Propofol Directly Increases Tau Phosphorylation

In Alzheimer's disease (AD) and other tauopathies, the microtubule-associated protein tau can undergo aberrant hyperphosphorylation potentially leading to the development of neurofibrillary pathology. Anesthetics have been previously shown to induce tau hyperphosphorylation through a mechanism involving hypothermia-induced inhibition of protein phosphatase 2A (PP2A) activity. However, the effects of propofol, a common clinically used intravenous anesthetic, on tau phosphorylation under normothermic conditions are unknown. We investigated the effects of a general anesthetic dose of propofol on levels of phosphorylated tau in the mouse hippocampus and cortex under normothermic conditions. Thirty min following the administration of propofol 250 mg/kg i.p., significant increases in tau phosphorylation were observed at the AT8, CP13, and PHF-1 phosphoepitopes in the hippocampus, as well as at AT8, PHF-1, MC6, pS262, and pS422 epitopes in the cortex. However, we did not detect somatodendritic relocalization of tau. In both brain regions, tau hyperphosphorylation persisted at the AT8 epitope 2 h following propofol, although the sedative effects of the drug were no longer evident at this time point. By 6 h following propofol, levels of phosphorylated tau at AT8 returned to control levels. An initial decrease in the activity and expression of PP2A were observed, suggesting that PP2A inhibition is at least partly responsible for the hyperphosphorylation of tau at multiple sites following 30 min of propofol exposure. We also examined tau phosphorylation in SH-SY5Y cells transfected to overexpress human tau. A 1 h exposure to a clinically relevant concentration of propofol in vitro was also associated with tau hyperphosphorylation. These findings suggest that propofol increases tau phosphorylation both in vivo and in vitro under normothermic conditions, and further studies are warranted to determine the impact of this anesthetic on the acceleration of neurofibrillary pathology

Microtubule-associated protein MAP2 preferentially binds to a dA/dT sequence present in mouse satellite DNA.

Microtubule-associated protein MAP2 binds to the Sau96.1 restriction monomer fragment of mouse satellite DNA. This fragment is also present in a lower proportion in bulk DNA. The digestion of MAP2-Sau96.1 fragment complex by DNase results in the protection of certain nucleotide sequences. The sequence poly(dA)4/poly(dT)4 is mainly protected against DNase digestion

C-reactive protein levels and clinically important predictive outcomes in stable COPD patients

6 pags.-1 fig.The aim of this study was to determine the relationship between C-reactive protein (CRP) levels and factors known to predict outcome in stable chronic obstructive pulmonary disease (COPD) patients. The following were studied in 130 stable COPD patients: spirometry, lung volume, arterial oxygen tension (Pa,O2,), dyspnoea, 6-min walk distance (6MWD), body mass index, fat-free mass index, BODE (body mass index, obstruction, dyspnoea and exercise capacity), health-related quality of life, smoking status, the presence of cardiovascular risk factors or disease, corticosteroid use and number of exacerbations in the previous year. CRP levels were measured in these patients and in 65 controls. Using univariate and multivariate analyses, any possible association with the predictors of outcomes was evaluated. CRP levels were higher in COPD patients than in controls (4.1 versus 1.8 mg-L-1, respectively). Correlation was found with the following variables: forced expiratory volume in one second (FEV1; -0.23), FEV1% (-0.20), forced vital capacity (FVC; -0.24), FVC% (-0.24), Global Initiative for Chronic Obstructive Lung Disease stage (0.17), BODE (0.17), inspiratory capacity/total lung capacity (-0.20), Pa,O2 (-0.40) and 6MWD (-0.30). Using multivariate analysis, Pa,O2 and 6MWD manifested the strongest negative association with CRP levels. C-reactive protein levels in stable chronic obstructive pulmonary disease patients are best correlated with arterial oxygen tension and 6-min walk distance. This should be considered when C-reactive protein levels are measured in stable chronic obstructive pulmonary disease patients. Copyright © ERS Journals Ltd 2006.Peer reviewe

Association of IL-6 gene polymorphisms and COPD in a Spanish Population

7 pag.-2 fig.- 3 tab.Interleukin-6 (IL-6) is a potential mediator of systemic effects of Chronic Obstructive Pulmonary Disease (COPD). In the present case-control study we investigated the association of promoter polymorphisms of this gene and COPD in a cohort of 191 patients, smokers without COPD (n = 75) and a healthy control population (n = 296). Besides spirometry, exercise capacity (6MWD, 6 min walking distance) and body mass index (BMI) were measured in COPD patients. Genotyping of the IL-6 polymorphisms at positions -174, -572 and -597 was performed. The -597G/A and -174G/C polymorphisms were not associated with the disease. However, the -572G/C polymorphism was significantly associated with COPD susceptibility under a dominant model of inheritance. The frequency of the genotypes containing the C allele was significantly lower in the COPD cases (9.9%) compared with the healthy control group (16.9%) and smokers (23.1%), (OR = 0.46, p = 0.032 and OR = 0.28, p = 0.012, respectively). The GCG (-597/-572/-174) haplotype was significantly associated with the disease (OR = 0.37, p = 0.022, COPD cases vs. healthy subjects and OR = 0.17, p = 0.011, COPD cases vs. smokers). Moreover, a borderline association was also found for the -572G allele and hypoxemia (PaO2 < 60 mmHg) (p = 0.05). Our data suggest that the IL-6 -572C allele may confer a diminished risk of developing COPD. © 2008 Elsevier Ltd. All rights reserved.To Bartolomé Celli, MD, PhD from the Pulmonary and Critical Care Department Caritas, St. Elizabeth's Medical Center, Boston, MA, USA for his valuable comments in the intellectual contents and for revising critically this manuscript. This research was supported by grants of the Fundación Canaria de Investigación y Salud (FUNCIS) and the Sociedad Española de Neumología y Cirugía Torácica (SEPAR).Peer reviewe