ­-2.93% and the upper limit (mean +1.96 SD) was 5.21% Conclusions: Transcutaneous determination of carbon dioxide pressure and oxygen saturation is useful for patients hospitalized for respiratory disease in view of its good correlation and agreement, although SpO2 does tend to overestimate SaO2

New 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives, with dual action at 5-HT1A serotonin receptors and serotonin transporter, as a new class of antidepressants.

In a search toward new and efficient antidepressants, 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor antagonism. This dual pharmacological profile should lead, in principle, to a rapid and pronounced enhancement in serotoninergic neurotransmission and consequently to a more efficacious treatment of depression. The design was based on coupling structural moieties related to inhibition of serotonin reuptake, such as gamma-phenoxypropylamines, to arylpiperazines, typical 5-HT1A ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and 5-HT1A receptors. Antidepressant-like activity was initially assayed in the forced swimming test with those compounds with Ki < 200 nM in both binding studies. Functional characterization was performed by measuring the intrinsic effect on rectal temperature in mice and also the antagonism to 8-OH-DPAT-induced hypothermia. The most efficacious compounds (12f, 23gE, 28a, and 28b) were further explored for their ability to antagonize 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP formation in a cell line expressing the 5-HT1A receptor. Furthermore, the antidepressant-like properties of 12f, 28a, and 28b, which exhibited 5-HT1A receptor antagonistic property in the latter study, were also evaluated in the learned helplessness test in rats. Among these three compounds, 28b (1-benzo[b]thiophene-3-yl)-3-[4-(2-methoxyphenyl)-1-ylpropan-1-ol) showed the higher affinity at both the 5-HT transporter and 5-HT1A receptors (Ki = 20 nM in both cases) and was also active in the other pharmacological tests. Such a pharmacological profile could lead to a new class of antidepressants with a dual mechanism of action and a faster onset of action.

New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants.

A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (8) show values (nM) of K(i)=30 and 2.3 for 5-HT1A receptors and K(i)=30 and 12 for serotonin transporters, respectively. In GTPgammaS binding assays, compound 8 revealed antagonist properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.

Early histological maturation in the hippocampus of the guinea pig.

The vesicular zinc-rich synaptic systems of the principal neurons of the hippocampus are well developed in newborn guinea pigs, a precocial species. In addition, alvear and fimbrial myelinated fibers as well as significant inhibitory interneurons (i.e. somatostatin, parvalbumin and opioid immunoreactive hippocampal interneurons) are also well developed. On the contrary, neither vesicular zinc synapses nor myelinated fibers nor the above mentioned immunoreactive interneurons are detectable in newborn specimens of other related altricial species such as rats or rabbits. These data suggest that early maturation of a highly integrative center related to cognitive map building such as the hippocampus is characteristic of precocial species.

Design, synthesis and biological evaluation of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives as potential antidepressants with a dual mode of action: serotonin reuptake inhibition and 5-HT1A receptor antagonism.

It has been suggested that the combination of a selective serotonin reuptake inhibitor (SSRI) and a 5-HT1A receptor antagonist may facilitate the onset of the SSRIs antidepressant action. Accordingly, we describe the synthesis of a series of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives with structural modifications performed in Ar1, Ar2 and Z (Z is different functional groups) to obtain the sought dual activity. Compounds were evaluated for in vitro affinity at 5-HT1A receptors and 5-HT transporter. The antidepressant-like activity of derivatives with the higher affinity was assessed initially using the forced swimming test (FST). Compound 1-(2,4-dimethylphenyl)-3-[(2-methoxyphenyl)piperazin-1-il]-1-propa none (III.1.a) showed the best antidepressant-like activity which was further confirmed in the learned helplessness test.

Radial glia and cell debris removal during lesion-regeneration of the lizard medial cortex.

Intraperitoneal injection of the neurotoxin 3-acetylpyridine (3AP) induces a rapid degeneration of the medial cerebral cortex (lizard fascia dentata) granular layer and of its zinc enriched axonal projection (lizard mossy fibres). After 6-8 weeks post-lesion the cell debris have been removed and the granular layer is repopulated by neurons generated in the subjacent ependyma. Both processes, neuron incorporation and debris removal, seem to be crucial for successful regeneration. Scavenging processes in the lesioned mammalian CNS are usually carried out by microglia and/or astrocytes. In the lizard cerebral cortex there are no free astrocytes and the only glial fibrillary acid (GFAP) immunoreactive cells are radial glia-ependymocytes, similar to those present during mammalian CNS development. Ependymocytes, in addition to their help in vertical migrations of just generated immature neurons, built the cortical glial scaffold, insulate the blood capillaries, form the outer glial limiting membrane, thus playing an essential role in the lizard cortical blood-brain barrier. In this study, by means of GFAP-immunocytochemistry and electron microscopy, we have shown that radial glial cells participate actively in the removal/phagocytosis of cellular debris generated in the lesion process: mainly degenerated synapses, but interestingly, also some neuronal somata. Cell debris taken up by ependymocyte lateral processes seem to be progressively transported to either distal (pial) or proximal (ventricular) poles of the cell, where they result in lipofuscin accumulations. The hypothetical subsequent exchange of debris from ependymoglia by microglia/macrophages and Kolmer cells is discussed.

