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.

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.

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.

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.

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.).

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.

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.

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.

Fear extinction and acute stress reactivity reveal a role of LPA(1) receptor in regulating emotional-like behaviors.

LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intercellular signaling molecule. It has been proposed that this receptor has a role in controlling anxiety-like behaviors and in the detrimental consequences of stress. Here, we sought to establish the involvement of the LPA1 receptor in emotional regulation. To this end, we examined fear extinction in LPA1-null mice, wild-type and LPA1 antagonist-treated animals. In LPA1-null mice we also characterized the morphology and GABAergic properties of the amygdala and the medial prefrontal cortex. Furthermore, the expression of c-Fos protein in the amygdala and the medial prefrontal cortex, and the corticosterone response following acute stress were examined in both genotypes. Our data indicated that the absence of the LPA1 receptor significantly inhibited fear extinction. Treatment of wild-type mice with the LPA1 antagonist Ki16425 mimicked the behavioral phenotype of LPA1-null mice, revealing that the LPA1 receptor was involved in extinction. Immunohistochemistry studies revealed a reduction in the number of neurons, GABA+ cells, calcium-binding proteins and the volume of the amygdala in LPA1-null mice. Following acute stress, LPA1-null mice showed increased corticosterone and c-Fos expression in the amygdala. In conclusion, LPA1 receptor is involved in emotional behaviors and in the anatomical integrity of the corticolimbic circuit, the deregulation of which may be a susceptibility factor for anxiety disorders and a potential therapeutic target for the treatment of these diseases.

Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits.

Lysophosphatidic acid (LPA) has emerged as a new regulatory molecule in the brain. Recently, some studies have shown a role for this molecule and its LPA(1) receptor in the regulation of plasticity and neurogenesis in the adult brain. However, no systematic studies have been conducted to investigate whether the LPA(1) receptor is involved in behavior. In this study, we studied the phenotype of maLPA(1)-null mice, which bear a targeted deletion at the lpa(1) locus, in a battery of tests examining neurologic performance, habituation in exploratory behavior in response to low and mild anxiety environments and spatial memory. MaLPA(1)-null mutants showed deficits in both olfaction and somesthesis, but not in retinal or auditory functions. Sensorimotor co-ordination was impaired only in the equilibrium and grasping reflexes. The mice also showed impairments in neuromuscular strength and analgesic response. No additional differences were observed in the rest of the tests used to study sensoriomotor orientation, limb reflexes and co-ordinated limb use. At behavioral level, maLPA(1)-null mice showed an impaired exploration in the open field and increased anxiety-like response when exposed to the elevated plus maze. Furthermore, the mice exhibit impaired spatial memory retention and reduced use of spatial strategies in the Morris water maze. We propose that the LPA(1) receptor may play a major role in both spatial memory and response to anxiety-like conditions.

Angioplastía y stenting carotideo: serie clínica en Clínica Las Condes / Carotid angioplasty and stenting: clinical series at Clinica Las Condes

En este artículo se describe una serie clínica de angioplastía y stenting carotideo con sistema de protección distal para el tratamiento de la estenosis significativa del bulbo carotideo en Clínica Las Condes. El análisis de trabajos clínicos multicéntricos, junto a nuestros resultados, permite concluir que la angioplastía y stenting carotideo es una alternativa válida y de bajo riesgo para el tratamiento de la estenosis carotidea significativa.

In this article we describe a case series of carotid angioplasty and stenting with distal protection technique for the treatment of significant carotid bulb stenosis in Clínica Las Condes. The results of past clinical trials, and our case series allow us to conclude that carotid angioplasty and stenting is a valid alternative therapy with low risks associated, for the treatment of significant carotid stenosis.

