In vivo murine model of acquired resistance in myeloma reveals differential mechanisms for lenalidomide and pomalidomide in combination with dexamethasone.

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.

[Usefulness of optical coherence tomography in the treatment and monitoring of posterior scleritis: report of a case]. / Utilidad de la tomografía de coherencia óptica en la monitorización terapéutica de la escleritis posterior: a propósito de un caso.

CASE REPORT: We describe the findings on optical coherence tomography before and after treatment with corticosteroids in a 51 year old patient with recurrent episodes of bilateral posterior scleritis without associated systemic disease. DISCUSSION: We believe that optical coherence tomography allows the pathological changes that occur in posterior scleritis to be monitored by objective and quantitative comparison of images, and even for therapeutic decisions.

Utilidad de la tomografía de coherencia óptica en la monitorización terapéutica de la escleritis posterior: a propósito de un caso / Usefulness of optical coherence tomography in the treatment and monitoring of posterior scleritis: Report of a case

Caso clínico: Se describen los hallazgos encontrados en la tomografía de coherencia óptica (OCT) antes y después del tratamiento con corticoides sistémicos en un paciente de 51 años con episodios recurrentes de escleritis posterior bilateral sin enfermedad sistémica asociada. Discusión: Consideramos que la OCT puede permitir hacer un seguimiento de las alteraciones patológicas que se suceden en la escleritis posterior, mediante la comparación objetiva y cuantitativa de imágenes, e incluso para la toma de decisiones terapéuticas(AU)

Case report: We describe the findings on optical coherence tomography before and after treatment with corticosteroids in a 51 year old patient with recurrent episodes of bilateral posterior scleritis without associated systemic disease. Discussion: We believe that optical coherence tomography allows the pathological changes that occur in posterior scleritis to be monitored by objective and quantitative comparison of images, and even for therapeutic decisions(AU)

Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients.

The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.

Direct promoter induction of p19Arf by Pit-1 explains the dependence receptor RET/Pit-1/p53-induced apoptosis in the pituitary somatotroph cells.

Somatotrophs produce growth hormone (GH) and are the most abundant secretory cells of the pituitary. Somatotrophs express the transcription factor Pit-1 and the dependence receptor RET, its co-receptor GFRa1 and ligand GDNF. Pit-1 is a transcription factor essential for somatotroph proliferation and differentiation and for GH expression. GDNF represses excess Pit-1 expression preventing excess GH. In the absence of GDNF, RET behaves as a dependence receptor, becomes intracellularly processed and induces strong Pit-1 expression leading to p53 accumulation and apoptosis. How accumulation of Pit-1 leads to p53 expression is unknown. We have unveiled the relationship of Pit-1 with the p19Arf gene. There is a parallel correlation of RET processing, Pit-1 increase and ARF protein and mRNA expression. Interfering the pathway with RET, Pit-1 or p19Arf siRNA blocked apoptosis. We have found a Pit-1 DNA-binding element within the ARF promoter. Pit-1 directly regulates the CDKN2A locus and binds to the p19Arft promoter inducing p19Arf gene expression. The Pit-1-binding element is conserved in rodents and humans. RET/Pit-1 induces p19Arf/p53 and apoptosis not only in a somatotroph cell line but also in primary cultures of pituitary somatotrophs, where ARF siRNA interference also blocks p53 and apoptosis. Analyses of the somatotrophs in whole pituitaries supported the above findings. Thus Pit-1, a differentiation factor, activates the oncogene-induced apoptosis (OIA) pathway as oncogenes exerting a tight control in somatotrophs to prevent the disease due to excess of GH (insulin-resistance, metabolic disease, acromegaly).

[Inter-observer variability in the diagnosis and classification of diabetic retinopathy through biomicroscopy]. / Variabilidad interobservador en el diagnóstico y clasificación de la retinopatía diabética mediante biomicroscopía.

