Predicting extracapsular involvement in prostate cancer through the tumor contact length and the apparent diffusion coefficient. / Predicción de la extensión extracapsular en el cáncer de próstata mediante la longitud del contacto tumoral y el coeficiente de difusión aparente.

OBJECTIVE: To evaluate the diagnostic performance of the length of the tumor contact with the capsule (LTC) and the apparent diffusion coefficient (ADC) map in the prediction of microscopic extracapsular extension in patients with prostate cancer who are candidates for radical prostatectomy. MATERIAL AND METHODS: We used receiver operating curves to retrospectively study the diagnostic performance of the ADC map and the LTC as predictors of microscopic extracapsular extension in 92 patients with prostate cancer and moderate to high risk who were examined between May 2011 and December 2013. RESULTS: The optimal cutoff for the ADC map was 0.87× 10-3 mm2/s, which yielded an area under the ROC curve of 72% (95% CI: 57%-86%), corresponding to a sensitivity of 83% and a specificity of 61%. The optimal cutoff for the LTC was 17.5mm, which yielded an area under the ROC curve of 74% (95% CI: 61%-87%), corresponding to a sensitivity of 91% and a specificity of 57%. Combining the two criteria improved the diagnostic performance, yielding an area under the ROC curve of 77% (95% CI: 62%-92%), corresponding to a sensitivity of 77% and a specificity of 61%. We elaborated a logistic regression model, obtaining an area under the ROC curve of 82% (95% CI: 73%-93%). CONCLUSIONS: Using quantitative measures improves the diagnostic accuracy of multiparametric magnetic resonance imaging in the staging of prostate cancer. The values of the ADC and LTC were predictors of microscopic extracapsular extension, and the best results were obtained when both values were used in combination.

Social avoidance and altered hypothalamic-pituitary-adrenal axis in a mouse model of anxious depression: The role of LPA1 receptor.

Anxious depression is a prevalent disease with devastating consequences. Despite the lack of knowledge about the neurobiological basis of this subtype of depression, recently our group has identified a relationship between the LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) for lysophosphatidic acid, with a mixed depressive-anxiety phenotype. Dysfunctional social behaviors, which have been related to increased activation of the hypothalamus-pituitary-adrenal (HPA) axis, are key symptoms of depression and are even more prominent in patients with comorbid anxiety and depressive disorders. Social behavior and HPA functioning were assessed in animals lacking the LPA1 receptor. For these purposes, we first examined social behaviors in wild-type and LPA1 receptor-null mice. In addition, a dexamethasone (DEX) suppression test was carried out. maLPA1-null mice exhibited social avoidance, a blunted response to DEX administration and an impaired circadian rhythm of corticosterone levels, which are features that are consistently dysregulated in many mental illnesses including anxious depression. Here, we have strengthened the previous experimental evidence for maLPA1-null mice to represent a good animal model of anxious depression, providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, particularly this subtype of depression.

Deforestation in Colombian protected areas increased during post-conflict periods.

Protected areas (PAs) are a foundational and essential strategy for reducing biodiversity loss. However, many PAs around the world exist on paper only; thus, while logging and habitat conversion may be banned in these areas, illegal activities often continue to cause alarming habitat destruction. In such cases, the presence of armed conflict may ultimately prevent incursions to a greater extent than the absence of conflict. Although there are several reports of habitat destruction following cessation of conflict, there has never been a systematic and quantitative "before-and-after-conflict" analysis of a large sample of PAs and surrounding areas. Here we report the results of such a study in Colombia, using an open-access global forest change dataset. By analysing 39 PAs over three years before and after Colombia's peace agreement with the Revolutionary Armed Forces of Colombia (FARC), we found a dramatic and highly significant increase in the deforestation rate for the majority of these areas and their buffer zones. We discuss the reasons behind such findings from the Colombian case, and debate some general conservation lessons applicable to other countries undergoing post-conflict transitions.

LPA1 receptor and chronic stress: Effects on behaviour and the genes involved in the hippocampal excitatory/inhibitory balance.

The LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA1-receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. However, to date, there is no available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA1 pathway may prevent the negative consequences of chronic stress, we assessed the effects of the continuous delivery of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Because a proper excitatory/inhibitory balance seems to be key for controlling the stress response system, the gene expression of molecular markers of excitatory and inhibitory neurotransmission was also determined. In addition, the hippocampal expression of mineralocorticoid receptor genes and glucocorticoid receptor genes and proteins as well as plasma corticosterone levels were determined. Contrary to our expectations, the continuous delivery of LPA in chronically stressed animals potentiated rather than inhibited some (e.g., anhedonia, reduced latency to the first immobility period), though not all, behavioural effects of stress. Furthermore, this treatment led to an alteration in the genes coding for proteins involved in the excitatory/inhibitory balance in the ventral hippocampus and to changes in corticosterone levels. In conclusion, the results of this study reinforce the assumption that LPA is involved in emotional regulation, mainly through the LPA1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour.

Use of microbial models to evaluate the effect of UV-C light and trans-cinnamaldehyde on the native microbial load of grapefruit (Citrus × paradisi) juice.

The aim of this research was to evaluate the storage stability (5 °C), and microbial modeling, of Rubi red grapefruit (Citrus × paradisi) juice treated with ultraviolet-C (UV-C) light (0, 10 and 20 min), alone or in combination with trans-cinnamaldehyde (trans-CAH) (0, 25 and 50 µg/mL). A 32 factorial design was used and data modeled with the Weibull, Modified Gompertz and Logistic models. A response surface model was used to evaluate the effect of modeling parameters for suggesting the optimum treatment conditions. Treated and some untreated juice lasted up to 9 days without physicochemical and microbial changes. At the higher combination of UV-C light and trans-CAH, the microbial load of grapefruit juice was maintained below 100 CFU/mL up to 15 days. For mesophiles, the three predictive models indicated that the parameters n and Nmax decreased and the parameters λ and tc increased as the combination of UV-C light and trans-CAH increased. The response surface modeling of the parameters obtained by the predictive models showed acceptable correlation for mesophiles (R2 = 0.815-0.977) but not for yeasts (R2 = 0.618-0.815). The three predictive models showed that, the concentration of trans-CAH had more effect on stopping the microbial growth than the UV-C light treatment.

Acute and subchronic effects of gamma-hydroxybutyrate on isolation-induced aggression in male mice.

Gamma-hydroxybutyrate (GHB) is a new drug with abuse potential popularly known as "liquid ecstasy". It is an endogenous compound of the mammalian brain which satisfies many of the criteria for consideration as a neurotransmitter or neuromodulator. Preliminary studies have found that GHB (100-200 mg/kg) reduces aggressive behavior in mice. This study was designed to assess the effects of low and intermediate doses of GHB (5, 25, 50 and 100 mg/kg, ip) on isolation-induced aggression in male mice, using an ethopharmacological approach. Moreover, the possible development of tolerance after its subchronic administration for 15 consecutive days was also examined. Individually housed mice were exposed to anosmic "standard opponents" 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. Acute treatment with GHB (25-100 mg/kg) significantly reduced offensive behaviors (threat and attack) without affecting immobility, whereas with the lowest dose used (5 mg/kg) a significant increase of attack behaviors was observed. This behavioral profile was maintained when GHB (25-100 mg/kg) was administered during 15 consecutive days, indicating an absence of tolerance to the initial antiaggressive action of the drug. However, the subchronic treatment with 5 mg/kg of GHB produced an opposite effect to that observed after single treatment, suggesting a possible desensitization of postsynaptic dopaminergic receptors.

IGF-II promotes neuroprotection and neuroplasticity recovery in a long-lasting model of oxidative damage induced by glucocorticoids.

