Brain radiotoxicity-related 15CAcBRT gene expression signature predicts survival prognosis of glioblastoma patients.

BACKGROUND: Glioblastoma is the most common and devastating primary brain cancer. Radiotherapy is standard of care; however, it is associated with brain radiation toxicity (BRT). This study used a multi-omics approach to determine whether BRT-related genes (RGs) harbor survival prognostic value and whether their encoded proteins represent novel therapeutic targets for glioblastoma. METHODS: RGs were identified through analysis of single-nucleotide variants associated with BRT (R-SNVs). Functional relationships between RGs were established using Protein-Protein Interaction networks. The influence of RGs and their functional groups on glioblastoma prognosis was evaluated using clinical samples from the Glioblastoma Bio-Discovery Portal database and validated using the Chinese Glioma Genome Atlas dataset. The identification of clusters of radiotoxic and putative pathogenic variants in proteins encoded by RGs was achieved by computational 3D structural analysis. RESULTS: We identified the BRT-related 15CAcBRT molecular signature with prognostic value in glioblastoma, by analysis of the COMT and APOE protein functional groups. Its external validation confirmed clinical relevance independent of age, MGMT promoter methylation status, and IDH mutation status. Interestingly, the genes IL6, APOE, and MAOB documented significant gene expression levels alteration, useful for drug repositioning. Biological networks associated with 15CAcBRT signature involved pathways relevant to cancer and neurodegenerative diseases. Analysis of 3D clusters of radiotoxic and putative pathogenic variants in proteins coded by RGs unveiled potential novel therapeutic targets in neuro-oncology. CONCLUSIONS: 15CAcBRT is a BRT-related molecular signature with prognostic significance for glioblastoma patients and represents a hub for drug repositioning and development of novel therapies.

Seric IgG anti-SARS-CoV-2 pre- and post- Covid-19 pandemic from Mexican asymptomatic subjects.

OBJECTIVE: To detect serum IgG anti-SARS-CoV-2 in pre-and post- Covid-19 pandemic in Mexican asymptomatic subjects in order to know the degree of viral dispersion. MATERIALS AND METHODS: Association of serum IgG antibodies (determined by ELISA) to sociodemographic and clinical data or contact with Covid-19 cases in three groups of subjects: 1) Covid-19 pre-pandemic blood donors (n= 538); 2) Covid-19 post-pandemic blood donors (n= 243); 3) Covid-19 post-pandemic neurological patients (n= 312). None of the subjects studied had been vaccinated. RESULTS: The positive rate of IgG anti-SARS-CoV-2 was notably higher in participants recruited during the pandemic (donors, 29.6%; neurological patients, 15.7%) than in those recruited pre-pan-demic (donors 0.6%) (p <0.001). Other conditions associated to antibody positivity were being a worker in sales or services, or having had previous contact with people with Covid-19, for donnors and neurological patients, and having diabetes mellitus, for neurological patients. Higher positivity levels of anti-SARS-CoV-2 IgG were found in females than in males. The highest proportion of subjects with anti-SARS-CoV-2 antibodies was found in central Mexico. CONCLUSIONS: The dispersion of SARS-CoV-2 in asymptomatic, unvaccinated subjects (donors and neurological patients) recruited in a Mexican health institution, who work in sales or services or had previously had contact with Covid-19 patients is 16 to 30%. The level of positivity for anti-SARS-CoV-2 IgG is higher in females than in males. SARS-CoV-2 antibody seropreva-lence follow-up studies must be favored among the general population, being mandatory for donors.

Serum anti-neural immunoreactivity in patients with fibromyalgia. Preliminary study.