OBJECTIVE: Analysis of the inter-observer variability of biomicroscopy used for the diagnosis of Diabetic Retinopathy. METHODS: This was a descriptive study. Parallel observer-blind evaluations of the degree of retinopathy in type 2 diabetic patients, as defined on biomicroscopic photographs, were performed by two ophthalmologists. The sample size required for the Kappa index among ophthalmologists with a disagreement ratio of 15%, precision ratio of 5% and confidence level of 95% is n=196 (<> being the number of eyes). The only variable measured was the degree of Diabetic Retinopathy, according to the modified Early Treatment Diabetic Research Study (ETDRS) classification. RESULTS: The average age of the 217 patients photographed was of 65.42 years (SE= 9.91). In 191 instances there was total agreement between the 2 ophthalmologists. In 24 instances the discrepancy was only of one degree of the classification of the ETDRS, and in 2 the discrepancy was of two degrees. In no case was it greater than this. (Quadratic weighed Kappa = 0.876, IC95%: 0.655-0.952 and linear weighed Kappa = 0.804, IC95%: 0.729-0.878). CONCLUSIONS: The Weighed Kappa index demonstrated a <> agreement of the degree of diabetic retinopathy. The discrepancies were slight, were of no clinical importance, and would not have affected treatment decisions. The results indicate that this examination, performed by a single ophthalmologist, can be utilised as a reference standard in Diabetic Retinopathy diagnosis.

Variabilidad interobservador en el diagnóstico y clasificación de la retinopatía diabética mediante biomicroscopía / Inter-observer variability in the diagnosis and classification of diabetic retinopathy through biomicroscopy

Objetivo: Análisis de la variabilidad interobservador de la biomicroscopía utilizada para el diagnóstico de retinopatía diabética. Métodos: Diseño: Observacional descriptivo. Valoración en paralelo, de forma ciega para los observadores, del grado de retinopatía diabética mediante biomicroscopía en pacientes diabéticos tipo 2. Muestra: Para la evaluación del índice Kappa, con una estimación de una proporción de desacuerdo del 15%, (precisión del 5% intervalo de confianza del 95%) muestra n=196, (siendo «n» el número de ojos). Variables a medir: grado de retinopatía diabética, según la clasificación del ETDRS modificada. Resultados: La edad media de los pacientes fotografiados fue de 65,42 años (DE= 9,91). De las 217 biomicroscopías realizadas, en 191 se encontró concordancia total. En 24 la discordancia fue tan sólo en un grado de la clasificación del ETDRS y en 2 la discordancia fue en dos grados. En ningún caso fue mayor. Kappa ponderado cuadrático = 0,876, IC95%: 0,655-0,952 y Kappa ponderado lineal =0,804, IC95%: 0,729-0,878. Conclusiones: El índice Kappa ponderado demuestra un grado de acuerdo «muy bueno». Las discrepancias producidas además de escasas no tienen trascendencia clínica, ya que no afectan a la decisión de tratamiento. La biomicroscopía leída por un solo oftalmólogo es un instrumento fiable como patrón de referencia para el diagnóstico de la retinopatía diabética

Objective: Analysis of the inter-observer variability of biomicroscopy used for the diagnosis of Diabetic Retinopathy. Methods: This was a descriptive study. Parallel observer-blind evaluations of the degree of retinopathy in type 2 diabetic patients, as defined on biomicroscopic photographs, were performed by two ophthalmologists. The sample size required for the Kappa index among ophthalmologists with a disagreement ratio of 15%, precision ratio of 5% and confidence level of 95% is n=196 («n» being the number of eyes). The only variable measured was the degree of Diabetic Retinopathy, according to the modified Early Treatment Diabetic Research Study (ETDRS) classification. Results: The average age of the 217 patients photographed was of 65.42 years (SE= 9.91). In 191 instances there was total agreement between the 2 ophthalmologists. In 24 instances the discrepancy was only of one degree of the classification of the ETDRS, and in 2 the discrepancy was of two degrees. In no case was it greater than this. (Quadratic weighed Kappa = 0.876, IC95%: 0.655-0.952 and linear weighed Kappa = 0.804, IC95%: 0.729-0.878). Conclusions: The Weighed Kappa index demonstrated a «very good» agreement of the degree of diabetic retinopathy. The discrepancies were slight, were of no clinical importance, and would not have affected treatment decisions. The results indicate that this examination, performed by a single ophthalmologist, can be utilised as a reference standard in Diabetic Retinopathy diagnosis