Insulin-like growth factor-II (IGF-II) is a naturally occurring hormone that exerts neurotrophic and neuroprotective properties in a wide range of neurodegenerative diseases and ageing. Accumulating evidence suggests that the effects of IGF-II in the brain may be explained by its binding to the specific transmembrane receptor, IGFII/M6P receptor (IGF-IIR). However, relatively little is known regarding the role of IGF-II through IGF-IIR in neuroprotection. Here, using adult cortical neuronal cultures, we investigated whether IGF-II exhibits long-term antioxidant effects and neuroprotection at the synaptic level after oxidative damage induced by high and transient levels of corticosterone (CORT). Furthermore, the involvement of the IGF-IIR was also studied to elucidate its role in the neuroprotective actions of IGF-II. We found that neurons treated with IGF-II after CORT incubation showed reduced oxidative stress damage and recovered antioxidant status (normalized total antioxidant status, lipid hydroperoxides and NAD(P) H:quinone oxidoreductase activity). Similar results were obtained when mitochondria function was analysed (cytochrome c oxidase activity, mitochondrial membrane potential and subcellular mitochondrial distribution). Furthermore, neuronal impairment and degeneration were also assessed (synaptophysin and PSD-95 expression, presynaptic function and FluoroJade B® stain). IGF-II was also able to recover the long-lasting neuronal cell damage. Finally, the effects of IGF-II were not blocked by an IGF-IR antagonist, suggesting the involvement of IGF-IIR. Altogether these results suggest that, in or model, IGF-II through IGF-IIR is able to revert the oxidative damage induced by CORT. In accordance with the neuroprotective role of the IGF-II/IGF-IIR reported in our study, pharmacotherapy approaches targeting this pathway may be useful for the treatment of diseases associated with cognitive deficits (i.e., neurodegenerative disorders, depression, etc.).

maLPA1-null mice as an endophenotype of anxious depression.

Anxious depression is a prevalent disease with devastating consequences and a poor prognosis. Nevertheless, the neurobiological mechanisms underlying this mood disorder remain poorly characterized. The LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intracellular signalling molecule. The loss of this receptor induces anxiety and several behavioural and neurobiological changes that have been strongly associated with depression. In this study, we sought to investigate the involvement of the LPA1 receptor in mood. We first examined hedonic and despair-like behaviours in wild-type and maLPA1 receptor null mice. Owing to the behavioural response exhibited by the maLPA1-null mice, the panic-like reaction was assessed. In addition, c-Fos expression was evaluated as a measure of the functional activity, followed by interregional correlation matrices to establish the brain map of functional activation. maLPA1-null mice exhibited anhedonia, agitation and increased stress reactivity, behaviours that are strongly associated with the psychopathological endophenotype of depression with anxiety features. Furthermore, the functional brain maps differed between the genotypes. The maLPA1-null mice showed increased limbic-system activation, similar to that observed in depressive patients. Antidepressant treatment induced behavioural improvements and functional brain normalisation. Finally, based on validity criteria, maLPA1-null mice are proposed as an animal model of anxious depression. Here, for we believe the first time, we have identified a possible relationship between the LPA1 receptor and anxious depression, shedding light on the unknown neurobiological basis of this subtype of depression and providing an opportunity to explore new therapeutic targets for the treatment of mood disorders, especially for the anxious subtype of depression.

[Update on gamma-hydroxybutyric acid]. / Actualización del ácido gamma-hidroxibutírico.

AIMS: The article offers an updated review of the main pharmacological aspects of gamma-hydroxybutyric acid (GHB), as well as its clinical and behavioural effects. DEVELOPMENT: A number of pharmacological, neurochemical and electrophysiological studies have clearly shown that endogenous GHB plays a role as a neurotransmitter and/or neuromodulator in the central nervous system (CNS). GHB displays specific synthesis, release and reuptake mechanisms, as well as particular binding sites that suggest the existence of a central GHBergic system. This substance, popularly known as 'liquid ecstasy', is also a potentially abusable drug; if administered for prolonged periods of time it can lead to dependence and withdrawal symptoms after the patient stops taking it. Its chief behavioural actions include sedation/sleepiness, induction of absence seizures, catalepsy or reduced aggression, among others. Some of these effects appear to be related to an interaction that has been reported to exist between the GHBergic system and the dopaminergic and GABAergic receptors in the CNS. From the clinical point of view, its use has been approved in some countries to treat the narcoleptic syndrome, and it has also been considered for possible use in the treatment of alcohol or opiate abuse. Finally, recent studies conducted with laboratory animals suggest the existence of a possible neurotoxic effect following prolonged administration in abusable dosages. CONCLUSIONS: GHB is an extraordinarily interesting compound. It acts as a neurotransmitter/neuromodulator in the CNS. It is also an abusable recreational drug and may also be used to treat a number of different pathological conditions, the most important of which is narcolepsy. The possible development of neurotoxicity following prolonged administration, however, imposes considerable limitations on its usefulness in clinical contexts.