INTRODUCTION: Fibromyalgia (FM) is a non-degenerative syndrome characterized by generalized, chronic musculoskeletal pain, as well as mood, memory and sleep disorders. OBJECTIVE: To search for serum anti-neural antibodies (ANeuA) in patients with FM (FMP) in order to rule out autoimmune etiology. METHODS: The Fibromyalgia Impact Questionnaire (FIQ) and Beck's depression inventory (BDI) were applied. Immunoreactivity and the target recognized on the sera from FMPs and healthy subjects were analyzed by indirect immunofluorescence and Western blot. RESULTS: Both FIQ and BDI values were significantly altered in FMPs in comparison with those of controls (FIQ, 70 ± 25 vs. 12 ± 12, p < 0.0001; BDI, 17 ± 11 vs. 4 ± 3, p < 0.0002). Only five out of 15 FMP sera had ANeuA specifically directed against neurons from the medial vestibular nucleus of the brainstem. This immunoreactivity was not detected in the sera from the 14 controls. ANeuA recognized a 45 kDa protein. CONCLUSIONS: 30% of FMPs have ANeuA that have not been described before. In future studies, it will be necessary for anti-neural immunoreactivity to be determined in a larger sample and for the role of ANeuAs in the pathophysiology of FM to be established.

INTRODUCCIÓN: La fibromialgia (FM) es un síndrome no degenerativo caracterizado por dolor musculoesquelético crónico y generalizado; así como por alteraciones anímicas, de memoria y sueño. OBJETIVO: Buscar anticuerpos antineurales (AANeu) séricos en pacientes con FM para descartar etiología autoinmune. MÉTODOS: Se aplicó el Cuestionario de Impacto en Fibromialgia (FIQ) y el Inventario de Depresión de Beck (BDI). La inmunorreactividad y el blanco reconocido por los sueros de pacientes con FM y sujetos sanos se analizó con inmunofluorescencia indirecta y Western blot. RESULTADOS: Los valores de FIQ y BDI estuvieron significativamente alterados en los pacientes con FM, en comparación con los de los controles (FIQ, 70 ± 25 versus 12 ± 12, p < 0.0001; BDI, 17 ± 11 versus 4 ± 3, p < 0.0002). Solo cinco de 15 sueros de pacientes con FM tuvieron AANeu dirigidos específicamente contra las neuronas del núcleo vestibular medio del tronco encefálico; estos no se detectaron en los 14 sueros de los controles. Los AANeu reconocieron una proteína de 45 kDa. CONCLUSIONES: El 30 % de los pacientes con FM tiene AANeu no descritos antes. Será necesario evaluar la inmunorreactividad antineural en una muestra más grande y determinar el papel de los AANeu en la fisiopatología de la FM.

Seric IgG anti-SARS-CoV-2 pre- and post- Covid-19 pandemic from Mexican asymptomatic subjects / IgG sérica anti-SARS-CoV-2 pre y post pandemia de Covid-19 en mexicanos asintomáticos

Abstract: Objective: To detect serum IgG anti-SARS-CoV-2 in pre- and post- Covid-19 pandemic in Mexican asymptomatic subjects in order to know the degree of viral dispersion. Materials and methods: Association of serum IgG antibodies (determined by ELISA) to sociodemographic and clinical data or contact with Covid-19 cases in three groups of subjects: 1) Covid-19 pre-pandemic blood donors (n= 538); 2) Covid-19 post-pandemic blood donors (n= 243); 3) Covid-19 post-pandemic neurological patients (n= 312). None of the subjects studied had been vaccinated. Results: The positive rate of IgG anti-SARS-CoV-2 was notably higher in participants recruited during the pandemic (donors, 29.6%; neurological patients, 15.7%) than in those recruited pre-pandemic (donors 0.6%) (p <0.001). Other conditions associated to antibody positivity were being a worker in sales or services, or having had previous contact with people with Covid-19, for donnors and neurological patients, and having diabetes mellitus, for neurological patients. Higher positivity levels of anti-SARS-CoV-2 IgG were found in females than in males. The highest proportion of subjects with anti-SARS-CoV-2 antibodies was found in central Mexico. Conclusions: The dispersion of SARS-CoV-2 in asymptomatic, unvaccinated subjects (donors and neurological patients) recruited in a Mexican health institution, who work in sales or services or had previously had contact with Covid-19 patients is 16 to 30%. The level of positivity for anti-SARS-CoV-2 IgG is higher in females than in males. SARS-CoV-2 antibody seroprevalence follow-up studies must be favored among the general population, being mandatory for donors.