Accidentes isquémicos transitorios: diagnóstico, etiología y manejo / The transient ischemic attacks: diagnosis, etiology and management

Las crisis o accidentes isquémicos transitorios cerebrales (AIT) han debido evolucionar desde una definición puramente clínica y temporal, a una basada en el compromiso del tejido cerebral, en especial porque las imágenes de difusión por resonancia nuclear magnética cerebral (dRNM), han permitido identificar AIT clínicamente típicas, con infartos cerebrales subyacentes, lo que ha llevado al concepto de AIT con infarto. Las AIT pueden ser producidas por diferentes mecanismos y existen varios tipos etiológicos, principalmente las por bajo flujo en grandes arterias, las embólicas y las de vasos penetrantes (lacunares), todo lo cual tiene implicancias terapéuticas. El diagnóstico y estudio urgente de las AIT es vital, siendo recomendado su hospitalización dentro de las 48 horas, lo cual permitirá un mejor y adecuado tratamiento. La antiagregación plaquetaria sigue siendo el pilar fundamental en el manejo de las AIT no cardioembólicas.

The transient ischemic attacks (TIA) had evolved from a purely clinical and temporary definition, to one based on brain tissue effects, especially because the diffusion-weighted images on nuclear magnetic cerebral resonance (DWI), has allowed to identify typical TIA, with cerebral underlying infarct, which has led to concept TIA with infarct. The AIT can be produced by different mechanisms and several etiologies, mainly TIA by large artery low flow, the embolic type and small-penetrating vessels (lacunar), all which has therapeutic implications. The early diagnosis and urgent study of the TIA are very important, being recommended TIA must hospitalized within the first 48 hours, what will allow a better and suitable treatment. The therapy antiplatelet continues as the mainstay in the treatment of the TIA noncardioembolic.

Tumor carcinoide apendicular / Carcinoid of the appendix. A case report

Tumors of the appendix constitute an heterogeneous group of malignancies with a variable evolution and prognosis...The aim of this reporte was to determine the prevalence of carcinoid tumors of the cecal appendix and its relationship with age, sex, clincal features and introspctive suspicion.

Migraña en el siglo XXI / Migraine in the XXI century

La cefalea es una de las causas más frecuentes de consulta en los servicios de urgencia, en la atención primaria y por supuesto en la consulta del neurólogo. Es una patología que afecta a la calidad de vida de las personas que la padecen y es una importante causa de ausentismo laboral. Dado lo transversal de esta patología, es que médicos de todas las especialidades nos vemos en la obligación de satisfacer la demanda de nuestros pacientes por un alivio. Este artículo no pretende hacer una revisión extensa sobre el tema, sino que en particular nos enfocaremos sobre algunos aspectos que han sido objeto debate, tales como "migraña y hormonas", "migraña y accidente cerebrovascular" y sobre aquellos aspectos que han tenido importantes avances en el último tiempo, tales como el conocimiento de la fisiopatología de la migraña, así como también el reconocimiento, diagnóstico y manejo de la cefalea crónica diaria.

Migraine is one of the most important reasons that explain emergency calls, general medicine and neurological office consultations. Migraine affects the patients quality of daily life and is a cause of working absenteeism. Therefore, many physicians may be in volved in the management of these patients and all of them must be updated about this prevalent condition.The aim of this review is not to make a thorough analysis of migraine; we will mainly focus on important issues such as migraine and hormones, migraine and stroke, a, advances in the understandig of migraine pathophysiology Finally, we address the appropriate diagno management of the prevalent chronic daily headache.

Loss of responsiveness to IGF-I in cells with reduced cathepsin L expression levels.

The lysosomal cysteine proteinase cathepsin L is involved in proteolytic processing of internalized proteins. In transformed cells, where it is frequently overexpressed, its intracellular localization and functions can be altered. Previously, we reported that treatment of highly metastatic, murine carcinoma H-59 cells with small molecule cysteine proteinase inhibitors altered the responsiveness of the type I insulin-like growth factor (IGF-I) receptor and consequently reduced cell invasion and metastasis. To assess more specifically the role of cathepsin L in IGF-I-induced signaling and tumorigenicity, we generated H-59 subclones with reduced cathepsin L expression levels. These clonal lines showed an altered responsiveness to IGF-I in vitro, as evidenced by (i) loss of IGF-I-induced receptor phosphorylation and Shc recruitment, (ii) reduced IGF-I (but not IGF-II)-induced cellular proliferation and migration, (iii) decreased anchorage-independent growth and (iv) reduced plasma membrane levels of IGF-IR. These changes resulted in increased apoptosis in vivo and an impaired ability of the cells to form liver metastases. The results demonstrate that cathepsin L expression levels regulate cell responsiveness to IGF-I and thereby identify a novel function for cathepsin L in the control of the tumorigenic/metastatic phenotype.