Bezoar de dinero: reporte de bezoar atípico, su manejo y una revisión de la literatura / Money Bezoar: Report of atypical bezoar, its treatment, and a literature review

Resumen Objetivos: Presentar el manejo laparoscópico en un caso de bezoar atípico y una revisión de la literatura. Materiales y métodos: Se presenta el caso de un paciente de sexo masculino de 67 años con síndrome pilórico debido a una obstrucción intestinal por cuerpo extraño. Resultados: Se encuentra como hallazgo endoscópico un bezoar atípico (bezoar de dinero) impactado en la región prepilórica sin posibilidad de resolución por este medio, por lo cual se considera el manejo laparoscópico. Discusión: Los bezoares se definen como cualquier objeto el cual tuvo una ingesta voluntaria o involuntaria, que se aloja en alguna parte del tracto gastrointestinal superior, con mayor frecuencia a nivel gástrico, y no se puede digerir por los mecanismos fisiológicos del cuerpo; además, se clasifican según su composición. Conclusiones: En pacientes con obstrucción intestinal alta debido a cuerpos extraños en los cuales el manejo endoscópico falla, el manejo quirúrgico mínimamente invasivo con cirugía laparoscópica es viable y eficaz.

Abstract Objectives: To describe the laparoscopic management of an atypical bezoar case and present a literature review. Materials and methods: This is the case of a 67-year-old male patient with pyloric stenosis due to intestinal obstruction by a foreign body. Results: The endoscopic finding was an atypical bezoar (Money bezoar) in the prepyloric region with no possible resolution by this route, so laparoscopic treatment was considered. Discussion: Bezoars are defined as any object that was voluntarily or involuntarily swollen and is obstructing some part of the upper gastrointestinal tract, usually the stomach, and cannot be digested using the physiological mechanisms of the body. They are categorized based on their composition. Conclusions: When endoscopic treatment fails to relieve upper gastrointestinal tract obstruction caused by foreign bodies, minimally invasive surgical treatment with laparoscopic surgery is a viable and efficient option.

Midkine as a novel target gene for the Wilms' tumor suppressor gene (WT1).

Midkine (MK) is a heparin-binding growth factor which is strongly expressed during the midgestation period of mouse embryogenesis. Wilms' tumor is an embryonal kidney malignancy in infants, and WT1 has been identified as its tumor suppressor gene. The high expression level of MK in all Wilms' tumor specimens so far examined and the presence of two WT1 elements (5'-GCGGGGGCG-3') in the human MK promoter region led us to examine the possible role of the WT1 gene product in the regulation of MK gene expression. A gel shift assay verified the complex formation between the WT1 gene product and WT1 consensus sequence of MK gene. DNase1 footprint analysis also demonstrated that the downstream WT1 element was protected from DNase1 cleavage by the addition of the WT1 protein. The human MK promoter fused with the chloramphenicol acetyltransferase gene (phMK2.3kCAT) was co-transfected with an effector plasmid containing the WT1 gene into several cell lines. Transient transfection assays showed suppression of the MK promoter by WT1 co-transfection in recipient cells; deletion of the WT1 binding site abolished the suppression. The evidence reported in this study indicates that MK gene is a newly identified WT1 target gene.

Mente Activa® Improves Impaired Spatial Memory in Aging Rats.

