Specific Phospholipid Modulation by Muscarinic Signaling in a Rat Lesion Model of Alzheimer's Disease.

Alzheimer's disease (AD) represents the most common cause of dementia worldwide and has been consistently associated with the loss of basal forebrain cholinergic neurons (BFCNs) leading to impaired cholinergic neurotransmission, aberrant synaptic function, and altered structural lipid metabolism. In this sense, membrane phospholipids (PLs) can be used for de novo synthesis of choline (Ch) for the further obtaining of acetylcholine (ACh) when its availability is compromised. Specific lipid species involved in the metabolism of Ch have been identified as possible biomarkers of phenoconversion to AD. Using a rat model of BFCN lesion, we have evaluated the lipid composition and muscarinic signaling in brain areas related to cognitive processes. The loss of BFCN resulted in alterations of varied lipid species related to Ch metabolism at nucleus basalis magnocellularis (NMB) and cortical projection areas. The activity of muscarinic receptors (mAChR) was decreased in the NMB and increased in the hippocampus according to the subcellular distribution of M1/M2 mAChR which could explain the learning and memory impairment reported in this AD rat model. These results suggest that the modulation of specific lipid metabolic routes could represent an alternative therapeutic strategy to potentiate cholinergic neurotransmission and preserve cell membrane integrity in AD.

Endocannabinoid and Muscarinic Signaling Crosstalk in the 3xTg-AD Mouse Model of Alzheimer's Disease.

The endocannabinoid system, which modulates emotional learning and memory through CB1 receptors, has been found to be deregulated in Alzheimer's disease (AD). AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus. Neurochemical correlates were simultaneously studied with both receptor and functional autoradiography for CB1 and muscarinic receptors, and regulations at the cellular level were depicted by immunofluorescence. 3xTg-AD mice exhibited increased acquisition latencies and impaired memory retention compared to age-matched non-transgenic mice. Neurochemical analyses showed changes in CB1 receptor density and functional coupling of CB1 and muscarinic receptors to Gi/o proteins in several brain areas, highlighting that observed in the basolateral amygdala. The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB1 receptor downregulation and CB1-mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes. A CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD.

Increase in cortical endocannabinoid signaling in a rat model of basal forebrain cholinergic dysfunction.

The basal forebrain cholinergic pathways progressively degenerate during the progression of Alzheimer's disease, leading to an irreversible impairment of memory and thinking skills. The stereotaxic lesion with 192IgG-saporin in the rat brain has been used to eliminate basal forebrain cholinergic neurons and is aimed at emulating the cognitive damage described in this disease in order to explore its effects on behavior and on neurotransmission. Learning and memory processes that are controlled by cholinergic neurotransmission are also modulated by the endocannabinoid (eCB) system. The objective of the present study is to evaluate the eCB signaling in relation to the memory impairment induced in adult rats following a specific cholinergic lesion of the basal forebrain. Therefore, CB1 receptor-mediated signaling was analyzed using receptor and functional autoradiography, and cellular distribution by immunofluorescence. The passive avoidance test and histochemical data revealed a relationship between impaired behavioral responses and a loss of approximately 75% of cholinergic neurons in the nucleus basalis magnocellularis (NBM), accompanied by cortical cholinergic denervation. The decrease in CB1 receptor density observed in the hippocampus, together with hyperactivity of eCB signaling in the NBM and cortex, suggest an interaction between the eCB and cholinergic systems. Moreover, following basal forebrain cholinergic denervation, the presynaptic GABAergic immunoreactivity was reduced in cortical areas. In conclusion, CB1 receptors present in presynaptic GABAergic terminals in the hippocampus are down regulated, but not those in cortical glutamatergic synapses.

Anatomical location of LPA1 activation and LPA phospholipid precursors in rodent and human brain.