Las versiones de la aplicación de la ley: a propósito de dos casos / The versions of the application of the law: two clinical cases

Cuando la Consejería de Familia tiene la custodia y/o guarda de un menor, otorga estas, en aplicación de la ley, al familiar más próximo que pueda y quiera hacerse cargo, dando prioridad a la familia sobre otras personas valorada su idoneidad. En la práctica clínica diaria de una unidad de salud mental infanto -juvenil, cada vez es más frecuente encontrarnos con esta situación. Partiendo de dos casos clínicos, analizamos “las versiones de la aplicación de la ley” así como la desaparición o no de los síntomas que presentan estos niños al acudir a consulta, según los acogedores familiares repitan o no los esquemas de funcionamiento de la familia de origen. Lo “mejor” según la ley, acaba en la práctica a veces siendo “enemigo de lo bueno” (AU)

When the Regional Govermment´s Family Ministry holds a minor´s custody and/or safekeeping, and it confers them, pursuant to the enforcement of the lay, to the closest relative who is able and wishes to be incharge, giving preference to the family over other people, once its suitablility has been asessed. In the daily clinical practice of a Child Mental Health Center this situation is increasingly more frequent. Starting from two case reports, we analyze “ the versions of the enforcement of the law” as well as the disappearance or presence of the symptoms these children show when searching consultation deppending on wether the family minors´ caregivers reproduce or nt the dynamic patterns of the family of origin. The “ best thing”, according to law may sometimes result in practice the "enemy of the good thing" (AU)

[Group 2A idiopathic parafoveal telangiectasis]. / Telangiectasias parafoveales idiopáticas tipo 2A.

CASE REPORT: Two cases of group 2A idiopathic parafoveal telangiectasis associated with abnormal glucose metabolism are reported with the typical sings of this disease as well as a foveal vitelliform lesion in one patient, an infrequent association. DISCUSSION: Group 2A idiopathic parafoveal telangiectasis are a disease with well characterized clinical signs, being some very infrequent such as a vitelliform maculopathy. Its pathogenesis seems to be linked to some alterations in the parafoveal capillary network endothelial cells. These alterations are similar to those that appear in the beginning of the diabetic retinopathy.

Melatonin influences on the neuroendocrine-reproductive axis.

The neuroendocrine-reproductive axis designates the functional activity of the hypothalamus-pituitary-gonadal axis. A delicate synchronization of many inputs at these three different levels is vital for normal reproductive function. From the median basal hypothalamus, the median eminence releases gonadotrophin releasing hormone into the portal circulation to reach the anterior pituitary gland. Gonadotrophin releasing hormone is obviously a key hormone for the regulation of the secretion of gonadotrophins LH and FSH.

Influence of maternal pineal gland on the developmental pattern of neurokinin A (NKA) and substance P (SP) in male-rat-offspring: relationship to the season of the year.

The present study examines the influence of maternal pineal gland on the frontal cortex, striatal and testicular concentrations of the tachykinins, neurokinin A (NKA) and substance P (SP). Control, pinealectomized (PIN-X) and PIN-X plus melatonin-treated (PIN-X + MEL) mother rats were prepared. Male offspring rats were studied at 21, 31 and 60 days of age, during the four seasons of the year. In control-offspring tachykinin concentrations in frontal cortex were found at their highest levels in 21-day-old rats with a moderate decrease up to 60 days of age. This developmental pattern was season-dependent, observed only during summer and fall. Maternal PIN-X or PIN-X + MEL resulted in alterations in the offspring, showing during spring and summer significantly higher concentrations (P < 0.01) and during fall significantly lower concentrations of tachykinins in the frontal cortex (P < 0.05, P < 0.01) as compared to control-offspring. The tachykinin concentration in the striatum of control-offspring showed no major modifications throughout the ages studied in the four seasons of the year. With very few exceptions, PIN-X- and PIN-X + MEL did not alter tachykinin concentrations in striatum. Testicular SP concentrations showed a decrease from 21 to 60 days of age. PIN-X or PIN-X + MEL only caused minor and inconsistent modifications in testicular SP levels. In conclusion, our data clearly indicate for the first time that the maternal pineal gland participates in the regulation of the postnatal tachykinin development in some areas of the central nervous system. This effect was more evident in the frontal cortex than in the striatum and testes.