Resumen: Objetivo: Detectar IgG sérica anti-SARS-CoV-2 antes y después de la pandemia de Covid-19 en sujetos mexicanos asintomáticos, con la intención de conocer el grado de dispersión viral. Material y métodos: Se analizó la asociación de anticuerpos IgG séricos (determinados por ELISA), datos sociodemográficos y clínicos y contacto con casos de Covid-19 en tres grupos de sujetos: 1) donadores de sangre reclutados antes de la pandemia de Covid-19 (n= 538); 2) donadores (n= 243) y 3) pacientes neurológicos (n= 312) reclutados durante la pandemia de Covid-19. Ninguno de los sujetos estudiados había sido vacunado. Resultados: La tasa de positividad de IgG anti-SARS-CoV-2 fue notablemente mayor en los participantes reclutados durante la pandemia (donadores, 29.6%; pacientes neurológicos, 15.7%) que en los reclutados prepandemia (donadores 0.6%). Otras condiciones asociadas con positividad de anticuerpos fueron trabajar en ventas o servicios, o haber tenido contacto previo con pacientes Covid-19, en donadores y pacientes neurológicos, y haber tenido diabetes mellitus, en pacientes neurológicos. Se encontraron mayores niveles de positividad de IgG anti-SARS-CoV-2 en mujeres que en hombres. La mayor proporción de sujetos con anticuerpos anti-SARS-CoV-2 procedía del centro de México. Conclusiones: La dispersión del SARS-CoV-2 en sujetos asintomáticos, no vacunados (donadores y pacientes neurológicos), reclutados en una institución de salud mexicana, que trabajan en ventas o servicios, o tienen contacto previo con pacientes Covid-19 es de 16 a 30%. El nivel de positividad de IgG anti-SARS-CoV-2 es más alto en mujeres que en hombres. Los estudios de seguimiento de la seroprevalencia del SARS-CoV-2 deben favorecerse en la población general, siendo obligatorios en los donadores.

Inmunorreactividad antineural sérica en pacientes con fibromialgia. Estudio preliminar / Serum anti-neural immunoreactivity in patients with fibromyalgia. Preliminary study

Resumen Introducción: La fibromialgia (FM) es un síndrome no degenerativo caracterizado por dolor musculoesquelético crónico y generalizado; así como por alteraciones anímicas, de memoria y sueño. Objetivo: Buscar anticuerpos antineurales (AANeu) séricos en pacientes con FM para descartar etiología autoinmune. Métodos: Se aplicó el Cuestionario de Impacto en Fibromialgia (FIQ) y el Inventario de Depresión de Beck (BDI). La inmunorreactividad y el blanco reconocido por los sueros de pacientes con FM y sujetos sanos se analizó con inmunofluorescencia indirecta y Western blot. Resultados: Los valores de FIQ y BDI estuvieron significativamente alterados en los pacientes con FM, en comparación con los de los controles (FIQ, 70 ± 25 versus 12 ± 12, p < 0.0001; BDI, 17 ± 11 versus 4 ± 3, p < 0.0002). Solo cinco de 15 sueros de pacientes con FM tuvieron AANeu dirigidos específicamente contra las neuronas del núcleo vestibular medio del tronco encefálico; estos no se detectaron en los 14 sueros de los controles. Los AANeu reconocieron una proteína de 45 kDa. Conclusiones: El 30 % de los pacientes con FM tiene AANeu no descritos antes. Será necesario evaluar la inmunorreactividad antineural en una muestra más grande y determinar el papel de los AANeu en la fisiopatología de la FM.

Abstract Introduction: Fibromyalgia (FM) is a non-degenerative syndrome characterized by generalized, chronic musculoskeletal pain, as well as mood, memory and sleep disorders. Objective: To search for serum anti-neural antibodies (ANeuA) in patients with FM (FMP) in order to rule out autoimmune etiology. Methods: The Fibromyalgia Impact Questionnaire (FIQ) and BECK’s depression inventory (BDI) were applied. Immunorreactivity and the target recognized on the sera from FMPs and healthy subjects were analyzed by indirect immunofluorescence and Western blot. Results: Both FIQ and BDI values were significantly altered in FMPs in comparison with those of controls (FIQ, 70 ± 25 vs. 12 ± 12, p < 0.0001; BDI, 17 ± 11 vs. 4 ± 3, p < 0.0002). Only five out of 15 FMP sera had ANeuA specifically directed against neurons from the medial vestibular nucleus of the brainstem. This immunoreactivity was not detected in the sera from the 14 controls. ANeuA recognized a 45 kDa protein. Conclusions: 30% of FMPs have ANeuA that have not been described before. In future studies, it will be necessary for anti-neural immunoreactivity to be determined in a larger sample and for the role of ANeuAs in the pathophysiology of FM to be established.