Lysophosphatidic acid (LPA) is a signaling molecule that binds to six known G protein-coupled receptors: LPA1 -LPA6 . LPA evokes several responses in the CNS, including cortical development and folding, growth of the axonal cone and its retraction process. Those cell processes involve survival, migration, adhesion proliferation, differentiation, and myelination. The anatomical localization of LPA1 is incompletely understood, particularly with regard to LPA binding. Therefore, we have used functional [(35) S]GTPγS autoradiography to verify the anatomical distribution of LPA1 binding sites in adult rodent and human brain. The greatest activity was observed in myelinated areas of the white matter such as corpus callosum, internal capsule and cerebellum. MaLPA1 -null mice (a variant of LPA1 -null) lack [(35) S]GTPγS basal binding in white matter areas, where the LPA1 receptor is expressed at high levels, suggesting a relevant role of the activity of this receptor in the most myelinated brain areas. In addition, phospholipid precursors of LPA were localized by MALDI-IMS in both rodent and human brain slices identifying numerous species of phosphatides and phosphatidylcholines. Both phosphatides and phosphatidylcholines species represent potential LPA precursors. The anatomical distribution of these precursors in rodent and human brain may indicate a metabolic relationship between LPA and LPA1 receptors. Lysophosphatidic acid (LPA) is a signaling molecule that binds to six known G protein-coupled receptors (GPCR), LPA1 to LPA6 . LPA evokes several responses in the central nervous system (CNS), including cortical development and folding, growth of the axonal cone and its retraction process. We used functional [(35) S]GTPγS autoradiography to verify the anatomical distribution of LPA1 -binding sites in adult rodent and human brain. The distribution of LPA1 receptors in rat, mouse and human brains show the highest activity in white matter myelinated areas. The basal and LPA-evoked activities are abolished in MaLPA1 -null mice. The phospholipid precursors of LPA are localized by MALDI-IMS. The anatomical distribution of LPA precursors in rodent and human brain suggests a relationship with functional LPA1 receptors.

Comparación de la capacidad de limpieza de tres sistemas rotatorios para la desobturación y retratamiento de conductos radiculares / Comparison of the cleaning ability of three rotary systems for the removal of filling materials in endodontic retreatment

El éxito de la reendodoncia está basado en gran parte en la correcta limpieza y preparación del sistema de conductos radiculares. Esto implica la eliminación de la obturación anterior y el remodelado del conducto. El material de obturación que queda en el conducto puede involucrar microorganismos y dentina infectada que comprometen el pronóstico del tratamiento. En este trabajo se comparó in vitro la eficacia de los sistemas ProTaper Universal Retratamiento (Dentsply Maillefer), D-RaCe Retratamiento (FKG) y Mtwo Retratamiento (VDW) para la remoción de conos de gutapercha y sellador. El sistema que dejó mayor residuo fue RaCe. De los otros dos sistemas, Mtwo tuvo el mejor desempeño,pero no llegó a presentar diferencias estadísticamente significativas con ProTaper. Mtwo logró una limpieza del 79,03 por ciento, seguido por el ProTaper con el 75,94 por ciento y RaCe con el 49,01 por ciento. La eliminación completa de la obturación endodóntica no se logró con ninguno de los sistemas de instrumentos investigados...

Comparación de la capacidad de limpieza en la desobturación para retratamiento con limas manuales y con los sistemas rotatorios ProTaper Universal y D-Race / Comparison of the cleaning ability of hand files and ProTaper Universal rotary systems and D-Race in the removal of filling material in retreatment

El éxito de la reendodoncia está basado en gran parte en la correcta limpieza y preparación del sistema de conductos radiculares. Esto implica la eliminación de la obturación anterior y el remodelado del conducto. El material de obturación que queda en el conducto, puede involucrar microorganismos y dentina infectada que comprometen el pronóstico del tratamiento. Por lo tanto, la eficiencia en la remoción del material de obturación es esencial para poder tener un acceso a los microorganismos remanentes y restos de tejido pulpar. El objetivo del presente trabajo fue comparar tres formas de desobturación in vitro y ver cuál eliminaba mejor el sellador y los conos de gutapercha y cuál lo lograba en menor tiempo. Se encontró que la mejor limpieza se logró con la desobturación manual. Con ProTaper se logró la limpieza en un 46 por ciento, con RaCe en un 60 por ciento y con manual en un 87,91 por ciento. Con las técnicas de desobturación mecanizada se logró el procedimiento en menor tiempo. El promedio fue de 3 min. 26 seg. con ProTaper, 2 min. 54 seg. con D-Race y de 13 min. 48 seg. con la técnica manual