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.

Dolor neuropático diagnóstico y tratamiento / Neuropathic pain diagnosis and treatment

El dolor neuropático tiene características semiológicas que facilitan su sospecha y diagnóstico, pero en ocasiones este no es fácil y tiende catalogarse como dolor neuropático, algunos dolores nociceptivos refractarios. Se requiere como pilar del diagnóstico la presencia de una enfermedad neurológica de base, ya sea periférica o central, que en general posee mecanismos fisiopatológicos múltiples, pero poco definidos. El manejo terapéutico si bien involucra múltiples alternativas de tratamiento, es difícil, con un número importante de pacientes con respuesta parcial o refractarios, lo cual plantea la necesidad de equipos multidisciplinarios para su manejo.

Actualización del ácido gamma-hidroxibutírico / Update on gamma-hydroxybutyric acid

Objetivo. Se presenta una revisión actualizada de losprincipales aspectos farmacológicos, junto con los efectos clínicosy conductuales, asociados al ácido gamma-hidroxibutírico (GHB).Desarrollo. Numerosos estudios farmacológicos, neuroquímicos yelectrofisiológicos indican claramente que el GHB endógeno desempeñaun papel como neurotransmisor y/o neuromodulador en el sistemanervioso central (SNC). Así, el GHB exhibe mecanismos específicosde síntesis, liberación y recaptación, así como lugares deunión específicos que sugieren la existencia de un sistema GHBérgicocentral. Esta sustancia, popularmente conocida como ‘éxtasislíquido’ es, además, una droga con potencial de abuso, cuya administraciónprolongada puede producir dependencia y un síndromede abstinencia tras el cese de su consumo. Sus principales accionesconductuales incluyen sedación/sueño, inducción de crisis de ausencia,catalepsia o reducción de la agresión, entre otras. Algunosde estos efectos parecen relacionarse con una interacción descritaentre el sistema GHBérgico y los receptores dopaminérgicos y gabérgicosen el SNC. Desde el punto de vista clínico, su uso ha aprobadoen algunos países para el tratamiento del síndrome narcoléptico,y se ha planteado también su posible utilidad en el tratamientode la dependencia del alcohol y los opiáceos. Finalmente, estudiosrecientes con animales de experimentación sugieren la existencia deun posible efecto neurotóxico tras su administración prolongada endosis con potencial de abuso. Conclusiones. El GHB es un compuestoextraordinariamente interesante. Funciona como un neurotransmisor/neuromodulador en el SNC. Es, además, una droga recreativacon potencial de abuso, y puede utilizarse para el tratamientode diversas patologías, especialmente de la narcolepsia. Sinembargo, el posible desarrollo de neurotoxicidad tras su administraciónprolongada limita considerablemente su utilidad en contextosclínicos

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 andelectrophysiological studies have clearly shown that endogenous GHB plays a role as a neurotransmitter and/or neuromodulatorin the central nervous system (CNS). GHB displays specific synthesis, release and reuptake mechanisms, as well asparticular binding sites that suggest the existence of a central GHBergic system. This substance, popularly known as ‘liquidecstasy’, is also a potentially abusable drug; if administered for prolonged periods of time it can lead to dependence andwithdrawal symptoms after the patient stops taking it. Its chief behavioural actions include sedation/sleepiness, induction ofabsence seizures, catalepsy or reduced aggression, among others. Some of these effects appear to be related to an interactionthat 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 alsobeen considered for possible use in the treatment of alcohol or opiate abuse. Finally, recent studies conducted with laboratoryanimals 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 isalso an abusable recreational drug and may also be used to treat a number of different pathological conditions, the mostimportant of which is narcolepsy. The possible development of neurotoxicity following prolonged administration, however,imposes considerable limitations on its usefulness in clinical contexts