Effects of remifentanil on human C20 microglial pro-inflammatory activation.

OBJECTIVE: Remifentanil (RF) is a potent short-acting µ-opioid receptor agonist. Although preferred for its unique pharmacokinetics, the clinical use may be limited by hyperalgesia. Preclinical studies have shown a potential role of microglia on the development of hyperalgesia, with limited and conflicting evidence on RF. Considering the role of microglia in the initiation and maintenance of brain inflammation and their different responses among species, we aimed at characterizing RF effects on human adult microglia in vitro. MATERIALS AND METHODS: RF was tested at clinically relevant concentrations on the human microglial C20 cell line. Expression and release of interleukin-6 (IL-6) and brain derived neurotrophic factor (BDNF) were assessed under basal and inflammatory conditions. RESULTS: The expression and secretion of IL-6 significantly increased in C20 cells in response to pro-inflammatory cytokines. RF did not modify this response neither under basal nor under inflammatory conditions. No toxicity due to RF was detected. The drug displayed a modest stimulatory effect on the production of BDNF. CONCLUSIONS: Although RF does not exert direct pro-inflammatory actions on human adult microglia, its effects on BDNF, a crucial mediator of pain transmission, suggest a possible role on neuroinflammation and pain perception.

Assisted reproductive technology and congenital overgrowth: some speculations on a case of Pallister-Killian syndrome.

We report on a boy with Pallister-Killian syndrome (PKS) who was conceived by assisted reproductive technology (ART), specifically in vitro fertilization (IVF) with parents' gametes. A prenatal diagnosis performed elsewhere by CVS failed to detect the presence of the isochromosome 12p that was demonstrated postnatally in approximately 50% of cultured skin fibroblasts. Given that the patient did not show the congenital overgrowth typical of PKS, we speculate that ART might have restricted overgrowth in this particular case. More broadly, we hypothesize that overgrowth might protect from early demise fetuses conceived by ART, a technology known to cause low and very low birth weight.

El tratamiento con L-acetilcarnitina del comportamiento hiperactivo de pacientes con el síndrome X frágil / L-acetylcarnitine treatment on fragile patient hyperactive behaviour

Introducción. La hiperactividad es un problema significativo en casi todos los varones afectados por el síndrome X frágil (SXF), la enfermedad hereditaria más frecuente de retraso mental. Los enfoques terapéuticos se basan actualmente en estimulantes del sistema nervioso central (SNC), cuyos mecanismos de funcionamiento y su eficacia no están claramente definidos, a la vez que reducen el limitado tiempo de atención del paciente. Desarrollo. Un estudio piloto con 17 varones con SXF tratados con L-acetilcarnitina (LAC) durante un año demostró una reducción significativa en el comportamiento hiperactivo evaluado con el cuestionario Conners de padres y profesores. El uso de LAC en pacientes con SXF se deriva de la hipótesis que las propiedades bioquímicas y fisiológicas de esta sustancia pueden preservar la actividad cerebral. La LAC es una molécula pequeña hidrosoluble que se difunde fácilmente en el espacio extracelular y entra en cualquier célula del sistema nervioso por medio de un transportador específico. Las diferentes áreas del cerebro utilizan de forma diferente esta molécula para metabolizar la glucosa y lípidos para abastecer de ATP y la síntesis de neurotransmisores. El grupo acetilo presente en la LAC representa un elemento de señalización metabólica de gran importancia, posiblemente mediando su efecto en el SNC. La administración exógena de LAC puede afectar la actividad cerebral en el SXF por: modulación o administración de carburante para la producción de energía, que a nivel mitocondrial se asocia con el papel metabólico de la síntesis de neurotransmisores del ciclo de Krebs; remodelación de la membrana lipídica en función de la determinación activa, por parte de la LAC, de la producción de ácidos grasos polinsaturados, y efecto preferencial en el componente de atención del sistema colinérgico que depende de su peculiar modalidad de comunicación en el SNC. Un estudio explorativo, doblemente ciego, controlado con placebo y multicéntrico, se está llevando a cabo en función de estas premisas. Se incluirá una población total de 160 niños de nueve centros europeos. El objetivo del estudio es determinar el efecto de la LAC en el comportamiento hiperactivo de los niños con SXF de acuerdo con la evaluación del cuestionario Conners de padres y profesores (AU)

Telomeric associations and chromosome instability in ataxia telangiectasia T cells characterized by TCL1 expression.

T-cell tumors in ataxia telangiectasia (AT), such as T-PLL/T-CLL, are first preceded by the development of a large clone of T-lymphocytes, characterized by chromosomal rearrangements, which usually involve specific regions such as the 14q11 region. Malignancy develops years later, after additional chromosomal changes resulting from the genomic instability consequent to ATM disruption and to the activation of the TCL1 oncogene. Here we report the results of a cytogenetic follow-up of an AT patient (AT94-1), still without signs of hematological abnormalities, bearing a T-lymphocyte clone characterized by the t(14;14)(q11;q32) rearrangement and having TCL1 expression. We demonstrated that in clonal cells TCL1 expression correlates with increasing genomic instability and in time this mainly induces chromosomal rearrangements and telomeric associations (tas). Chromosome 21 is not randomly involved; in particular, an i(21q) indicates that it is a subclone prone to additional genetic changes and could represent an early chromosomal rearrangement involved in tumorigenesis. With regard to the increase in tas, we observed that: (i) it is inversely correlated with the proliferative ability of AT94-1 lymphocytes in PHA-stimulated short-term cultures (cell aging in vitro); (ii) this increase is not due to changes either in cell radiosensitivity (measured as bleomycin (BML)-sensitivity) or due to an illegitimate recombination (measured as adriamycin-sensitivity), which may not be sufficient for tumor development.

[L-acetylcarnitine treatment on fragile X patients hyperactive behaviour]. / El tratamiento con L-acetilcarnitina del comportamiento hiperactivo de pacientes con el síndrome X frágil.

Hyperactivity is a significant problem for almost all young males affected by fragile X syndrome (FXS), the most common inherited disease causing mental retardation. Therapeutical approaches are actually based on Central Nervous System (CNS) stimulants lacking a well defined rationale and efficacy while they further decrease the patient's limited attention span. A pilot study on 17 fragile X male treated with L-acetylcarnitine (LAC) over one year, showed a significant reduction of their hyperactivity behaviour tested by the Conners Abbreviated Parent-Teacher Questionnaire. LAC use in FXS patients derives from the hypothesis that the biochemical and physiological properties this substance has may preserve brain activity. LAC is a small, hydrosoluble molecule that easily diffuses in the extracellular space and enters any cell in the nervous system through specific transporters. Different cerebral areas use this molecule differently to metabolize glucose and lipids to provide for ATP and neurotrasmitters synthesis. The acetyl group LAC carriers represents a key metabolic signaling element possibly mediating its effect in the CNS. The exogenous administration of LAC may affect brain activity in FXS by: I) modulation of fuel partitioning for energy production, which at the mithocondrial level is associated with the Kreb's cycle metabolic role in neurotransmitter synthesis; II) remodelling of lipid membrane in terms of LAC actively determining the production of polyunsaturated fatty acids; III) preferential effect on the attention component of the cholinergic system which relies on its peculiar modality of communication in the CNS. Based on the above premises an explorative, double-blind, placebo controlled, multicenter study is ongoing. A total population of 160 children from nine European centers will be enrolled. The objective of this study is to determine the effect of LAC on the hyperactive behaviour of FXS children as evaluated by the administration of the Conners Abbreviated Parent Questionnaire.