Comparación de la capacidad de limpieza en la desobturación para retratamiento con limas manuales y con los sistemas rotatorios ProTaper Universal y D-Race / Comparison of the cleaning ability of hand files and ProTaper Universal rotary systems and D-Race in the removal of filling material in retreatment

El éxito de la reendodoncia está basado en gran parte en la correcta limpieza y preparación del sistema de conductos radiculares. Esto implica la eliminación de la obturación anterior y el remodelado del conducto. El material de obturación que queda en el conducto, puede involucrar microorganismos y dentina infectada que comprometen el pronóstico del tratamiento. Por lo tanto, la eficiencia en la remoción del material de obturación es esencial para poder tener un acceso a los microorganismos remanentes y restos de tejido pulpar. El objetivo del presente trabajo fue comparar tres formas de desobturación in vitro y ver cuál eliminaba mejor el sellador y los conos de gutapercha y cuál lo lograba en menor tiempo. Se encontró que la mejor limpieza se logró con la desobturación manual. Con ProTaper se logró la limpieza en un 46 por ciento, con RaCe en un 60 por ciento y con manual en un 87,91 por ciento. Con las técnicas de desobturación mecanizada se logró el procedimiento en menor tiempo. El promedio fue de 3 min. 26 seg. con ProTaper, 2 min. 54 seg. con D-Race y de 13 min. 48 seg. con la técnica manual(AU)

Anatomical distribution of lipids in human brain cortex by imaging mass spectrometry.

Molecular mass images of tissues will be biased if differences in the physicochemical properties of the microenvironment affect the intensity of the spectra. To address this issue, we have performed-by means of MALDI-TOF mass spectrometry-imaging on slices and lipidomic analysis in extracts of frontal cortex, both from the same postmortem tissue samples of human brain. An external calibration was used to achieve a mass accuracy of 10 ppm (1σ) in the spectra of the extracts, although the final assignment was based on a comparison with previously reported species. The spectra recorded directly from tissue slices (imaging) show excellent s/n ratios, almost comparable to those obtained from the extracts. In addition, they retain the information about the anatomical distribution of the molecular species present in autopsied frozen tissue. Further comparison between the spectra from lipid extracts devoid of proteins and those recorded directly from the tissue unambiguously show that the differences in lipid composition between gray and white matter observed in the mass images are not an artifact due to microenvironmental influences of each anatomical area on the signal intensity, but real variations in the lipid composition.

Liposarcoma mixoide de mama. A propósito de un caso y revisión de la literatura / Myxoid liposarcoma of the breast. A case report and review of the literature

Presentamos el caso de una mujer de 40 años, sin antecedentes de interés, que consulta por palpación de nódulo mamario. La mamografía muestra una lesión nodular, bien delimitada, heterogénea, de 34mm, en el cuadrante superoexterno/prolongación axilar derecha. Se estudia mediante biopsia guiada por ecografía, con resultado de tumor mesenquimal con estroma mixoide, patrón vascular plexiforme y ocasionales células compatibles con lipoblastos. Con este diagnóstico se procede a la exéresis total de la lesión, que a la sección macroscópica muestra nódulo de bordes expansivos, de aspecto gelatinoso y características microscópicas de liposarcoma mixoide. Se presenta el caso y se revisa la literatura médica(AU)

