Poly-microbial Clostridium cadaveris bacteremia in an immune-compromised patient.

Clostridium cadaveris (C. cadaveris), a strict anaerobic gram-positive rod, is rarely reported in clinical specimens. Since its detection in 1899, it has always been linked to the decay of dead bodies. C. cadaveris is considered non-pathogenic to humans, however infrequently it can cause severe infections including bacteremia. The latter was typically associated with gastro-intestinal pathologies. We report the first case of C. cadaveris invasive infection at Sultanate Oman. The source was most probably an infected decubitus ulcer.

Validación del instrumento: conocimientos, creencias y aceptación de la vacuna del virus del papiloma humano / Validation of the instrument: knowledge, beliefs and acceptance of the human papillomavirus vaccine

Introducción: El virus del papiloma humano es la primera causa de cáncer cervicouterino, contar con un instrumento que mida la aceptación de la vacuna del VPH, así como los factores que intervienen, es una necesidad para la prevención del VPH. El objetivo fue realizar la validación del instrumento conocimientos, creencias y aceptación de la vacuna del virus del papiloma humano.Materiales y Métodos: El proceso de validación se realizó a traves de un estudio descriptivo, transversal y de proceso de dos fases. La población fue de 393 madres de niñas de 9 a 11 años, pertenecientes al Estado de Puebla, con un muestreo no probabilístico por conveniencia, la muestra se consideró por razón de 10:1.Resultados: Se obtuvo un instrumento válido y confiable con un coeficiente de Alfa de Cronbach de .70, un valor de p<.000 para la prueba de esfericidad de Bartlett y la prueba de Kaiser-Meyer Olkin obtuvo un resultado de .82, en este sentido el análisis factorial dio como resultado un total de 40 ítems divididos en seis dimensiones.Discusión:El proceso metodológico permitió contar con un indicador empírico adaptado y valido al contexto mexicano, debido a que es el único dentro del contexto que mide los factores relacionados con la aceptación de la vacuna del virus del papiloma humano.Conclusión: Se concluye que tener un indicador empírico adaptado al idioma español, que mida la aceptación y los factores relacionados, es un aporte de gran importancia para la sociedad y un avance para la ciencia en enfermería (AU)

Introduction: The human papilloma virus (HPV) is the leading cause of cervical cancer. Having aninstrument that measures the acceptance of the HPV vaccine, as well as the factors involved in theacceptance process, is an urgent need for HPV prevention. The objective was to validate theknowledge, beliefs, and acceptance of the human papillomavirus vaccine instrument.Materials and Methods: The validation process was carried out through a descriptive, cross-sectional study and a two-phaseprocess. The population consisted of 393 mothers of girls between the ages of 9 and 11 years,belonging to the State of Puebla, with a non-probabilistic sampling for convenience; the sample wasconsidered at a ratio of 10: 1.Results: A valid and reliable instrument was obtained with a Cronbach's Alpha of .70, a value of p<.000 for Bartlett’s sphericity test, and .82 for the KMO test. In this sense, the factor analysis resulted ina total of 40 items divided into six dimensions.Discussion: The methodological process allowed to have an empirical indicator adapted and validatedfor the Mexican context, since it is the only one within the context that measures the factors related tothe acceptance of the HPV vaccine.Conclusion: We conclude that having an empirical indicator adapted to the Spanish language, whichmeasures acceptance and related factors, is a contribution of great importance to society and anadvance in nursing science (AU)

Colecistectomía extendida mínimamente invasiva en pacientes con cáncer de vesícula biliar / Minimal invasive extended cholecystectomy in gallbladder cancer patients