NMR-based metabolomics of human cerebrospinal fluid identifies signature of brain death.

INTRODUCTION: Brain death (BD) is the irreversible cessation of all functions of the entire brain, including the brainstem. Cerebrospinal fluid (CSF) is a biological liquid that circulates in brain and spine. Metabolomics is able to reveal the response of biological systems to diverse factors in a specific moment or condition. Therefore, the study of this neurological condition through metabolic profiling using high resolution Nuclear Magnetic Resonance (NMR) spectroscopy is important for understanding biochemical events. OBJECTIVES: The aim of the current study is to identify the metabolomics signature of BD using 1H-NMR spectroscopy in human CSF. METHODS: 1H-NMR spectroscopy has been employed for metabolomic untargeted analysis in 46 CSF samples: 22 control and 24 with BD. Spectral data were further subjected to multivariate analysis. RESULTS: Statistically significant multivariate models separated subject's samples with BD from controls and revealed twenty one discriminatory metabolites. The statistical analysis of control and BD subjects using Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) model resulted in R2X of 0.733 and Q2 of 0.635. An elevation in the concentration of statistically discriminant metabolites in BD was observed. CONCLUSION: This study identifies a metabolic signature associated with BD and the most relevant enriched selected metabolic pathways.

[Descriptive epidemiology and frequency variations of astrocytic tumors in the National Institute of Neurology and Neurosurgery of Mexico]. / Epidemiología descriptiva y cambios en la frecuencia de tumores astrocíticos en el Instituto Nacional de Neurología y Neurocirugía de México.

OBJECTIVE: To determine distribution, localization and frequency variations of astrocytic tumors (AT) in a Mexican Institute of neurology. MATERIALS AND METHODS: Institutional registries of AT from five decades were analyzed. AT/ Surgical discharges (SD) and AT/Central Nervous System Tumors (CNST) from 1995 to 2014 were compared. RESULTS: Two thousand two hundred and eighty-seven AT (1 356 men and 931 women) were analyzed. The most common glioma was glioblastoma multiforme (GBM), found in young adults with a higher frequency to that reported in other studies. Relation of AT/SD, as well as, relation of AT/CNST was similar between 1995 and 2014. CONCLUSIONS: In general, the frequency of AT worldwide, being higher in the subgroup of young adults with GBM. There was not significant variation in the frequency of AT during the time studied.

OBJETIVO: Determinar distribución, localización y cambios de la frecuencia de tumores astrocíticos (TA) en un instituto mexicano de neurología. MATERIAL Y MÉTODOS: Se revisaron los registros institucionales de TA de cinco décadas. Se compararon las relaciones TA/egresos quirúrgicos (EQ) y TA/total de tumores del sistema nervioso central (TSNC) de 1995 a 2014. RESULTADOS: Se analizaron 2 287 TA (1 356 en hombres y 931 en mujeres). El glioma más común fue el glioblastoma multiforme (GBM), que estuvo presente en adultos jóvenes con una frecuencia mayor a la reportada en otros estudios. La relación TA/EQ y TA/TNSC fue similar entre 1995 y 2014. CONCLUSIONES: En general, la frecuencia de TA atendidos en el Instituto es similar a la reportada internacionalmente. No obstante, los casos de TA en el subgrupo de adultos jóvenes con GBM son más frecuentes (40%) que las incidencias reportadas en otros estudios (menores al 5%). No se encontró variación significativa en la frecuencia de TA durante las últimas dos décadas.