A 40 year old woman presented with a palpable swelling in her right breast. She had no relevant past medical history. Mammography revealed a 34mm, well-defined heterogeneous nodular mass in the axillary tail of the upper external quadrant of the right breast. An ultrasound guided biopsy was performed, in which a mesenchymal tumour was found, with myxoid stroma, a plexiform capillary pattern and scattered cells that resembled lipoblasts. Subsequently, the tumour was excised. Macroscopy showed regular margins on the cut surface and a myxoid lesion. Microscopically the lesion was diagnosed as myxoid liposarcoma. The clinico-pathological features of the case are described and the pertinent literature discussed(AU)

[Self-medication and the elderly. The reality of the home medicine cabinet]. / Automedicación y ancianos. La realidad de un botiquín casero.

OBJECTIVE: To estimate the prevalence of self-medication in the elderly, to describe the characteristics of self-medication and home medicine cabinets. DESIGN: Cross-sectional descriptive study. SETTING: An urban primary health care (PHC) centre in Spain. PARTICIPANTS: A total of 240 patients 75 years of age or older. MAIN MEASUREMENTS: A structured questionnaire filled in by home care nurses from April to June 2006. Self-medication was classified into 4 sub-groups: pharmacological or herbal, exclusively pharmacological, exclusively herbal and pharmacological and herbal. The study variables were: age, sex, living alone, number of chronic diseases, number of chronic prescriptions and medicine cabinet characteristics (drugs accumulation, expired drugs, chronic drugs out of prescription, location of medicine chest and periodic review). Other variables were: drug types, source, and acute/chronic reason for self-medication. RESULTS: Self-medication frequency was 31,2% (95% CI, 26-36), with 22.9% (95% CI, 17.5-27.5) being pharmacological and 15.4% (95% CI, 23.1-17.3), herbal. The drugs most used in self-medication were analgesics (30.9%) and cold remedies (27.2%). The pharmacy was the most usual source (49.3%). A total of 41.6% contained drugs that were out of chronic prescription, and 34.4% accumulated more than three boxes of the same medication. CONCLUSIONS: There is a significant prevalence of self-medication among the elderly. Accumulating drugs in homes is a very extensive practice. Pharmacists and PHC professionals need to be trained in the responsible use of chronic and self-medication. Although self-care has to be encouraged, PHC professionals must make their patients aware of the harmful effects of self-medication.

Automedicación y ancianos. La realidad de un botiquín casero / Self-medication and the elderly. The reality of the home medicine cabinet

Objetivo: Estimar la prevalencia de automedicación en ancianos y describir las características de la automedicación y el estado de los botiquines caseros.Diseño: Estudio descriptivo transversal.EmplazamientoCentro de atención primaria (AP) de ámbito urbano.Participantes: 240 pacientes de edad ≥ 75 años.Medidas principalesCuestionario estructurado recogido por enfermería a domicilio entre abril y junio de 2006. Se definió automedicación en cuatro subgrupos: farmacológica o de herboristería, exclusivamente farmacológica, exclusivamente de herboristería y farmacológica y de herboristería. Las variables de estudio fueron: edad, sexo, vivir solo, número enfermedades crónicas, número de prescripciones crónicas y características del botiquín (acumulación de fármacos, fármacos caducados, fármacos fuera de prescripción crónica, lugar del botiquín y revisión periódica). Otras variables: tipos de fármacos, fuente y motivo agudo/crónico de la automedicación.Resultados: La frecuencia de automedicación fue del 31,2% (intervalo de confianza [IC], 36%–26%), farmacológica en el 22,9% (IC, 27,5%–17,5%) y de herboristería 15,4% (IC, 17,3%–13,1%). Los fármacos más utilizados para la automedicación fueron los analgésicos (30,9%) y los fármacos para el resfriado (27,2%). La fuente más habitual fue la farmacia (49,3%). El 41,6% contenía fármacos fuera de la prescripción crónica y el 23,4% acumulaba más de tres cajas del mismo medicamento.Conclusiones: Hay una importante prevalencia de ancianos que se automedican. Acumular fármacos en los domicilios es una práctica muy extendida. Es necesaria la educación sanitaria por diferentes ámbitos, farmacéuticos y profesionales de AP, en el uso responsable de la medicación tanto crónica como en la automedicación. Pese a la necesidad de promover el autocuidado, es necesario que los profesionales de AP sensibilizen a los pacientes sobre los efectos nocivos de la automedicación(AU)