OBJECTIVES: Aging is accompanied by a decline in several aspects of the cognitive function, having negative personal and socioeconomic impacts. Dietary supplements could be beneficial for preventing age-related cognitive decline. In this context, we examined whether the nutritional supplement Mente Activa® has beneficial effects on aging-related cognitive deficits without inducing side effects. METHODS: Mente Activa® was administered to old rats (n= 30 treated rats and n= 30 control rats) during 5 months, and the Morris water maze was used to test the learning capacities of the animals. The first assessment was conducted before the nutritional intervention (age of 18-19 months), to determine the baseline of the performance of animals on this test, and the second assessment was performed at the end of the treatment (23-24 moths). In order to examine possible secondary effects of this nutritional supplement, plasma, heart anatomy and liver parameters were evaluated. RESULTS: Our data indicate that supplemented rats showed less escape latency, distance swum, higher use of spatial search strategies, and crossed the former platform location with higher frequency than control rats. These effects were specific of the treatment, indicating that this nutritional supplement has a beneficial effect on spatial memory. On the other hand, the regular intake of Mente Activa® did not induce any negative effects in plasma parameters and heart size. CONCLUSIONS: Aged rats under a sustained dietary intake of the nutritional supplement Mente Activa® displayed improved learning and memory abilities compared to the non-treated rats. These results suggest the therapeutic potential and safety of use of Mente Activa® for age-related cognitive deficits, particularly, in the onset of the first cognitive dysfunction symptoms.

Evaluación del efecto acaricida de Momordica charantia, Megaskepasma erythrochlamys y Gliricidia sepium sobre Rhipicephalus microplus / Acaricidal effect of Momordica charantia, Megaskepasma erythrochlamys and Gliricidia sepiumon the Rhipicephalus microplus

RESUMEN Objetivo. Se evaluó la actividad acaricida de Momordica charantia (Mc), Megaskepasma erythrochlamys (Me) y Gliricidia sepium (Gs) sobre Rhipicephalus microplus (Rm). Materiales y métodos. Se realizó la marcha fitoquímica preliminar de hojas del extracto metanólico de Mc (EMc), del extracto etanólico de Me (EMe) y del extracto acetónico de Gs (EGs) a través de la técnica de colorimetría y cromatografía en capa delgada (CCD). La actividad acaricida se realizó a través de pruebas in-vitro utilizando la prueba de inmersión de larvas (LIT) y la prueba de inmersión de adultos (AIT). Para las pruebas in-situ se usaron bovinos en pastoreo infestados naturalmente con garrapatas, utilizando las CL50 obtenidas en las pruebas in-vitro AIT; posteriormente las teleoginas se llevaron a incubación para evaluar su capacidad reproductiva. Resultados. Se determinó la presencia de varios grupos de metabolitos secundarios de interés acaricida. Se demostró el efecto acaricida de los extractos de las plantas sobre teleoginas; aunque sólo EGs mostró actividad larvicida. Los extractos a 160 mg/mL afectaron el ciclo de vida de Rm inhibiendo la ovoposición en un 46.9%, 66.1% y 84.03% (p<0.05) para EGs, EMc y EMe, respectivamente. Por otro lado, en las pruebas in situ se observó diferencia significativa (p<0.05) entre el tratamiento de EMc y EMe respecto a los grupos controles. Conclusiones. Los resultados obtenidos son prometedores para fortalecer la posibilidad de vinculación de los extractos de estas plantas dentro de planes integrados de control de garrapatas en sistemas de producción de bovinos.

ABSTRACT Objective. The acaricidal activity of Momordica charantia (Mc), Megaskepasma erythrochlamys (Me) and Gliricidia sepium (Gs) on Rhipicephalus microplus (Rm) was evaluated. Materials and methods. Preliminary phytochemical analysis of leaves of the methanolic extract of Mc (EMc), the ethanolic extract of Me (EMe) and the acetone extract of Gs (EGs) were carried out through the technique of colorimetry and thin layer chromatography (CCD). The acaricidal activity was performed through in-vitro tests using the larval immersion test (LIT) and the adult immersion test (AIT). For in-situ tests, grazing cattle naturally infested with ticks were used, using the LC50 obtained from the in-vitro AIT tests; later the teleogines were taken to incubation to evaluate their reproductive capacity. Results. The presence of several groups of secondary metabolites of acaricidal interest was determined. The acaricidal effect of the extracts of the plants on teleogines was demonstrated; although only EGs showed larvicidal activity. Extracts at 160 mg/mL affected the life cycle of Rm by inhibiting ovoposition in 46.9%, 66.1% and 84.03% (p<0.05) for EGs, EMc and EMe, respectively. On the other hand, the in-situ tests showed a significant difference (p<0.05) between the treatment of EMc and EMe with respect to the control groups. Conclusions. The results obtained are promising to strengthen the possibility of linking the extracts of these plants into integrated plans for the control of ticks in cattle systems.