Microglial cells during the lesion-regeneration of the lizard medial cortex.

The lizard medial cortex (lizard fascia dentata) is capable of neural regeneration after being lesioned by the anti-metabolite 3-acetylpyridine (3AP). This study was aimed at detecting microglial behaviour during the medial cortex lesion-regeneration process using tomato lectin histochemistry to label microglia (both with light and electron microscopy) and proliferating cell nuclear antigen (PCNA) immunocytochemistry to label proliferating cells. As expected, 1-2 days post-injection lectin-labelled microglia cells could not be observed in the medial cortex plexiform layers, but later (7 days post-injection) abundant lectin-labelled microglia cells re-populated the regenerating medial cortex. Abundant PCNA-immunolabelled nuclei were detected both in the subjacent ependymal neuroepithelium (neuroblasts, maximum at 2 days post-injection) as well as in some parenchymal cells which were also lectin-labelled (microglia, maximum at 7-15 days post-injection). Re-invasive microglia were also detected in the vicinity of ventricular ependymal lining, blood vessels and meninges. The electron microscope demonstrated that these microglial cells participate in cell debris removal, especially of neural granular cell somata. Other cell types related to microglia (mast cells, peri-vascular cells and meningeal cells) were also present during the scavenging process. Significant numbers of microglial cells remained in close relationship with the ependymal proliferative areas, even in control non-lesioned animals. This is indirect evidence for the working hypothesis that microglia are not only implicated in cell debris removal, but also in the regulation of newly generated neuroblast incorporation onto the cortical areas. Whether they phagocytose immature neuroblasts or induce cell death in them or even prevent their migration onto the principal layer areas are likely possibilities that remain to be proven.

Synthesis of thiophene carboxamide derivatives as serotonin 5-HT4 receptor agonists.

New thiophene carboxamide derivatives 3 (a-j) were synthesized as serotonin 5-HT4 receptor agonists. Preliminary results showed that the compounds 3a, 3d, 3e and 3f caused concentration dependent relaxation of carbachol-induced contraction in tunica muscularis mucosae in rat oesophagus.

Zinc-positive presynaptic boutons of the rabbit hippocampus during early postnatal development.

The evolution of vesicular zinc-containing boutons in the developing rabbit hippocampus has been studied during early postnatal life using the selenite-Danscher histochemical method. By P3, large immature mossy fiber boutons with labeled synaptic vesicles were seen in the hilus of the dentate gyrus and in the stratum lucidum of the CA3-CA4 hippocampal areas. After P5, smaller boutons with labeled vesicles were identified in the stratum oriens and stratum radiatum of all hippocampal areas, and even transiently in the stratum lacunosum of P6 animals. Vesicular zinc-containing boutons increased in number and underwent ultrastructural maturation; light microscope densitometric-volumetric measurements were used to quantify their presence in every hippocampal lamina. Electron microscope stereologic analysis permitted accurate estimation of the actual numbers along early postnatal development. Three main phases of zinc-positive bouton growth were detected during the first postnatal month. The first phase, starting at P5, is characterised by an abrupt rise in vesicular zinc content which at P8-P9 begins to decrease. The second phase is characterised by a consistent rise in vesicular zinc content from P10 to P12 to a level which is maintained until P18; this steady period is the result of partial and sequential elimination of zinc-positive boutons in some areas (i.e. oriens of CA3 by P11, radiatum of CA3 by P13, and radiatum of CA1 and lucidum of CA3 by P15) while they continue to increase in other areas. The final phase is a continuous increase to almost adult levels.

Synthesis and 5-HT3 affinity of new 3-substituted indoles at central nervous system.

A series of 3-imino and 3-aminomethyl-N-methylindoles, in which the amine substituents were 3-quinuclidyl and 1-adamantyl groups, were synthesized and their in vitro affinity towards 5-HT3 central receptors evaluated. Of the nine compounds tested, three caused displacement of 3H-BRL 43694 binding to 5-HT3. 2-Chloro-3-(3-quinuclidylimino)-1-methylindole, 4, was the most potent compound with an IC50 = 5.15 10(-8) M. Moreover, the monoamine oxidase inhibition activity was tested and three compounds were shown to be MAO inhibitors, their IC50 was in the range of that of (-)-Deprenyl. Again, 4 was the most potent compound. Structure-activity relationships within the series are briefly discussed.