Resumen Objetivo: Describir resultados en términos de morbilidad y mortalidad de la colecistectomía extendida laparoscópica (CELap) en pacientes con cáncer de vesícula biliar (CVB) incidental. Materiales y Método Serie de casos de pacientes con CVB incidental sometidos a CELap en el Hospital Regional de Temuco entre diciembre de 2017 y marzo de 2019. Resultados: Incluimos 10 pacientes, con edad promedio de 59,2 ± 11 años, 90% de género femenino. Respecto a la invasión de pared de la vesícula biliar (TNM), 1 presentó invasión hasta mucosa (T1a) con invasión de senos de Rokitansky Aschoff y 9 hasta subserosa (T2). Dos tuvieron ganglio cístico positivo en biopsia inicial. Respecto a la CELap, el tiempo operatorio promedio fue 333 ± 40 minutos. El promedio de ganglios resecados fue 4 ± 2,78, presentando lecho hepático positivo en 1 paciente. La clasificación TNM obtenida: un paciente T1aN0M0, siete T2N0M0 y dos T2N1M0. La estancia hospitalaria promedio fue 5 ± 2,3 días. Siete pacientes recibieron, posteriormente, quimioterapia con gemcitabina + cisplatino. Hubo morbilidad en 2 pacientes, tipo I de Dindo-Clavien. No reportamos mortalidad. El seguimiento promedio fue 7,1 ±5,1 meses, no reportamos recurrencia. Discusión: Esta serie presenta menor número de ganglios resecados que otros estudios (posiblemente por ser nuestra serie inicial) y mayor morbilidad, pero sólo tipo I de Dindo-Clavien. Presentamos una estancia hospitalaria similar a series internacionales y menor presencia de metástasis según reportan análisis retrospectivos. Conclusión: La CELap es una opción terapéutica aceptable y presenta cifras de morbilidad y mortalidad comparables con series nacionales e internacionales.

Aim: Describe results in terms of morbidity and mortality of minimally invasive treatment in patients with gallbladder cancer until subserosal layer. Materials and Method: Case series of patients with gallbladder cancer undergoing CELap at Hospital Regional of Temuco between December 2017 and March 2019. Results: Ten patients were included, the average age was 59,2 ±11 years. Ninety percent female. According to the invasion in gallbladder layers (TNM Classification), 1 patient was T1a (mucosa) with invasion of Rokytansky-Aschoff sinus and 9 patients T2 (subserosa). Two patients had a positive cystic node. The average operating time of CELap was 333 ± 40 minutes. The average number of resected nodes was 4 ± 2,78 and a positive liver bed was found in 1 patient. The TNM classification was 1 patient T1aN0M0, 7 patients T2N0M0 and 2 patients T2N1M0. Mean hospitalization was 5 ± 2,3 days. Seven patients subsequently received chemotherapy with gemcitabine + cisplatin. There was 2 patients with morbidity, type I of Dindo-Clavien scale. No mortality is reported. The average follow-up was 7,1 ±5,11 months and no recurrence was reported. Discussion: This series has a lower number of resected nodes than other studies (possibly because it is our initial series) and higer morbidity, but only Dindo-Clavien type I. Furthermore, we present a hospital stay similar to international series and a lower presence of metastases as reported in retrospective analysis. Conclusion: CELap is an acceptable therapeutic option and presents morbidity and mortality comparable with the national and international series.

Characterization of a presymptomatic stage in a Drosophila Parkinson's disease model: Unveiling dopaminergic compensatory mechanisms.

Parkinson's disease (PD) is a degenerative disorder characterized by several motor symptoms including shaking, rigidity, slow movement and difficult walking, which has been associated to the death of nigro-striatal dopaminergic neurons. >90% of PD patients also present olfactory dysfunction. Although the molecular mechanisms responsible for this disease are not clear, hereditary PD is linked to mutations in specific genes, including the PTEN-induced putative kinase 1 (PINK1). In this work we provide for the first time a thorough temporal description of the behavioral effects induced by a mutation in the PINK1 gene in adult Drosophila, a previously described animal model for PD. Our data suggests that the motor deficits associated to PD are fully revealed only by the third week of age. However, olfactory dysfunction is detected as early as the first week of age. We also provide immunofluorescence and neurochemical data that let us propose for the first time the idea that compensatory changes occur in this Drosophila model for PD. These compensatory changes are associated to specific components of the dopaminergic system: the biosynthetic enzymes, Tyrosine hydroxylase and Dopa decarboxylase, and the Dopamine transporter, a plasma membrane protein involved in maintaining dopamine extracellular levels at physiologically relevant levels. Thus, our behavioral, immunofluorescence and neurochemical data help define for the first time presymptomatic and symptomatic phases in this PD animal model, and that compensatory changes occur in the dopaminergic neurons in the presymptomatic stage.

The activation of metabotropic glutamate 5 receptors in the rat ventral tegmental area increases dopamine extracellular levels.

