Increased kynurenine concentration attenuates serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl hydrocarbon receptor.

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has been shown to produce serotonergic damage in the brains of primates, including humans, and of rats. Tryptophan, the precursor of serotonin, is primarily degraded through the kynurenine (KYN) pathway, producing among others KYN, the main metabolite of this route. KYN has been reported as an endogenous agonist of the aryl hydrocarbon receptor (AhR), a transcription factor involved in several neurological functions. This study aims to determine the effect of MDMA on the KYN pathway and on AhR activity and to establish their role in the long-term serotonergic neurotoxicity induced by the drug in rats. Our results show that MDMA induces the activation of the KYN pathway, mediated by hepatic tryptophan 2,3-dioxygenase (TDO). MDMA also activated AhR as evidenced by increased AhR nuclear translocation and CYP1B1 mRNA expression. Autoradiographic quantification of serotonin transporters showed that both the TDO inhibitor 680C91 and the AhR antagonist CH-223191 potentiated the neurotoxicity induced by MDMA, while administration of exogenous l-kynurenine or of the AhR positive modulator 3,3'-diindolylmethane (DIM) partially prevented the serotonergic damage induced by the drug. The results demonstrate for the first time that MDMA increases KYN levels and AhR activity, and these changes appear to play a role in limiting the neurotoxicity induced by the drug. This work provides a better understanding of the physiological mechanisms that attenuate the brain damage induced by MDMA and identify modulation of the KYN pathway and of AhR as potential therapeutic strategies to limit the negative effects of MDMA.

Resultados de un programa de cirugía mayor ambulatoria en oftalmología / Results an outpatient major surgery program in ophthalmology

Objetivo: Evaluar los resultados de un programa de cirugía mayor ambulatoria en pacientes intervenidos quirúrgicamente de diversas patologías oculares en nuestro hospital. Métodos: Este estudio retrospectivo incluye 13.878 pacientes intervenidos de forma programada por el Servicio de Oftalmología desde septiembre de 1998 a diciembre de 2004. En 11.187 pacientes se realizaron diferentes procedimientos quirúrgicos de forma ambulatoria, siendo la cirugía de catarata (facoemulsificación) la operación mayoritaria (8.155 casos). Se han analizado diversos índices (sustitución, suspensión, ingresos, reingresos), así como el rendimiento quirúrgico y las complicaciones sistémicas y oculares que surgieron dentro de las primeras 72 horas tras la cirugía. La medición de las variables se realizó mediante frecuencias relativas. El análisis utilizado para la evolución de las complicaciones en el período de estudio fue la Chi cuadrado de tendencias. Resultados: 13.878 pacientes fueron intervenidos en el período indicado, de los que 11.187 se operaron de forma ambulatoria (índice de sustitución global del 80,6%). El rendimiento quirúrgico medio fue 74,36%. El índice de ingresos tras la cirugía fue 4,46% (499 pacientes), siendo ingresos inmediatos en el 92,18% de los casos (460). 21 pacientes sufrieron complicaciones graves (cardiovasculares, neurológicas, metabólicas, infecciosas), representando un riesgo proporcional de 1:532. En 45 pacientes aparecieron complicaciones de menor gravedad (hipertensión arterial, nauseas, vómitos, síncope vasovagal) que requirieron su ingreso hospitalario. Las complicaciones oftalmológicas ocurrieron en 79 casos (0,56%). Conclusiones: La cirugía mayor ambulatoria (CMA) es un excelente modelo organizativo de asistencia quirúrgica multidisciplinar que permite tratar pacientes bien seleccionados de una manera efectiva, segura y eficiente. A pesar del cumplimiento de los requisitos óptimos, existe un porcentaje pequeño de complicaciones postoperatorias de gravedad variable, aunque afortunadamente la mortalidad es prácticamente nula