Seasonal changes of SP and NKA in frontal cortex, striatum and testes in the rat. Role of maternal pineal gland.

The concentrations of neurokinin A (NKA) and substance P (SP), members of tachykinins family, have been studied in all seasons of the year in frontal cortex, striatum and testes of male offspring 21-, 31-, or 60 days old of mother Wistar rats: control, pinealectomized (PIN-X) and pinealectomized + melatonin during pregnancy (PIN- X + MEL) kept under 12h:12h L:D. Control-offspring: in spite of having been kept under constant environmental conditions throughout the year, had marked differences in tachykinin concentrations. The highest tachykinin concentrations in the frontal cortex were found in summer and fall and the lowest in winter and spring. Maternal PIN-X resulted in alterations of this developmental pattern, mainly in PIN-X- and PIN- X + MEL-offspring in which the highest tachykinin concentrations at 21 and 31 days of age were only observed during summer. The alterations were observed up to 60 days of age for both tachykinins, when at this age control-offspring showed similar NKA concentrations. Seasonal variations were still observed in PIN-X- and PIN- X + MEL-offspring. In striatum and testes no mayor modifications throughout the four seasons of the year were found, with very few exceptions. PIN-X did not alter tachykinin concentrations, neither treatment with melatonin did it. In conclusion, our data clearly indicate for the first time that NKA and SP do indeed have seasonal rhythms in frontal cortex and that the maternal pineal gland plays a role in their entrainment already during fetal life.

Daily rhythm and regulation of clock gene expression in the rat pineal gland.

Rhythms in pineal melatonin synthesis are controlled by the biological clock located in the suprachiasmatic nuclei. The endogenous clock oscillations rely upon genetic mechanisms involving clock genes coding for transcription factors working in negative and positive feedback loops. Most of these clock genes are expressed rhythmically in other tissues. Because of the peculiar role of the pineal gland in the photoneuroendocrine axis regulating biological rhythms, we studied whether clock genes are expressed in the rat pineal gland and how their expression is regulated.Per1, Per3, Cry2 and Cry1 clock genes are expressed in the pineal gland and their transcription is increased during the night. Analysis of the regulation of these pineal clock genes indicates that they may be categorized into two groups. Expression of Per1 and Cry2 genes shows the following features: (1) the 24 h rhythm persists, although damped, in constant darkness; (2) the nocturnal increase is abolished following light exposure or injection with a beta-adrenergic antagonist; and (3) the expression during daytime is stimulated by an injection with a beta-adrenergic agonist. In contrast, Per3 and Cry1 day and night mRNA levels are not responsive to adrenergic ligands (as previously reported for Per2) and daily expression of Per3 and Cry1 appears strongly damped or abolished in constant darkness. These data show that the expression of Per1 and Cry2 in the rat pineal gland is regulated by the clock-driven changes in norepinephrine, in a similar manner to the melatonin rhythm-generating enzyme arylalkylamine N-acetyltransferase. The expression of Per3 and Cry1 displays a daily rhythm not regulated by norepinephrine, suggesting the involvement of another day/night regulated transmitter(s).

[Fundus albipunctatus associated with cone dystrophy. A familial case report]. / Fundus albipunctatus asociado a distrofia de conos. A propósito de un caso familiar.