The mesocorticolimbic circuit projects to the prefrontal cortex, hippocampus, amygdala, and nucleus accumbens, among others, and it originates in the dopaminergic neurons of the ventral tegmental area (VTA). The VTA receives glutamatergic inputs from the prefrontal cortex and several subcortical regions. The glutamate released activates dopaminergic neurons and its action depends on the activation of ionotropic and metabotropic glutamate receptors. VTA dopaminergic neurons release dopamine (DA) from axon terminals in the innervated regions and somatodendritically in the VTA itself. DA release in the VTA is directly correlated with the activity of dopaminergic neurons. We hypothesized that metabotropic glutamate 5 receptors (mGlu5) directly regulate the activity of VTA dopaminergic neurons. To test this hypothesis, the extracellular levels of VTA DA and glutamate were studied by in-vivo microdialysis after an intra-VTA perfusion of (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), selective mGlu5 agonist. We observed that CHPG induced a significant increase in VTA DA and glutamate extracellular levels. To determine whether the effect of CHPG on DA levels is because of the increase in glutamate release, we perfused kynurenic acid, an ionotropic glutamate receptor antagonist, through the probe. Our results showed that kynurenic acid did not block the ability of CHPG to cause DA release. Thus, our results suggest that CHPG acts directly on mGlu5 in dopaminergic neurons to induce the release of DA.

Bioequivalence and Pharmacokinetic Evaluation Study of Acetaminophen vs. Acetaminophen Plus Caffeine Tablets in Healthy Mexican Volunteers.

OBJECTIVE: The aim of this clinical trial was to establish the bioequivalence of two tablets containing acetaminophen 650 mg (reference) and acetaminophen 650 mg plus caffeine 65 mg (test), administered orally, in fasting conditions in healthy Mexican volunteers. METHODS: Blood samples were taken from 21 male and five female individuals, during a 24-h period, to characterize the pharmacokinetic profile of acetaminophen. Plasma samples were quantified by ultra-performance liquid chromatography, tandem mass spectrometry. Pharmacokinetic metrics (maximum plasma concentration, area under the curve from time zero to the last sampling time, and area under the curve from time zero to infinity) were used to determine the 90 % confidence interval of the test/reference coefficient. RESULTS: The geometric mean values for maximum plasma concentration obtained for the reference and test products were 9.46 ± 34.21 and 9.72 ± 32.38 µg/mL, respectively, whereas for the area under the curve from time zero to the last sampling time the values obtained were 34.93 ± 32.58 and 35.89 ± 31.03 µg h/mL for the reference and test formulations, respectively. The 90 % confidence intervals were within the acceptance range (80-125 %). CONCLUSIONS: The test product was bioequivalent to the reference product. A faster absorption was seen in the test formulation in the Mexican population.

Desove espontáneo, ontogenia y crecimiento en cautiverio de Cynoscion squamipinnis (Perciformes: Sciaenidae) / Spontaneous spawning, ontogeny and growth in captivity of Cynoscion squamipinnis (Perciformes: Sciaenidae)

ResumenLas corvinas son especies de interés comercial que han sido sobreexplotadas en el Golfo de Nicoya, Costa Rica. El objetivo de este estudio fue describir por primera vez, el desove espontáneo y la ontogenia de las larvas de la corvina aguada Cynoscion squamipinnis en cautiverio, con el fin de realizar repoblamiento y proyectos de maricultura. Reproductores silvestres (n= 6, 1-2 Kg), fueron capturados y mantenidos en la Estación de Biología Marina Juan Bertoglia Richards (Puntarenas, Costa Rica) por un periodo de dos años (octubre 2006-diciembre 2008). Durante este periodo, el estado de madurez de las hembras (n= 3) fue registrado mediante muestras de cánula y los machos (n= 3) mediante masaje abdominal. Todos los reproductores fueron colocados juntos en un tanque de 18 t, con aireación, a una salinidad entre 33-35 ups y expuestos a una temperatura constante (29 ± 1 °C). De enero a marzo 2009 ocurrió un periodo de desove espontáneo, obteniéndose 162 000 huevos en tres desoves. El porcentaje de fertilización fue de 50-60 %, y la supervivencia después de la eclosión fue entre 60-85 %. El diámetro de los huevos fue de 0.852 mm (Desviación Estándar= 0.039), con una gota de aceite de 0.269 mm (DE= 0.016). En el desarrollo embrionario, la primera división mitótica ocurrió una hora después del desove (hdd), la segunda división 1:30 hdd, la tercera división 2 hdd, la cuarta división a las 2:30 hdd, y la quinta 3:00 hdd. La mórula fue observada a las 3:30 hdd, la blástula a las 4:30 hdd, la gástrula a las 8:30 hdd, la forma C a las 10:00 hdd, y la forma S ocurrió de las 10-19 hdd. La eclosión ocurrió 19 hdd. La larva midió 2.234 mm (DE= 0.122) de longitud total (LT), y 2.179 mm (DE= 0.119) de longitud notocordial (LN). La preflexión inició 49 hdd, la flexión 11 días después del desove (ddd) (3.767 mm LT, DE= 0.209), y la postflexión a los 14 ddd (4.015 mm LT, DE= 0.302). A los 45 ddd, los juveniles pesaron 3.68 g (DE= 1.09). El tiempo de eclosión de las larvas de la corvina aguada fue menor al de otras especies de corvina. Los tiempos de formación en las etapas embrionarias difirieron poco con respecto a los tiempos observados para otras especies de corvinas. Las diferencias observadas con respecto a otras especies, probablemente responden a las características genéticas propias de cada especie y a la temperatura de incubación de los huevos. La obtención de desoves espontáneos sin aplicaciones hormonales a los reproductores, y la producción de juveniles en cautiverio demostraron que la corvina aguada puede ser considerada en programas de repoblamiento y proyectos de maricultura.