Purpose: To evaluate the outcomes in our hospital of an ambulatory major surgery program in patients with a variety of different ocular pathologies. Method: This retrospective study includes 13,878 patients who underwent programmed surgery by the Department of Ophthalmology between September 1998 and December 2004. Different ophthalmological surgical procedures were performed as outpatient surgery in 11,187 patients, with cataract surgery (phacoemulsification) being the most frequent operation performed (8,155 cases). We have analysed several indicators (substitution, suspension, admission and readmission rates), as well as surgical yield and systemic and ocular complications which appeared within 72 hours after surgery. The variables were measured as relative frequencies. The evolution of complications during the study period was analysed by the Chi-square trend test. Results: 13,878 patients had ophthalmic surgery during the study period; 11,187 had outpatient surgery with a global substitution ratio of 80.6%. The median surgical yield was 74.36%. The admission rate after surgery was 4.46% (499 patients), with 92.18% (460) of these requiring immediate admission. Twenty-one patients suffered from severe complications (cardiovascular, neurological, metabolic, infectious), representing a proportional risk of 1:532. Forty-five patients had less severe complications (arterial hypertension, nausea, vomiting, vasovagal syncope) that required admission to hospital. Ophthalmologic complications occurred in 79 cases (0.56%). Conclusions: Ambulatory major surgery (AMS) is an excellent organization model of multidisciplinary surgical assistance that makes it possible to treat well selected patients in an effective, safe and efficient manner. There is a low incidence of postoperative complications of variable severity despite following the optimum requisites, although fortunately mortality is practically absent

[Results of an outpatient major surgery program in ophthalmology]. / Resultados de un programa de cirugía mayor ambulatoria en oftalmología.

PURPOSE: To evaluate the outcomes in our hospital of an ambulatory major surgery program in patients with a variety of different ocular pathologies. METHOD: This retrospective study includes 13,878 patients who underwent programmed surgery by the Department of Ophthalmology between September 1998 and December 2004. Different ophthalmological surgical procedures were performed as outpatient surgery in 11,187 patients, with cataract surgery (phacoemulsification) being the most frequent operation performed (8,155 cases). We have analysed several indicators (substitution, suspension, admission and readmission rates), as well as surgical yield and systemic and ocular complications which appeared within 72 hours after surgery. The variables were measured as relative frequencies. The evolution of complications during the study period was analysed by the Chi-square trend test. RESULTS: 13,878 patients had ophthalmic surgery during the study period; 11,187 had outpatient surgery with a global substitution ratio of 80.6%. The median surgical yield was 74.36%. The admission rate after surgery was 4.46% (499 patients), with 92.18% (460) of these requiring immediate admission. Twenty-one patients suffered from severe complications (cardiovascular, neurological, metabolic, infectious), representing a proportional risk of 1:532. Forty-five patients had less severe complications (arterial hypertension, nausea, vomiting, vasovagal syncope) that required admission to hospital. Ophthalmologic complications occurred in 79 cases (0.56%). CONCLUSIONS: Ambulatory major surgery (AMS) is an excellent organization model of multidisciplinary surgical assistance that makes it possible to treat well selected patients in an effective, safe and efficient manner. There is a low incidence of postoperative complications of variable severity despite following the optimum requisites, although fortunately mortality is practically absent.

[Efficiency of voriconazole in fungal keratitis caused by candida albicans]. / Eficacia del voriconazol en queratitis fúngica por cándida albicans.

CASE REPORT: A 70-year-old woman, with a history of diabetes and persistent corneal ulceration, developed a severe keratitis caused by Candida albicans. It evolved rapidly to corneal perforation in spite of treatment with topical amphotericin B and oral itraconazole. An amniotic membrane transplant was performed as an emergency, associated with systemic administration of voriconazole. The infection was solved successfully, although the patient needed a penetrating keratoplasty to restore the corneal transparency. DISCUSSION: Fungal keratitis caused by Candida albicans usually follows an aggressive course and may simulate a bacterial aetiology. Voriconazole is a new antifungal drug that appears to be very effective in the management of ocular infections caused by many filamentous and levaduriform fungi.

