Effect of Anodal Transcranial Direct Current Stimulation over the Motor Cortex for Cognition

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates cortical excitability and influences cognition. The role of the primary motor cortex (M1) in cognition is controversial. Here, we investigated the offline effects of anodal and sham tDCS over M1 on cognitive tasks that require comparable motor skills, but different levels of working memory and attention. Twenty healthy young female adults received anodal tDCS and sham tDCS to the M1 on two separate testing days in a counter balanced order. The cognitive functions outcome variables were the response time from the Attention Switching Task (AST) and Motor Screening Task (MST) tests using the Cambridge Neuropsychological Test Automated Battery before and after the anodal/sham tDCS. Anodal tDCS significantly improved AST response times from baseline in congruent and incongruent condition and MST mean correct latency (all p < 0.05). There was a significant difference for AST tasks variable include AST Switching cost (mean, correct), AST Mean correct latency, in congruent, incongruent, blocks 3, 5 (non-switching blocks), block 7 (switching block) (p < 0.01) and MST mean latency (p < 0.05) between anodal and sham conditions. These results indicate that tDCS is a promising tool to an improvement in response time in task related attention and motor speed. However, this study warrants further research to determine the long-term effect on other cognitive functions and in different age and gender groups.

Papel del eje TGF-beta-endotelina 1 en la fibrosis: lecciones del endotelio y el fibroblasto / No disponible

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Investigación y proyectos: algunas matizaciones / No disponible

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Time course of necrosis/apoptosis and neovascularization during experimental gastric conditioning.

Apoptosis, necrosis and neovascularization are three processes that occur during ischemic preconditioning in a range of organs. In the stomach, the effect of this preconditioning (the delay phenomenon) has helped to improve gastric vascularization prior to esophagogastric anastomosis after esophagectomy. Here we present a sequential study of the histological recovery of the gastric fundus and the phenomena of apoptosis, necrosis and neovascularization in an experimental model of partial gastric ischemia. Partial gastric devascularization was performed by ligature of the left gastric vessels in Sprague-Dawley rats. Rats were assigned to groups in accordance with their evaluation period: control, 1, 3, 6, 10, 15 and 21 days. Histological analysis, caspase-3 activity, DNA fragmentation and vascular endothelial cell proliferation (Ki-67) were measured in tissue samples after sacrifice. After 24 h of partial gastric ischemia, rates of apoptosis and necrosis were higher in the experimental groups than in controls. Tissue injury was higher 3 and 6 days post-ischemia. From day 10 after partial gastric ischemia, apoptosis and necrosis started to decrease, and on days 15 and 21 showed no differences in relation to controls. Neovascularization began between days 1 and 3, reaching its peak at 15 days after ischemia and coinciding with complete histological recovery. Both necrosis and apoptosis play a role in tissue injury during the first days after partial gastric ischemia. After 15 days, the evolution of both the histology and the neovascularization suggested that this is the optimal time for performing gastric transposition.

Screening of the endothelin1 gene (EDN1) in a cohort of patients with essential left ventricular hypertrophy.

Our objective was to analyse the role of endothelin1 gene (EDN1) variation in essential left ventricular hypertrophy (LVH). We searched for EDN1 variants in 145 Spanish patients with an essential form of LVH (not secondary to hypertension, aortic stenosis, or any other disease that could explain the hypertrophy). The five EDN1 coding exons and 1.5 kilobases of the promoter region were analysed through single strand conformation analysis and direct sequencing. We found four nucleotide changes: -1224 C/A (promoter), -131 ins/del A (exon 1, 5'-non-translated sequence), A/G in codon 106 (exon 3, silent), and G/T in codon 198 (exon 5, lys198asn). To determine the association between these polymorphisms and cardiac hypertrophy, we compared the genotype frequencies from these 145 patients with 250 healthy controls. We found a higher frequency of patients homozygous for 198 lys (198 KK) (65% vs. 52%; p = 0.01; OR = 1.76) and for -1224 AA (73% vs. 66%; p = 0.19). Homozygotes for -1224 A + 198 K (AA+KK) were significantly more frequent in patients (62% vs. 45%; p = 0.0007; OR = 2.10; 95% CI = 1.35-3.25). The expression of the -1224 C/A and exon 5 K198N variants was analysed with cells in culture. These in vitro studies showed that these variations did not differ in their expression levels. In conclusion, our work has shown that EDN1 variation, and in particular homozygosity for the -1224A/198K haplotype, is associated with the risk of developing cardiac hypertrophy. However, these EDN1 variants do not affect in vitro gene expression.

Paradoxical recovery in a bilingual patient with aphasia after right capsuloputaminal infarction.

We report the case of a bilingual dextral patient, who presented with an uncommon pattern of aphasic deficit following a right capsulo-putaminal infarction. In this patient, the linguistic deficit concerned the use of her mother tongue (Galician, L1) much more than the lesser practised second language (Spanish, L2). Our patient presented spontaneous fluent speech in L2 but not in L1, automatic translation into L2, and impaired repetition in L1, whereas comprehension was spared in both L1 and L2. Reading and writing were less valuable due to educational interference (reduced schooling). Spontaneous speech 16 months after the stroke showed the stability of the impairment. This is the first reporting of a crossed subcortical aphasia in a bilingual patient.