Interleukin-1beta stimulates cyclic GMP efflux in brain astrocytes.

In rat brain astroglia-enriched cultures long-term treatment with interleukin-1beta induces NO release and stimulation of soluble guanylyl cyclase. The cGMP formed is recovered in the extracellular medium but not in the cell monolayer. The interleukin-1beta effect is mediated by type I receptor and potentiated by interferon-gamma. In cells treated with bacterial endotoxin a larger NO-dependent cGMP accumulation occurs only intracellularly, however a significant cGMP egression is observed when cells are co-treated with interleukin-1beta. The non-selective anion transport inhibitors probenecid and verapamil block cGMP efflux, indicating that interleukin-1beta stimulates a cGMP transporter.

A retinoic acid-responsive element in human midkine gene.

Midkine is a growth/differentiation factor which is found as a product of a retinoic acid-responsive gene. The 2.3-kb upstream sequence of the human MK gene has cis acting elements which confer retinoic acid-induced expression of fused chloramphenicol acetyl-transferase (CAT) gene in F9 embryonal carcinoma cells. In the 5'-region of the human gene, a sequence resembling the DR5-type retinoic acid-responsive element (AGGTCA-related direct repeats separated by 5 nucleotides) was present in a small block of highly homologous 5'-sequences shared by the human and mouse genes. Deletion of this direct repeat reduced retinoic acid-induced CAT gene expression. The core element in the human gene differs from the consensus sequence of retinoic acid-responsive element in two nucleotides and from the retinoic acid responsive element of the mouse MK gene in one nucleotide.

The fourth armadillo repeat of plakoglobin (gamma-catenin) is required for its high affinity binding to the cytoplasmic domains of E-cadherin and desmosomal cadherin Dsg2, and the tumor suppressor APC protein.

Plakoglobin is a member of a protein family with a repeated amino acid motif, the armadillo repeat, and is a cytoplasmic protein found in both adherens junctions and desmosomes. Plakoglobin has been shown to form distinct complexes with cadherins or desmosomal cadherins. Also, plakoglobin has been shown to complex with APC, the tumor suppressor gene product. Recently we isolated a cDNA clone encoding plakoglobin lacking the fourth armadillo repeat of the original 13-repeat protein [Ozawa et al. (1995) J. Biochem. 118, 836-840]. In this study, we established an in vitro assay system to study the molecular interaction of plakoglobin with cadherins, the APC gene product, and alpha-catenin. Establishment of the system and cloning of an alternate form of plakoglobin cDNA allowed us to examine the biological activity of plakoglobin lacking the fourth armadillo repeat. Experiments with the bacterially expressed 12-repeat plakoglobin revealed that the protein binds to E-cadherin, desmoglein (Dsg2), and APC with lower affinity than the 13-repeat form does. Consistent with the observation that the affinity of alpha-catenin for these two alternate forms was similar, we found amino acid residues 104 to 145 of plakoglobin, the residues present in both isoforms, are sufficient for its binding to alpha-catenin.

Mapping and characterization of a retinoic acid-responsive enhancer of midkine, a novel heparin-binding growth/differentiation factor with neurotrophic activity.