UNLABELLED: We report a familial case of fundus albipunctatus associated with cone dystrophy. CASE REPORT: Thirty-eight year-old male diagnosed with retinitis pigmentosa in another center. The main complain is a worsening of his night and color vision. Clinical and electrophysiological studies confirm the association of fundus albipuncatus with cone dystrophy. The family study found another cone dystrophy-associated case in his thirty-three year-old affected brother. DISCUSSION: Though it is considerated a stationary disease, we report the association of fundus albipunctatus with symptoms and signs related to cone dysfunction. We review the possible nature of this association.

Fundus albipunctatus asociado a distrofia de conos. A propósito de un caso familiar / Fundus albipunctatus associated with cone dystrophy. A familial case report

Se presenta un caso familiar de fundus albipunctatus asociado a distrofia de conos. Caso clinico: Varón de 38 años diagnosticado en otro centro de retinitis pigmentosa que se revisa por empeoramiento de la visión nocturna y mala percepción de los colores. El estudio clínico y electrofisiológico demuestra la existencia simultánea de una distrofia de conos y de un fundus albipunctatus. El estudio de su hermano revela igualmente el inicio de una distrofia de conos en un paciente con fundus albipunctatus. Discusión: Considerada en general como una enfermedad de carácter estacionario, se presenta la asociación de un fundus albipunctatus con síntomas relacionados con una disfunción generalizada de conos en dos pacientes adultos. Se revisa la posible naturaleza de esta asociación (AU)

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Frosted branch angiitis and late peripheral retinochoroidal scar in a patient with acquired toxoplasmosis.

PURPOSE: To report a case of acute frosted branch angiitis associated with acquired toxoplasmosis in which a late peripheral chorioretinal scar developed. RESULTS: A 32-year-old man without systemic symptoms presented with sudden visual loss in his left eye. Examination demonstrated frosted branch angiitis without necrotizing chorioretinitis. Serologic tests showed elevated Toxoplasma gondii-specific immunoglobulin M antibody titers. Antitoxoplasmic therapy and oral steroids healed the ocular inflammation. In a follow-up visit one year later, a peripheral chorioretinal scar was noted. CONCLUSIONS: Acute frosted branch angiitis without focal necrotizing chorioretinitis can be a manifestation of acquired toxoplasmosis. This could be an important, and sometimes forgotten, sign of the disease.

[Neurotrophic keratopathy management with cyanoacrylate tarsorraphy and autologous serum]. / Manejo de la queratopatía neurotrófica mediante tarsorrafia con cianoacrilato y suero autólogo.

PURPOSE/METHODS: Neurotrophic keratopathy is a degenerative corneal disease with a highly complex treatment caused by an impairment of corneal sensitivity. We report the case of a 47 year-old man with a refractory postherpetic neurotrophic keratopathy in his right eye and we discuss the treatment options. RESULTS/CONCLUSION: The combination of cyanoacrylate with temporary tarsorraphy along with the administration of topical autologous serum eyedrops and systemic tetracycline, allowed to control the progression of the disease and to regenerate the corneal surface. This unpublished therapeutic strategy might be an effective and safe alternative in the management of neurotrophic keratopathy (Arch Soc Esp Oftalmol 2003; 78: 119-122).

Manejo de la queratopatía neurotrófica mediante tarsorrafia con cianoacrilato y suero autólogo / Neurotrophic keratopathy management with cyanoacrylate tarsorraphy and autologous serum

Objetivo/método: La queratopatía neurotrófica es una patología corneal degenerativa de tratamiento complejo, causada por una alteración en la sensibilidad corneal. Presentamos el caso clínico de un varón de 47 años con una queratopatía neurotrófica postherpética refractaria en OD y discutimos las opciones de tratamiento actuales. Resultados/conclusiones: La combinación de la tarsorrafia temporal con cianoacrilato junto a la administración tópica de suero autólogo al 20 por ciento y sistémica de tetraciclina permitió controlar la progresión del proceso y regenerar la superficie epitelial. Esta asociación terapéutica no publicada podría constituir una alternativa eficaz y segura en la queratopatía neurotrófica (AU)