Abstract:The croakers or drums are commercial species, which have been overfished in the Nicoya Gulf, Costa Rica. This study aimed to describe, for the first time, the reproduction and the ontogeny of weakfish, Cynoscion squamipinnis in captivity, in order to perform restocking and mariculture projects. Wild fish (n= 6, 1-2 Kg) were captured and maintained in the Estación de Biología Marina Juan Bertoglia Richards (Puntarenas, Costa Rica) for a two years period (October 2006- December 2008). During this period, maturation stage was monitored periodically by cannula samples in the females (n= 3) and gentle massage in males (n= 3). All fish were stocked in an 18 t tank, with aeration, 33-35 ups of salinity, and a constant temperature (29 ± 1 °C). The spawning period occurred from January to March 2009, producing 162 000 eggs in three spontaneous spawns. The fertilization percentage was 50-60%, and survival after hatching was 60-85%. The egg diameter was 0.852 mm (Standard deviation (SD)= 0.039), and oil drop of 0.269 mm (SD= 0.016). In the embryonary development, the first mitotic division (MD) was observed one hour after spawning (has), the second MD was 1:30 has, the third MD was 2:00 has, the fourth MD was 2:30 has, and fifth MD at 3:00 has. Morule was observed 3:30 has, the blastule 4:30 has, the gastrule 8:30 has, C shape at 10:00 has, and C shape at 12:00 has. After 19 has hatching larvae occurred. The total length (TL) of the larvae was 2.234 mm (SD= 0.122), and the nothochordial length (NL) was 2.179 mm (SD= 0.119). Preflexion stage was observed 49 has, flexion stage was 11 days after spawn (das) (3.767 mm LT (SD= 0.209)), and postflexion stage was 14 das (4.015 mm LT (SD= 0.302)). After 45 das, the juvenile weights 3.68 g (SD= 1.09). Hatch time of the weakfish larvae was minor than of others croaker species. The stages times of embrionary development were a little different from others croaker species, and probably respond to genetic characteristics of each species and the eggs incubation temperature. The spontaneously spawning without broodstock hormonal applications, and the juveniles production in captivity showed that weakfish is a potential species for restocking programs and mariculture projects. Rev. Biol. Trop. 64 (3): 991-1005. Epub 2016 September 01.

Aminochrome induces dopaminergic neuronal dysfunction: a new animal model for Parkinson's disease.

L-Dopa continues to be the gold drug in Parkinson's disease (PD) treatment from 1967. The failure to translate successful results from preclinical to clinical studies can be explained by the use of preclinical models which do not reflect what happens in the disease since these induce a rapid and extensive degeneration; for example, MPTP induces a severe Parkinsonism in only 3 days in humans contrasting with the slow degeneration and progression of PD. This study presents a new anatomy and develops preclinical model based on aminochrome which induces a slow and progressive dysfunction of dopaminergic neurons. The unilateral injection of aminochrome into rat striatum resulted in (1) contralateral rotation when the animals are stimulated with apomorphine; (2) absence of significant loss of tyrosine hydroxylase-positive neuronal elements both in substantia nigra and striatum; (3) cell shrinkage; (4) significant reduction of dopamine release; (5) significant increase in GABA release; (6) significant decrease in the number of monoaminergic presynaptic vesicles; (7) significant increase of dopamine concentration inside of monoaminergic vesicles; (8) significant increase of damaged mitochondria; (9) significant decrease of ATP level in the striatum (10) significant decrease in basal and maximal mitochondrial respiration. These results suggest that aminochrome induces dysfunction of dopaminergic neurons where the contralateral behavior can be explained by aminochrome-induced ATP decrease required both for anterograde transport of synaptic vesicles and dopamine release. Aminochrome could be implemented as a new model neurotoxin to study Parkinson's disease.