Epidemiología descriptiva y cambios en la frecuencia de tumores astrocíticos en el Instituto Nacional de Neurología y Neurocirugía de México / Descriptive epidemiology and frequency variations of astrocytic tumors in the National Institute of Neurology and Neurosurgery of Mexico

Resumen: Objetivo: Determinar distribución, localización y cambios de la frecuencia de tumores astrocíticos (TA) en un instituto mexicano de neurología. Material y métodos: Se revisaron los registros institucionales de TA de cinco décadas. Se compararon las relaciones TA/egresos quirúrgicos (EQ) y TA/total de tumores del sistema nervioso central (TSNC) de 1995 a 2014. Resultados: Se analizaron 2 287 TA (1 356 en hombres y 931 en mujeres). El glioma más común fue el glioblastoma multiforme (GBM), que estuvo presente en adultos jóvenes con una frecuencia mayor a la reportada en otros estudios. La relación TA/EQ y TA/TNSC fue similar entre 1995 y 2014. Conclusiones: En general, la frecuencia de TA atendidos en el Instituto es similar a la reportada internacionalmente. No obstante, los casos de TA en el subgrupo de adultos jóvenes con GBM son más frecuentes (40%) que las incidencias reportadas en otros estudios (menores al 5%). No se encontró variación significativa en la frecuencia de TA durante las últimas dos décadas.

Abstract: Objective: To determine distribution, localization and frequency variations of astrocytic tumors (AT) in a Mexican Institute of neurology. Materials and methods: Institutional registries of AT from five decades were analyzed. AT/Surgical discharges (SD) and AT/Central Nervous System Tumors (CNST) from 1995 to 2014 were compared. Results: Two thousand two hundred and eighty-seven AT (1 356 men and 931 women) were analyzed. The most common glioma was glioblastoma multiforme (GBM), found in young adults with a higher frequency to that reported in other studies. Relation of AT/SD, as well as, relation of AT/CNST was similar between 1995 and 2014. Conclusions: In general, the frequency of AT attended at the Institute is similar to that found worldwide, being only higher the number of GBM in younger adults. There was not significant variation in the frequency of AT during the time studied.

Sildenafil Inhibits Myelin Expression and Myelination of Oligodendroglial Precursor Cells.

Phosphodiesterases (PDEs) have previously been implicated in oligodendrocyte maturation and myelination of central nervous system axons. Sildenafil citrate is a phosphodiesterase inhibitor known to block PDE5, which also reduces inflammation in the experimental autoimmune encephalomyelitis demyelinating model. To find out whether this inhibitor might exert beneficial effects on central nervous system myelin repair activities, we investigated to what degree sildenafil modulates differentiation and maturation of cultured primary rat oligodendroglial precursor cells (OPCs). To this end, gene and protein expression of 2',3'-cyclic-nucleotide 3'-phosphodiesterase, myelin basic protein, and myelin oligodendrocyte glycoprotein, as well as of negative regulators of myelin expression (Hes1, Hes5, Id2, Id4, Rock2, and p57Kip2) were measured in OPCs treated with sildenafil. Moreover, the subcellular distribution of the p57kip2 protein was determined after sildenafil treatment, as this revealed to be an early predictor of the oligodendroglial differentiation capacity. In vitro myelination assays were done to measure the myelination capacity of oligodendrocytes treated with sildenafil. We found that sildenafil significantly diminished myelin gene expression and protein expression. Moreover, sildenafil also increased the expression of Id2 and Id4 negative transcriptional regulators, and the degree of OPCs with cytoplasmic p57kip2 protein localization was reduced, providing evidence that the PDE blocker impaired the differentiation capacity. Finally, sildenafil also interfered with the establishment of internodes as revealed by in vitro myelination assays. We therefore conclude that blocking PDE5 activities exerts a negative impact on intrinsic oligodendroglial differentiation processes.

Nanobiomaterials' applications in neurodegenerative diseases.