Purpose/Methods: Neurotrophic keratopathy is a degenerative corneal disease with a highly complex treatment caused by an impairment of corneal sensitivity. We report the case of a 47 year-old man with a refractory postherpetic neurotrophic keratopathy in his right eye and we discuss the treatment options. Results/Conclusion: The combination of cyanoacrylate with temporary tarsorraphy along with the administration of topical autologous serum eyedrops and systemic tetracycline, allowed to control the progression of the disease and to regenerate the corneal surface. This unpublished therapeutic strategy might be an effective and safe alternative in the management of neurotrophic keratopathy (AU)

Developmental pattern of tachykinins during aging in several organs: effect of exogenous melatonin.

Mammalian neurokinin A (NKA) and substance P (SP) are neuropeptides widely distributed in the body; they are potential regulators of the basal blood flow and therefore of the function of many organs and tissues. In the present investigation, we studied the age-dependent changes in NKA and SP in ovary, liver, pancreas and spleen as well as the role of exogenous melatonin on these changes. Female rats of 5, 15 or 25 months of age were studied. In the ovary, NKA concentrations did not change during aging. SP concentrations in the control group were significantly higher (P<0.01) in old rats than in the other two age groups studied. Melatonin treatment resulted in reduced concentrations as compared with those of the control old rats. In the pancreas, NKA and SP concentrations increased during aging, the young rats showing significantly lower values (P<0.01) than middle-aged and old rats for NKA and significantly lower (P<0.01) than the old rats for SP. After melatonin treatment the differences in NKA concentrations disappeared and SP decreased in middle-aged as compared with those in old rats. In the liver, NKA and SP concentrations in the control and melatonin-treated groups did not differ significantly for the three age groups studied. Splenic NKA in control and melatonin-treated groups increased from young to middle-age up to old ages. SP concentrations showed similar values at all ages except in melatonin-treated old rats; in these animals there were significantly higher concentrations than in young melatonin-treated rats. The effect of melatonin was mainly observed on the ovary and pancreas in old rats, with a reduction in the concentrations as compared with those observed in the young groups.

Efectos de la melatonina sobre el mantenimiento de parámetros corporales durante el envejecimiento. Estudio en Rattus norvegicus / Effects of melatonin on the maintenance of body parameters during aging. Study in Rattus norvegicus

INTRODUCCIÓN Y OBJETIVO: Con la edad, la biosíntesis de melatonina disminuye, coincidiendo con cambios fisiológicos propios del envejecimiento. Ante este hecho, diversos investigadores han abordado estudios encaminados a valorar si la administración de melatonina podría retardar el proceso del envejecimiento. En este estudio hemos valorado la influencia de la melatonina sobre el mantenimiento de diversos parámetros y necesidades energéticas corporales, basándonos en hallazgos previos que ponen de manifiesto modificaciones de los mismos asociadas al envejecimiento. MATERIAL Y MÉTODOS: Hemos administrado melatonina en el agua de bebida (2 µg/ml), durante cinco meses, en ratas jóvenes (4-5 meses), mediana edad (15-18 meses) y edad avanzada (23-25 meses).Los parámetros estudiados fueron: peso corporal, peso de grasa retroperitoneal y de ovarios, ingesta sólida e hídrica y niveles de citrato sérico. RESULTADOS: La acción de la melatonina sobre la ingesta sólida se hizo notar en la edad avanzada, provocando menor consumo que en el grupo control. Sin embargo, sobre la ingesta hídrica, el suplemento con melatonina influyó en todas las edades desencadenando menor consumo. La administración de melatonina a ratas de edad avanzada disminuye el contenido de grasa retroperitoneal. Igualmente reduce el peso de los ovarios en ratas de mediana edad e impide que los niveles de citrato sérico en ratas de edad avanzada muestren valores significativamente elevados con respecto a las otras dos edades, como se observa en el grupo control. CONCLUSIONES: La administración de melatonina a ratas de edad avanzada conduce a un mejor aprovechamiento energético (AU)