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.

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.

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.

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.

Preemptive analgesic effectiveness of oral ketorolac plus local tramadol after impacted mandibular third molar surgery.

OBJECTIVE: The aim of this study was to compare preemptive analgesia of oral ketorolac plus submucous local placebo with oral ketorolac plus submucous local tramadol after impacted mandibular third molar surgery. STUDY DESIGN: A double-blind, randomized, placebo-controlled clinical trial was conducted. Patients were randomized into two treatment groups (n = 15 per group): group A, oral ketorolac 10 mg, 30 minutes before surgery plus submucous local placebo (1 mL saline solution); group B, oral ketorolac 10 mg, 30 minutes before surgery plus submucous local tramadol (50 mg diluted in 1 mL saline solution). We evaluated the intensity of pain, time for the first analgesic rescue medication, and total analgesic consumption. RESULTS: Pain intensity, number of patients requiring analgesic rescue medication, number of patients in each group not requiring analgesic rescue medication, and total analgesic consumption showed statistical significance. CONCLUSIONS: Preemptive use of oral ketorolac plus submucous local tramadol is an alternative treatment for acute pain after surgical removal of an impacted mandibular third molar.

Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder.

Several reports suggest that antidepressants may improve cognitive functioning in patients with major depressive disorder (MDD). The present work aims to study the effects of selective serotonin reuptake inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments on the performance of working memory, attention and executive functions in patients with MDD. A total of 73 subjects meeting the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) criteria for MDD, and 37 control subjects were assessed with the Hamilton Depression Rating Scale and a neuropsychological battery. The subjects were medicated with escitalopram (n=36) or duloxetine (n=37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same tests. The depressed subjects showed alterations in attention and cognitive functions when compared to the control group. The administration of both treatments improved working memory, as well as attention and all the executive functions, but the cognitive functions of depressed patients do not improve enough to reach the levels of performance of the control subjects. Our results suggest that both SSRI and SNRI treatments presented the same efficacy in improving attention and the remaining executive functions.

NMDA receptors mediate an early up-regulation of brain-derived neurotrophic factor expression in substantia nigra in a rat model of presymptomatic Parkinson's disease.

The clinical symptoms of Parkinson's disease (PD) appear late and only when the degenerative process at the level of the nigrostriatal dopamine (DA) pathway is quite advanced. An increase in brain-derived neurotrophic factor (BDNF) expression may be one of the molecular signals associated to compensatory and plastic responses occurring in basal ganglia during presymptomatic PD. In the present study, we used in vivo microdialysis, semiquantitative reverse transcriptase-polymerase chain reaction, and immunohistochemistry to study N-methyl-D-aspartic acid (NMDA) receptor regulation of BDNF expression in substantia nigra (SN) of adult rats after partial lesioning of the nigrostriatal DA pathway with unilateral striatal injections of 6-hydroxydopamine (6-OHDA). A time-dependent partial decrease of striatal DA tissue content as well as parallel and gradual increases in extracellular glutamate and aspartate levels in SN were found 1 to 7 days after unilateral 6-OHDA intrastriatal injection. Instead, the number of tyrosine hydroxylase-immunoreactive (IR) cells in the ipsilateral SN pars compacta remained statistically unchanged after neurotoxin injection. Intrastriatal administration of 6-OHDA also produced an early and transient augmentation of pan-BDNF, exon II-BDNF, and exon III-BDNF transcripts in the ipsilateral SN. The pan-BDNF and exon II-BDNF transcript increases were completely abolished by the prior systemic administration of MK-801, a selective antagonist of NMDA receptors. MK-801 also blocked the increase in BDNF-IR cells in SN observed 7 days after unilateral 6-OHDA intrastriatal injections. Our findings suggest that a coupling between glutamate release, NMDA receptor activation, and BDNF expression may exist in the adult SN and represent an important signal in this midbrain nucleus triggered in response to partial DA loss occurring in striatal nerve endings during presymptomatic PD.

Cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder.

Cognitive effects of antidepressants and cognitive predictors of antidepressant treatment response are recent focuses of interest in the neuropsychology of depression. We studied the cognitive predictors of treatment response to bupropion and its neuropsychological effects in patients with major depressive disorder. Twenty subjects meeting the DSM-IV criteria for major depressive disorder were assessed with the Hamilton Depression Rating Scale and a neuropsychological battery. Subjects were medicated with 150 mg/day of bupropion sustained release for 8 weeks. At the end of the trial, 12 subjects were classified as responders to treatment and 8 were non-responders. Our findings suggest that low pretreatment measures of visual memory and low levels of mental processing speed are predictive of good response to bupropion. The cognitive effects of bupropion after the treatment showed that patients improved in visual memory measures and in mental processing speed. Our results suggest that cognitive predictors of treatment response to bupropion and cognitive effects of bupropion in patients with major depressive disorder could be closely related. These findings need to be replicated due to the exploratory nature of the present work.

Expression of the metalloproteases MMP-1, MMP-2, MMP-3, MMP-9, MMP-11, TIMP-1 and TIMP-2 in angiocentric midfacial lymphomas.