[Spontaneous spawning, ontogeny and growth in captivity of Cynoscion squamipinnis (Perciformes: Sciaenidae)]. / Desove espontáneo, ontogenia y crecimiento en cautiverio de Cynoscion squamipinnis (Perciformes: Sciaenidae).

The croakers or drums are commercial species, which have been overfished in the Nicoya Gulf, Costa Rica. This study aimed to describe, for the first time, the reproduction and the ontogeny of weakfish, Cynoscion squamipinnis in captivity, in order to perform restocking and mariculture proyects. Wild fish (n= 6, 1-2 Kg) were captured and maintained in the Estación de Biología Marina Juan Bertoglia Richards (Puntarenas, Costa Rica) for a two years period (October 2006- December 2008). During this period, maturation stage was monitored periodically by cannula samples in the females (n= 3) and gentle massage in males (n= 3). All fish were stocked in an 18 t tank, with aeration, 33-35 ups of salinity, and a constant temperature (29 ± 1 °C). The spawning period occurred from January to March 2009, producing 162 000 eggs in three spontaneous spawns. The fertilization percentage was 50-60%, and survival after hatching was 60-85%. The egg diameter was 0.852 mm (Standard deviation (SD)= 0.039), and oil drop of 0.269 mm (SD= 0.016). In the embryonary development, the first mitotic division (MD) was observed one hour after spawning (has), the second MD was 1:30 has, the third MD was 2:00 has, the fourth MD was 2:30 has, and fifth MD at 3:00 has. Morule was observed 3:30 has, the blastule 4:30 has, the gastrule 8:30 has, C shape at 10:00 has, and C shape at 12:00 has. After 19 has hatching larvae occurred. The total length (TL) of the larvae was 2.234 mm (SD= 0.122), and the nothochordial length (NL) was 2.179 mm (SD= 0.119). Preflexion stage was observed 49 has, flexion stage was 11 days after spawn (das) (3.767 mm LT (SD= 0.209)), and postflexion stage was 14 das (4.015 mm LT (SD= 0.302)). After 45 das, the juvenile weights 3.68 g (SD= 1.09). Hatch time of the weakfish larvae was minor than of others croaker species. The stages times of embrionary development were a little different from others croaker species, and probably respond to genetic characteristics of each species and the eggs incubation temperature. The spontaneously spawning without broodstock hormonal applications, and the juveniles production in captivity showed that weakfish is a potential species for restocking programs and mariculture projects.

Exposure to repeated immobilization stress inhibits cocaine-induced increase in dopamine extracellular levels in the rat ventral tegmental area.

A higher vulnerability to drug abuse has been observed in human studies of individuals exposed to chronic or persistent stress, as well as in animal models of drug abuse. Here, we explored the effect of repeated immobilization stress on cocaine-induced increase in dopamine extracellular levels in VTA and its regulation by corticotropin-releasing factor (CRF) and GABA systems. Cocaine (10mg/Kg i.p.) induced an increase of VTA DA extracellular levels in control rats. However, this effect was not observed in repeated stress rats. Considering the evidence relating stress with CRF, we decided to perfuse CRF and CP-154526 (selective antagonist of CRF1 receptor) in the VTA of control and repeated stress rats, respectively. We observed that perfusion of 20µM CRF inhibited the increase of VTA DA extracellular levels induced by cocaine in control rats. Interestingly, we observed that in the presence of 10µM CP-154526, cocaine induced a significant increase of VTA DA extracellular levels in repeated stress rats. Regarding the role of VTA GABA neurotransmission, cocaine administration induced a significant increase in VTA GABA extracellular levels only in repeated stress rats. Consistently, cocaine was able to increase VTA DA extracellular levels in repeated stress rats when 100µM bicuculline, an antagonist of GABAA receptor, was perfused intra VTA. Thus, both CRF and GABA systems are involved in the lack of response to cocaine in the VTA of repeated stress rats. It is tempting to suggest that the loss of response in VTA dopaminergic neurons to cocaine, after repeated stress, is due to an interaction between CRF and GABA systems.