MK is a gene that is activated by retinoic acid in embryonal carcinoma (EC) cells and is expressed temporarily during the mid-gestation period of mouse embryogenesis. Midkine, the product of the gene is a novel heparin-binding growth/differentiation factor with neurite outgrowth and neurotrophic activities. The regulatory DNA element in the retinoic acid-induced expression of the MK gene has been investigated. The 1.9 kb 5'-flanking region of the MK gene can mediate retinoic acid-responsive gene expression in F9 and HM-1 EC cells. Analysis of this region by deletion mutagenesis in F9 EC cells shows that there is a retinoic acid-responsive enhancer (designated as REM1) around 900 bp upstream from the transcription start site. This enhancer is composed of two sequence elements, which are located between -1006 and -895 and between -901 and -794. The core element of the upstream region (-971 to -955), whose deletion abolished the retinoic acid responsiveness, contained a sequence highly homologous to a binding site for retinoic acid receptors. Binding of a retinoic acid receptor heterodimer to this core element was verified by gel shift assay. Thus, retinoic acid and the receptor complex can directly induce the expression of a growth/differentiation factor gene.

Tiapride-induced catalepsy is potentiated by gamma-hydroxybutyric acid administration.

1. The effect of administration of gammahydroxybutyrate (GHB) and tiapride, either alone or in combination, on catalepsy behavior was examined in male mice. 2. Catalepsy was measured by bar and grid tests. Two successive evaluations were carried out 30 and 60 min after injections. 3. Tiapride (175 and 200 mg/kg) and gammahydroxybutyrate (200 mg/kg) provoked an increase of catalepsy scores, exhibiting different time courses. GHB produced a marked but short lasting catalepsy with a peak of action at 30 min, while tiapride produced a catalepsy state with a peak of action at 60 min. 4. Tiapride-induced catalepsy was potentiated by gammahydroxybutyrate administration at 30 min (bar test) and 60 min (bar and grid tests). 5. These results underlie the view that GHB interacts with central dopamine D2 transmission.

PGE1 protection against apoptosis induced by D-galactosamine is not related to the modulation of intracellular free radical production in primary culture of rat hepatocytes.

D-galactosamine (D-GalN) toxicity is a useful experimental model of liver failure in human. It has been previously observed that PGE1 treatment reduced necrosis and apoptosis induced by D-GalN in rats. Primary cultured rat hepatocytes were used to evaluate if intracellular oxidative stress was involved during the induction of apoptosis and necrosis by D-GalN (0-40mM). Also, the present study investigated if PGE1 (1 microM) was equally potent reducing both types of cell death. The presence of hypodiploid cells, DNA fragmentation and caspase-3 activation were used as a marker of hepatocyte apoptosis. Necrosis was measured by lactate dehydrogenase (LDH) release. Oxidative stress was evaluated by the intracellular production of hydrogen peroxide (H2O2), the disturbances on the mitochondrial transmembrane potential (MTP), thiobarbituric-reacting substances (TBARS) release and the GSH/GSSG ratio. Data showed that intermediate range of D-GalN concentrations (2.5-10mM) induced apoptosis in association with a moderate oxidative stress. High D-GalN concentration (40 mM) induced a reduction of all parameters associated with apoptosis and enhanced all those related to necrosis and intracellular oxidative stress, including a reduction of GSH/GSSG ratio and MTP in comparison with D-GalN (2.5-10 mM)-treated cells. Although PGE1 reduced apoptosis induced by D-GalN, it was not able to reduce the oxidative stress and cell necrosis induced by the hepatotoxin in spite to its ability to abolish the GSH depletion.

Uracil/tegafur plus oral calcium folinate in advanced breast cancer.

Uracil and tegafur (in a molar ratio of 4:1 [UFT]) has proven activity against breast cancer and is delivered in an easy-to-administer oral formulation. Orzel, which combines UFT with the oral biomodulator, calcium folinate, may provide even greater antitumor efficacy against breast cancer. Here, we describe the preliminary results of this phase II trial investigating the feasibility of 250 mg/m2/day of UFT plus 45 mg/day of oral calcium folinate administered to highly pretreated patients with advanced breast cancer. The results indicate a highly tolerable regimen and an overall response rate of 27.8% in a group of poor-prognosis patients. These findings warrant continued investigation.