BACKGROUND: Extranodal T/NK cell lymphomas possess distinctive clinico-pathological characteristics: they are angiocentric, exhibit extensive necrosis. Prognosis is poor in the short term. The objective is to explore the expression of different MMPs in the cells and stroma which are around of the blood vessels damaged and their correlation with clinico-pathological parameters. PATIENTS AND METHODS: Twenty cases of this type of lymphomas were studied and collected patient clinical data. The expressions of MMP-1, 2, 3, 9, 11, 13 and TIMP-1, 2 were studied by immunohistochemistry. Ultrastructural studies were performed in two cases. Statistical analysis was done with Fisher's exact test, Chi(2) test. RESULTS: Of the 20 patients, 13 were men with median age of 43 years. In 13 patients the primary tumor was localized in the nasal cavity. Treatment was combined chemotherapy and radiotherapy in 60%. The 55% advanced clinical stages, 70% died from the disease. There were neoplastic cell and peritumoral fibroblasts positivity to MMP-1 and MMP-11 in most of the cases. The MMPs-2, 3 and 9 were expressed in neoplastic cell between 30 to 65%of the cases. TIMP-1 was presented mainly in the epithelium and TIMP-2 was poor expressed of the all cases. CONCLUSION: There were no statistical significance between the different enzymes used and the clinical parameters, besides status and survival of the patients. It is necessary to study more enzymes and focus them to quantify and determine their activity, in order to have a better correlation with histological features in this type of neoplasm.

Adult-derived human liver mesenchymal-like cells as a potential progenitor reservoir of hepatocytes?

It is currently accepted that adult tissues may develop and maintain their own stem cell pools. Because of their higher safety profile, adult stem cells may represent an ideal candidate cell source to be used for liver cell therapies. We therefore evaluated the differentiation potential of mesenchymal-like cells isolated from adult human livers. Mesenchymal-like cells were isolated from enzymatically digested adult human liver and expanded in vitro. Cell characterization was performed using flow cytometry, RT-PCR, and immunofluorescence, whereas the differentiation potential was evaluated both in vitro after incubation with specific media and in vivo after intrasplenic transplantation of uPA(+/+)-SCID and SCID mice. Adult-derived human liver mesenchymal-like cells expressed both hepatic and mesenchymal markers among which albumin, CYP3A4, vimentin, and alpha-smooth muscle actin. In vitro differentiation studies demonstrated that these mesenchymal-like cells are preferentially determined to differentiate into hepatocyte-like cells. Ten weeks following intrasplenic transplantation into uPA(+/+)-SCID mice, recipient livers showed the presence of human hepatocytic cell nodules positive for human albumin, prealbumin, and alpha-fetoprotein. In SCID transplanted liver mice, human hepatocyte-like cells were mostly found near vascular structures 56 days posttransplantation. In conclusion, the ability of isolated adult-derived liver mesenchymal stem-like cells to proliferate and differentiate into hepatocyte-like cells both in vitro and in vivo leads to propose them as an attractive expandable cell source for stem cell therapy in human liver diseases.

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.

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.

Modulation of dendritic release of dopamine by metabotropic glutamate receptors in rat substantia nigra.

A superfusion system was used to study the effects of metabotropic glutamate receptor (mGluR) ligands upon the release of [(3)H]dopamine ([(3)H]DA) previously taken up by rat substantia nigra (SN) slices. trans-(+/-)-1-Amino-(1S,3R)-cyclopentane dicarboxylic acid (trans-ACPD; 100 and 600 microM), a group I and II mGluR agonist, evoked the release of [(3)H]DA from nigral slices. This last effect was reduced significantly by (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)-glycine (MCCG; 300 microM), an antagonist of group II mGluR, or by the addition of tetrodotoxin (D-APV; 1 microM) to the superfusion medium. D-(-)-2-Amino-5-phosphono-valeric acid (100 microM), an N-methyl-D-aspartate receptor antagonist, or the presence of Mg(2+) (1.2mM) in the superfusion medium did not modify trans-ACPD-induced [(3)H]DA release. In addition, a group II mGluR agonist such as (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG-IV; 100 microM) significantly induced the release of [(3)H]DA from nigral slices, whereas a group I mGluR agonist such as (RS)-3,5-dihydroxyphenylglycine (DHPG; 50 and 100 microM) did not modify the release of the [(3)H]-amine. Further experiments showed that the NMDA (100 microM)-evoked release of [(3)H]DA was decreased significantly by prior exposure of SN slices to trans-ACPD. Finally, partial denervation of the DA nigro-striatal pathway with 6-hydroxydopamine (6-OH-DA) increased trans-ACPD-induced release of [(3)H]DA, whereas it decreased trans-ACPD inhibitory effects on NMDA-evoked release of [(3)H]DA from nigral slices. The present results suggest that the dendritic release of DA in the SN is regulated by mGluR activation. Such nigral mGluR activation may produce opposite effects upon basal and NMDA-evoked release of DA in the SN. In addition, such mGluR-induced effects in the SN are modified in response to partial denervation of the DA nigro-striatal pathway.

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.