Eficacia del voriconazol en queratitis fúngica por Cándida Albicans / Efficency of voriconazole in fungal kerititis caused by Candida Albicans

Caso clínico: Mujer de 70 años de edad, con antecedentes de diabetes y ulceración corneal persistente, que desarrolló una queratitis grave por Candida albicans. Evolucionó rápidamente hacia la perforación corneal a pesar del tratamiento con anfotericina B tópica e itraconazol oral, realizándose de urgencia un trasplante de membrana amniótica asociado a administración sistémica de voriconazol. La infección se resolvió satisfactoriamente, aunque precisó después una queratoplastia penetrante para restaurar la transparencia corneal. Discusión: Las queratitis fúngicas causadas por Candida albicans suelen cursar de una forma agresiva y simulan una etiología bacteriana. El voriconazol es un nuevo fármaco antifúngico que parece ser muy eficaz en el tratamiento de infecciones oculares causadas por numerosos hongos, tanto filamentosos como levaduriformes(AU)

Case report: A 70-year-old woman, with a history of diabetes and persistent corneal ulceration, developed a severe keratitis caused by Candida albicans. It evolved rapidly to corneal perforation in spite of treatment with topical amphotericin B and oral itraconazole. An amniotic membrane transplant was performed as an emergency, associated with systemic administration of voriconazole. The infection was solved successfully, although the patient needed a penetrating keratoplasty to restore the corneal transparency. Discussion: Fungal keratitis caused by Candida albicans usually follows an aggressive course and may simulate a bacterial aetiology. Voriconazole is a new antifungal drug that appears to be very effective in the management of ocular infections caused by many filamentous and levaduriform fungi(AU)

bcl-2 Overexpression eliminates deprivation-induced cell death of brainstem auditory neurons.

Deprivation of afferent input in young animals results in transneuronal degeneration of postsynaptic sensory neurons in a variety of species and sensory pathways. Transneuronal degeneration is generally not seen in adult animals. The cellular and molecular basis for this dramatic developmental change in susceptibility is not understood. One possibility is that genes involved in the apoptotic process are involved in determining cell death or survival after afferent deprivation. To further investigate this possibility, we performed unilateral cochlear ablation on wild-type and bcl-2-overexpressing mice at a variety of ages. In postnatal day 5 (P5) or P8 wild-type mice, cochlea removal resulted in a 54% or 31% neuronal loss in the anteroventral cochlear nucleus (AVCN), respectively. When the same manipulation is performed on a P30 mouse, no loss of AVCN neurons occurs. This confirmed a rather abrupt change in the sensitivity to disruption of afferent input, a critical period. However, in littermates expressing bcl-2 under a neuron-specific enolase promoter, no significant loss of AVCN neurons was observed at any age after unilateral cochlear ablation. Furthermore, wild-type mice demonstrate rapid expression of activated caspase-3 in AVCN neurons within hours of deafferentation, whereas bcl-2-overexpressing mice do not. This suggests that bcl-2 can influence cell survival after removal of afferent input during the critical period and is consistent with the hypothesis that caspase-3 is one effector of cell death under these circumstances. These data are the first to indicate that known apoptotic mediators can play a role in central neuronal plasticity in models of afferent deprivation.

Patterns of cell death in mouse anteroventral cochlear nucleus neurons after unilateral cochlea removal.

Developmental changes that influence the results of removal of afferent input on the survival of neurons of the anteroventral cochlear nucleus (AVCN) of mice were examined with the hope of providing a suitable model for understanding the cellular and molecular basis for these developmental changes in susceptibility. We performed unilateral cochlear ablation on wild-type mice at a variety of ages around the time of hearing onset to determine developmental changes in the sensitivity of AVCN neurons to afferent deprivation. In postnatal day 5 (P5) mice, cochlea removal resulted in 61% neuronal loss in the AVCN. By age P14, fewer than 1% of AVCN neurons were lost after this manipulation. This reveals a rather abrupt change in the sensitivity to disruption of afferent input, a critical period. We next investigated the temporal events associated with neuron loss after cochlea removal in susceptible animals. We demonstrate that significant cell loss occurs within 48 hours of cochlea removal in P7 animals. Furthermore, evidence of apoptosis was observed within 12 hours of cochlea removal, suggesting that the molecular events leading to cell loss after afferent deprivation begin to occur within hours of cochlea removal. Finally, we began to examine the role of the bcl-2 gene family in regulating afferent deprivation-induced cell death in the mouse AVCN. AVCN neurons in mature bcl-2 knockout mice demonstrate susceptibility to removal of afferent input comparable to neonatal sensitivity of wild-type controls. These data suggest that bcl-2 is one effector of cell survival as these cells switch from afferent-dependent to -independent survival mechanisms.