Cardiovascular and renal effects of bromocriptine in diabetic patients with stage 4 chronic kidney disease.

OBJECTIVE: The objective of this study was to investigate the effect of bromocriptine (BEC) on left ventricular mass index (LVMI) and residual renal function (RRF) in chronic kidney disease (CKD) patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A 6-month double-blind randomized controlled trial was conducted in 28 patients with T2D and stage 4 CKD with increased LVMI. Fourteen patients received BEC (2.5 mg, initially 1 tablet with subsequent increase to three times a day) and 14 received a placebo (PBO; initially 1 tablet with subsequent increase to three times a day). Cardiovascular changes were assessed by monitoring 24 h ambulatory blood pressure, two-dimensional-guided M-mode echocardiography, and N-terminal brain natriuretic peptide (NT-proBNP) plasma levels. RRF was evaluated by creatinine clearance and cystatin-C plasma levels. RESULTS: Both BEC and PBO groups decreased blood pressure-but the effect was more pronounced in the BEC group. Average 24 h, diurnal and nocturnal blood pressures, and circadian profile showed improved values compared to the PBO group; LVMI decreased by 14% in BEC and increased by 8% in PBO group. NT-proBNP decreased in BEC (0.54 ± 0.15 to 0.32 ± 0.17 pg/mL) and increased in PBO (0.37 ± 0.15 to 0.64 ± 0.17 pg/mL). Creatinine clearance did not change in the BEC group and decreased in the PBO group. CONCLUSIONS: BEC resulted in a decrease on blood pressure and LVMI. BEC also prevented the progression of CKD while maintaining the creatinine clearance unchanged.

Prediction of the time-course pattern of remission in depression by using clinical, neuropsychological, and genetic variables.

BACKGROUND: The prediction of remission in pharmacologically-treated MDD patients has been scarcely studied. The goal of our work is to study the possible effect of clinical variables, neuropsychological performance, and the 5HTTLPR, the rs25531 of the SLC6A4 gene, and the val108/58Met of the COMT gene polymorphisms on the prediction of the speed of remission in MDD patients. METHODS: Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluoxetine treatment. RESULTS: From this original sample 51 patients were considered as remitters at the end of week 12. Thirteen out of those showed a rapid response pattern, 24 showed an oscillating response pattern, and 14 showed a slow response pattern. The following variable combination is capable of showing a statistically significant relationship with the pattern of remission of patients with MDD: initial Hamilton score, age at first depressive episode, AG and GG alleles of the val108/58Met COMT polymorphism, Stroop PC, and SWM Strategy. LIMITATIONS: We have a slightly small sample size, which came to prominence during the data analysis since we were working with 3 subgroups. In this study, the placebo effect has not been controlled. DISCUSSION: Our data suggest that the patients with MDD who remit after a 12-week treatment with fluoxetine show one of the following time-course patterns: a rapid symptomatic improvement, or a slow or oscillating pattern of remission. A combination of clinical, neuropsychological, and genetic variables allows us to predict these response patterns.

4-Methylthioamphetamine increases dopamine in the rat striatum and has rewarding effects in vivo.

4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative whose use has been associated with severe intoxications. MTA is usually regarded as a selective serotonin-releasing agent. Nevertheless, previous data have suggested that its mechanism of action probably involves a catecholaminergic component. As little is known about dopaminergic effects of this drug, in this work the actions of MTA upon the dopamine (DA) transporter (DAT) were studied in vitro, in vivo and in silico. Also, the possible abuse liability of MTA was behaviourally assessed. MTA exhibited an in vitro affinity for the rat DAT in the low micromolar range (6.01 µM) and induced a significant, dose-dependent increase in striatal DA. MTA significantly increased c-Fos-positive cells in striatum and nucleus accumbens, induced conditioned place preference and increased locomotor activity. Docking experiments were performed in a homology model of the DAT. In conclusion, our results show that MTA is able to increase extracellular striatal DA levels and that its administration has rewarding properties. These effects were observed at concentrations or doses that can be relevant to its use in human beings.

An NR2B-Dependent Decrease in the Expression of trkB Receptors Precedes the Disappearance of Dopaminergic Cells in Substantia Nigra in a Rat Model of Presymptomatic Parkinson's Disease.