The blood-brain barrier is the interface between the blood and brain, impeding the passage of most circulating cells and molecules, protecting the latter from foreign substances, and maintaining central nervous system homeostasis. However, its restrictive nature constitutes an obstacle, preventing therapeutic drugs from entering the brain. Usually, a large systemic dose is required to achieve pharmacological therapeutic levels in the brain, leading to adverse effects in the body. As a consequence, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. One such tool is nanotechnology, in which nanostructures that are 1-100 nm are designed to deliver drugs to the brain. In this review, we examine many nanotechnology-based approaches to the treatment of neurodegenerative diseases. The review begins with a brief history of nanotechnology, followed by a discussion of its definition, the properties of most reported nanomaterials, their biocompatibility, the mechanisms of cell-material interactions, and the current status of nanotechnology in treating Alzheimer's, Parkinson's diseases, and amyotrophic lateral sclerosis. Of all strategies to deliver drug to the brain that are used in nanotechnology, drug release systems are the most frequently reported.

Historical distribution of central nervous system tumors in the Mexican National Institute of Neurology and Neurosurgery.

OBJECTIVE: To determine the frequency of central nervous system (CNS) tumors in the first fifty years of the National Institute of Neurology and Neurosurgery of Mexico Manuel Velasco Suárez (Instituto Nacional de Neurología y Neurocirugía de México, INNN) from 1965 to 2014. MATERIALS AND METHODS: A total of 16 116 institutional records of CNS tumors were analyzed. The frequency and distribution of CNS tumors were evaluated by tumor type, patient age and patient gender. The annual relationship between CNS tumors and surgical discharges (SD) over the last 20 years was estimated. RESULTS: The frequencies of most CNS tumors were consistent with those found worldwide, and the most common tumors were neuroepithelial tumors (33%), particularly astrocytic tumors (67%); meningeal tumors (26%); and pituitary tumors (20%). The incidence of pituitary tumors in these data was twice as high as that reported in other regions of the world, and the relationship between CNS tumors and SD was consistent over time (0.22-0.39). CONCLUSION: This study summarizes the largest sample of CNS tumor cases analyzed in Mexico and provides an important reference of the frequency of this tumor type in the country. This work will serve as a basis for conducting studies evaluating factors associated with the presence of CNS tumors and for identifying adequate public health interventions.

Historical distribution of central nervous system tumors in the Mexican National Institute of Neurology and Neurosurgery / Distribución histórica de neoplasias del sistema nervioso central en el Instituto Nacional de Neurología y Neurocirugía de México

Abstract Objective: To determine the frequency of central nervous system (CNS) tumors in the first fifty years of the National Institute of Neurology and Neurosurgery of Mexico Manuel Velasco Suárez (Instituto Nacional de Neurología y Neurocirugía de México, INNN) from 1965 to 2014. Materials and methods: A total of 16 116 institutional records of CNS tumors were analyzed. The frequency and distribution of CNS tumors were evaluated by tumor type, patient age and patient gender. The annual relationship between CNS tumors and surgical discharges (SD) over the last 20 years was estimated. Results: The frequencies of most CNS tumors were consistent with those found worldwide, and the most common tumors were neuroepithelial tumors (33%), particularly astrocytic tumors (67%); meningeal tumors (26%); and pituitary tumors (20%). The incidence of pituitary tumors in these data was twice as high as that reported in other regions of the world, and the relationship between CNS tumors and SD was consistent over time (0.22-0.39). Conclusion: This study summarizes the largest sample of CNS tumor cases analyzed in Mexico and provides an important reference of the frequency of this tumor type in the country. This work will serve as a basis for conducting studies evaluating factors associated with the presence of CNS tumors and for identifying adequate public health interventions.

Resumen Objetivo: Determinar la frecuencia de neoplasias del sistema nervioso central (NSNC) en los primeros 50 años del Instituto Nacional de Neurología y Neurocirugía de México (INNN). Material y métodos: Se analizaron 16 116 registros institucionales de las NSNC, atendidas en el INNN de 1965 a 2014; se estimó su frecuencia y distribución por tipo de neoplasia, edad y género, y se determinó la relación anual de NSNC y egresos quirúrgicos (EQ) en un período de 20 años. Resultados: Las frecuencias de la mayoría de NSNC fueron consistentes con las encontradas a nivel mundial. Las más frecuentes fueron las neuroepiteliales (33%), entre las cuales destacaron las astrocíticas (67%); meníngeas (26%), e hipofisiarias (20%). El número de neoplasias hipofisiarias en esta serie fue dos veces mayor al reportado en otras regiones del mundo y la relación NSNC/EQ fue similar a través del tiempo (0.22-0.39). Conclusión: Ésta es la mayor serie de casos de NSNC analizados en México y proporciona un referente importante sobre la frecuencia de este tipo de neoplasias en el país. Este trabajo servirá de base para llevar a cabo estudios de los factores asociados a la presencia de NSNC e identificar intervenciones de salud pública adecuadas.

IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients.

Fibromyalgia (FM) is a chronic disease that has been linked to inflammatory reactions and changes in the systemic levels of proinflammatory cytokines that modulate responses in the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. We found that concentrations of IL-6 and IL-8 were elevated in FM patients. Both cytokines correlated with clinical scores, suggesting that IL-6 and IL-8 have additive or synergistic effects in perpetuating the chronic pain in FM patients. These findings indicate that IL-6 and IL-8 are two of the most constant inflammatory mediators in FM and that their levels correlate significantly with the severity of symptoms.

[The clinical use of cryopreserved human skin allografts for transplantation]. / El uso clínico de aloinjertos de piel humana criopreservados con fines de trasplante.

BACKGROUND: The biological recovery of human skin allografts is the gold standard for preservation in Skin Banks. However, there is no worldwide consensus about specific allocation criteria for preserved human skin allografts with living cells. A report is presented on the results of 5 years of experience of using human skin allografts in burned patient in the Skin and Tissue Bank at the "Instituto Nacional de Rehabilitacion" MATERIAL AND METHODS: The human skin allografts were obtained from multi-organ donors. processed and preserved at -80 °C for 12 months. Allocation criteria were performed according to blood type match, clinical history, and burned body surface. RESULTS: Up to now, the Skin and Tissue Bank at 'Instituto Nacional de Rehabilitacion" has processed and recovered 125,000 cm(2) of human skin allografts. It has performed 34 surgical implants on 21 burned patients. The average of burn body surface was 59.2%. More than two-thirds (67.7%) of recipients of skin allografts were matched of the same to type blood of the donor, and 66.6% survived after 126 days hospital stay. CONCLUSION: It is proposed to consider recipient's blood group as allocation criteria to assign tissue; and use human skin allografts on patiens affected with burns over 30% of body surface (according the "rule of the 9").

Influence of quinacrine and chloroquine on the in vitro 3'-azido-3'-deoxythymidine antiretroviral effect.

BACKGROUND: Antimalarials quinacrine (Qc) and chloroquine (Cq) intercalate DNA, potentiate the activity of other drugs and have lysosomotropic, anti-inflammatory and antiviral activities that could increase the effect of the 3'-azido-3'-deoxythymidine (AZT) antiretroviral agent. The aim of the current study was to evaluate if Qc and Cq could improve the in vitro effect of the antiretroviral AZT agent. FINDINGS: Inhibition of viral replication in human immunodeficiency virus (HIV)SF33-infected peripheral blood mononuclear cells treated with Qc or Cq, alone or combined with a low dose of AZT was measured. Viral replication increased with Qc and decreased with high doses of Cq. The increase of replication caused by Qc was reversed by AZT. Neither Qc nor Cq significantly changed the antiviral activity of AZT. CONCLUSION: Cq does not potentiate the effect of AZT, but it is effective by itself at high doses. The rise of HIV replication by Qc could be deleterious in HIV endemic regions, where it is used as antimalarial. The mechanisms associated to this phenomenon must be identified.

Distribution of hydroxychloroquine in lymphoid tissue in a rabbit model for HIV infection.

Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy.

Chronic deep brain stimulation of the hypothalamic nucleus in wistar rats alters circulatory levels of corticosterone and proinflammatory cytokines.