Objective: To estimate the prevalence of self-medication in the elderly, to describe the characteristics of self-medication and home medicine cabinets.Design: Cross-sectional descriptive study.Setting: An urban primary health care (PHC) centre in Spain.Participants: A total of 240 patients 75 years of age or older.Main measurements: A structured questionnaire filled in by home care nurses from April to June 2006. Self-medication was classified into 4 sub-groups: pharmacological or herbal, exclusively pharmacological, exclusively herbal and pharmacological and herbal. The study variables were: age, sex, living alone, number of chronic diseases, number of chronic prescriptions and medicine cabinet characteristics (drugs accumulation, expired drugs, chronic drugs out of prescription, location of medicine chest and periodic review). Other variables were: drug types, source, and acute/chronic reason for self-medication.Results: Self-medication frequency was 31,2% (95% CI, 26–36), with 22.9% (95% CI, 17.5–27.5) being pharmacological and 15.4% (95% CI, 23.1–17.3), herbal. The drugs most used in self-medication were analgesics (30.9%) and cold remedies (27.2%). The pharmacy was the most usual source (49.3%). A total of 41.6% contained drugs that were out of chronic prescription, and 34.4% accumulated more than three boxes of the same medication.Conclusions: There is a significant prevalence of self-medication among the elderly. Accumulating drugs in homes is a very extensive practice. Pharmacists and PHC professionals need to be trained in the responsible use of chronic and self-medication. Although self-care has to be encouraged, PHC professionals must make their patients aware of the harmful effects of self-medication(AU)

Profiling and imaging of lipids on brain and liver tissue by matrix-assisted laser desorption/ ionization mass spectrometry using 2-mercaptobenzothiazole as a matrix.

2-Mercaptobenzothiazole (MBT) is employed for the first time as a matrix for the analysis of lipids from tissue extracts using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We demonstrate that the performance of MBT is superior to that of the matrixes commonly employed for lipids, due to its low vapor pressure, its low acidity, and the formation of small crystals, although because of the strong background at low m/z, it precludes detection of species below approximately 500 Da. This inconvenience can be partly overcome with the formation of Cs adducts. Using a polymer-based dual calibration, a mass accuracy of approximately 10 ppm in lipid extracts and of approximately 80 ppm in tissues is achieved. We present spectra from liver and brain lipid extracts where a large amount of lipid species is identified, in both positive and negative ion modes, with high reproducibility. In addition, the above-mentioned special properties of MBT allow its employment for imaging mass spectrometry. In the present work, images of brain and liver tissues showing different lipid species are presented, demonstrating the advantages of the employment of MBT.

Psicosis paranoide recurrente: primera manifestación de feocromocitoma / Relapsing paranoid psychosis as the first manifestation of phaeochromocytoma

Aunque de vez en cuando se ven manifestaciones psiquiátricas en los pacientes con feocromocitoma, éstas se limitan normalmente a estados de ansiedad. Otras manifestaciones menos frecuentes son la depresión y los síntomas psicóticos. En este artículo describimos a un paciente que presentó una psicosis paranoide como única manifestación de un feocromocitoma mucho antes de que éste fuera diagnosticado de dicha enfermedad. El trastorno delirante, que se trató con fármacos antipsicóticos durante dos años, desapareció tras la resección del tumor. Se podría especular que las catecolaminas podrían tener relación con el estado psicótico de este paciente y nos planteamos hasta que punto el feocromocitoma podría ser un "ejemplo natural" para explicar la fisiopatología catecolaminérgica involucrada en algunos trastornos psicóticos (AU)