Compensatory changes occurring during presymptomatic stages of Parkinson's disease (PD) would explain that the clinical symptoms of the disease appear late, when the degenerative process is quite advanced. Several data support the proposition that brain-derived neurotrophic factor (BDNF) could play a role in these plastic changes. In the present study, we evaluated the expression of the specific BDNF receptor, trkB, in a rat model of presymptomatic PD generated by intrastriatal injection of the neurotoxin 6-OHDA. Immunohistochemical studies revealed a decrease in trkB expression in SN pars compacta (SNc) seven days after 6-OHDA injection. At this time point, no change in the number of tyrosine hydroxylase (TH) immunoreactive (TH-IR) cells is detected, although a decrease is evident 14 days after neurotoxin injection. The decrease in TH-positive cells and trkB expression in SNc was significantly prevented by systemic administration of Ifenprodil, a specific antagonist of NR2B-containing NMDA receptors. Therefore, an NR2B-NMDA receptor-dependent decrease in trkB expression precedes the disappearance of TH-IR cells in SNc in response to 6-OHDA injection. These results support the idea that a functional coupling between NMDA receptors and BDNF/trkB signalling may be important for the maintenance of the dopaminergic phenotype in SNc during presymptomatic stages of PD.

Ras inhibition in hepatocarcinoma by S-trans-trans-farnesylthiosalicyclic acid: association of its tumor preventive effect with cell proliferation, cell cycle events, and angiogenesis.

Activation of Ras and its downstream signaling pathways, likely contribute to the development of hepatocarcinoma. We have previously shown that intraperitoneal injections of the Ras inhibitor S-trans, trans-farnesylthiosalicyclic acid (FTS) blocks Ras activation and prevents heptocarcinoma development in rats receiving weekly injections of the carcinogene diethylnitrosamine (DEN) for 16 wk. Using this in vivo model, we evaluated the relationship between the tumor preventive effect of Ras inhibition and activation of downstream signaling pathways, cell proliferation, cell cycle events, and angiogenesis. Western blotting, quantitative PCR, immunohistochemistry, and transcription factor activity assays were used. DEN-induced activation of NFkB and Stat3 was abrogated by FTS treatment. FTS treatment showed no effect on DEN-induced elevation of TNFα, interleukin 6 and TLR4, known activators of these transcription factors. FTS significantly reduced phosphorylation of the MAPkinase p38 and of the p70S6 kinase, a surrogate marker for mTor activation, without affecting ERK and AKT phosphorylation. These events were associated with reduced c-myc and cyclin D expression as well as reduced cell proliferation in transformed, GSTp-positive hepatocytes. Moreover, FTS treatment shifted cell proliferation from transformed hepatocytes to apparently normal, GSTp negative hepatocytes. FTS treatment did not down-regulate expression of angiogenesis markers HIFα, VEGF, VEGF receptor1, and placenta growth factor. FTS treatment inhibits important signaling pathways involved in cellular proliferation leading to strongly reduced proliferation of transformed hepatocytes without affecting normal hepatocytes. This re-adjustment of the proliferation balance likely contributes to the tumor preventive of FTS in the context of Ras inhibition in hepatocarcinogenesis.

Prediction of remission of depression with clinical variables, neuropsychological performance, and serotonergic/dopaminergic gene polymorphisms.

OBJECTIVE: The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms on the prediction of depression remission after 12 weeks' treatment with fluoxetine. These variables have been studied as potential predictors of depression remission, but they present poor prognostic sensitivity and specificity by themselves. METHODS: Seventy-two depressed patients were genotyped according to the aforementioned polymorphisms and were clinically and neuropsychologically assessed before a 12-week fluxetine treatment. RESULTS: Only the La allele of rs25531 polymorphism and the GG and AA forms of the val 108/158 Met polymorphism predict major depressive disorder remission after 12 weeks' treatment with fluoxetine. None of the clinical and neuropsychological variables studied predicted remission. CONCLUSIONS: Our results suggest that clinical and neuropsychological variables can initially predict early response to fluoxetine and mask the predictive role of genetic variables; but in remission, where clinical and neuropsychological symptoms associated with depression tend to disappear thanks to the treatment administered, the polymorphisms studied are the only variables in our model capable of predicting remission. However, placebo effects that are difficult to control require cautious interpretation of the results.