Deep brain stimulation (DBS) is a therapeutic option for several diseases, but its effects on HPA axis activity and systemic inflammation are unknown. This study aimed to detect circulatory variations of corticosterone and cytokines levels in Wistar rats, after 21 days of DBS-at the ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl), unilateral cervical vagotomy (UCVgX), or UCVgX plus DBS. We included the respective control (C) and sham (S) groups (n = 6 rats per group). DBS treated rats had higher levels of TNF-α (120%; P < 0.01) and IFN-γ (305%; P < 0.001) but lower corticosterone concentration (48%; P < 0.001) than C and S. UCVgX animals showed increased corticosterone levels (154%; P < 0.001) versus C and S. UCVgX plus DBS increased IL-1ß (402%; P < 0.001), IL-6 (160%; P < 0.001), and corsticosterone (178%; P < 0.001 versus 48%; P < 0.001) compared with the C and S groups. Chronic DBS at VMHvl induced a systemic inflammatory response accompanied by a decrease of HPA axis function. UCVgX rats experienced HPA axis hyperactivity as result of vagus nerve injury; however, DBS was unable to block the HPA axis hyperactivity induced by unilateral cervical vagotomy. Further studies are necessary to explore these findings and their clinical implication.

[Steroid drugs and GM-CSF modulates activity of Egr-1 in glioma cells]. / Fármacos esteroides y el GM-CSF modulan la actividad de Egr-1 en células de glioma.

INTRODUCTION: The Egr-1 protein is a transcriptional factor responsive to early growth. Transcriptional regulation of the promoter has been described like responsive to physical stress, osmotic changes, and cellular growth marker. However, there is no report about the pharmacological effect on the transcriptional regulation in gliomas. Hereby we report the modulation of the Egr-1 promoter transcriptional activity induced by the Granulocytes Macrophages Colony Stimulating Factor (GM-CSF) and steroid drugs in human glioma cells (CH235-GM Grade II, U373-GM Grade III, D54-GM Grade IV) using a reporter system transduced by a recombinant adenoviral vector AdEgr-1/luc7. METHODS: Human glioma cells shows with different malignity grade (CH235-GM Grado II; U373-GM Grado III; D54-GM Grado IV) were transduced with no replicative adenoviral vector AdEgr-1/Luc7 and exposed to drugs as progesterone, ß-estradiol and betametasone, and GM-CSF. Transcriptional activity of the egr-1 promoter was quantified by Luciferase reporter gene, cloned downstream to the tata box. Luciferase activity was quantified from whole cell proteins using luminometry assays. RESULTS: U373-GM cell line with GM-CSF, shows an increment on transcriptional activity of Egr-1 promoter, also in endogen way. U373-GM showed a positive regulation of Egr-1, with steroid drugs on the times analyzed. Steroid drugs as progesterone, ß-estradiol and betametasone, shows a pleiotropic behavior on CH235-GM and D54-GM, glioma cell lines. CONCLUSIONS: Inhibition or activation response of Egr-1 promoter shows new framework to explore a mechanism of action of steroid drugs on genetic and epigenetic regulation on tumoral process.

Vinpocetine inhibits oligodendroglial precursor cell differentiation.

BACKGROUND: In multiple sclerosis during periods of remission a limited degree of myelin repair can be observed mediated by oligodendroglial precursor cells. Phosphodiesterase inhibitors act as anti-inflammatory agents and might hold promise for future multiple sclerosis treatment. AIMS: To investigate whether phosphodiesterase inhibitors could also influence myelin repair. METHODS: We stimulated primary oligodendroglial precursor cells with cilostazol, rolipram and vinpocetine and assessed their effects on repair related cellular processes. RESULTS: We found that vinpocetine exerted a strong negative effect on myelin expression while cilostazol and rolipram did not show such effects. In addition, vinpocetine decreased morphological complexities suggesting an overall negative impact on oligodendroglial cell maturation. We provide evidence that this is not mediated via a blockade of phosphodiesterase-1 but rather by inhibition of IĸB kinase. CONCLUSION: These findings suggest that vinpocetine via IĸB inhibition exerts a strong negative impact on oligodendroglial cell maturation and may therefore provide the rationale to restrict its application during periods of remission in multiple sclerosis patients. This is of particular interest since vinpocetine is widely used as a health supplement thought to act as a cognitive and memory enhancer for healthy people and patients with neurological or muscle diseases.