Testing the use of juvenile Salmo trutta L. as biomonitors of heavy metal pollution in freshwater.

Individual specimens of Salmo trutta were captured, from four sampling sites in Galician rivers (NW Spain) affected by different types of contamination: diffuse urban waste, run-off from an unrestored dump at a copper mine and waste from a fish farm. The ages of the captured trouts were established and only those belonging to the 1+ age class were selected for study. The liver and kidney were removed from each fish and analysed to determine the tissue concentrations of Cu, Fe and Zn. The results obtained showed that: (i) the use of 1+ individuals allowed differentiation of contamination scenarios on the basis of the tissue concentrations of metal; (ii) the use of 1+ individuals allowed standardization of the time of exposure, which was sufficiently long for differential uptake to have taken place; (iii) liver tissue provided the best results as, less effort was required than for processing kidney tissue, and significant differences between sampling sites were detected because the intrapopulational variability in metal levels was lower than for kidney, and (iv) the levels of elements detected were not affected by basal tissue concentrations or residual concentrations due to past contamination, which older trouts may have been exposed to. In addition, the use of 1+ trout may provide better results in annual environmental sampling surveys.

Validation of the Spanish version of the Addenbrooke's Cognitive Examination in a rural community in Spain.

BACKGROUND: The Addenbrooke's Cognitive Examination (ACE) is a brief cognitive test battery designed to detect and differentiate Alzheimer's disease (AD) and frontotemporal dementia (FTD). Translations of this instrument into French and Malayalam have been recently published OBJECTIVE: To adapt and validate the ACE into Spanish in a rural population of low-educational level. SUBJECTS: A clinical group, composed of 70 patients affected by dementia and 25 patients with memory complaints without dementia, was compared with 72 controls matched for gender, age and educational level METHOD: The clinical group was studied with standard neuropsychological instruments, all patients underwent neuroimaging [Computerized Tomography (CT) or Magnetic Resonance Imaging (MRI), and Single Photon Emission Tomography (SPECT) in all cases of suspected FTD], as well as routine neurological examination. Both groups were studied with the ACE and Clinical Dementia Rating scale (CDR). Sensitivity, specificity, area under curve, reliability and Verbal-Language/ Orientation-Memory (VLOM) ratio were calculated. Subsequently, the sample was stratified regarding educational level in two groups. Receiver Operating Characteristics (ROC) curves were calculated for these conditions. Different cut-off points were calculated addressing educational level. RESULTS: ROC curves demonstrated the superiority of the ACE in the sub sample of patients that finished school at over 14 years old. VLOM ratio confirmed its usefulness for differential diagnosis between AD and FTD CONCLUSIONS: The Spanish version of the ACE is a useful instrument for dementia diagnosis. In our sample VLOM ratio results were useful for differential diagnosis between AD and FTD. Different cut-off points must be used for different educational levels.

Oxidative and nitrosative stress in kidney disease: a case for cyclosporine A.

The immunosuppresor cyclosporine A (CsA) has been associated to human endothelial dysfunction and accelerated atherosclerosis. Sympathetic overactivity, relative deficiency of nitric oxide, TGFb-1, endothelin-1, reactive oxygen (ROS) and nitrogen species (RNS) and vasoconstrictor eicosanoids are mediators of vascular dysfunction associated to cyclosporine A. In CsA-treated cells (BAEC) an increase in reactive oxygen and nitrogen intermediates may lead to the intracellular formation of peroxynitrite. This agent could be one important mediator by which CsA produces an antioxidant-sensitive nitration of tyrosine, a marker for endothelial damage by nitrosative stress. Superoxide anion is the limiting factor in the formation of peroxynitrite in CsA-treated endothelial cells. Treatment with CsA may lead to the nitration of specific proteins such as manganese superoxide dismutase (MnSOD). We propose that peroxynitrite and tyrosine nitration may represent mechanisms of damage in pathophysiological situations where superoxide anion generation is increased.

B) Avances en fisiopatología vascular: Óxido nítrico y degradación de la matriz extracelular, ¿un papel en la aterosclerosis? / No disponible

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Native and oxidized low density lipoproteins oppositely modulate the effects of insulin-like growth factor I on VSMC.

OBJECTIVE: Changes in the local expression and signaling activity of the insulin-like growth factor-I (IGF-I) axis regulate growth and survival of plaque-derived vascular smooth muscle cells (VSMC) and influence plaque fate. Recent evidence suggests that accumulation of low density lipoproteins (LDL) in VSMC during the progression of atherogenesis is linked to local changes in IGF-I signaling. We investigated the effects of LDL on the biological actions and downstream signaling pathways mediated by this growth factor in A10 VSMC. METHODS AND RESULTS: We first characterized the effects of LDL on the proliferative and anti-apoptotic actions of IGF-I in A10 VSMC. Native LDL were mitogenic and synergistically enhanced DNA synthesis induced by IGF-I from 4-, 9- up to 7.8-fold, while having no effect on its anti-apoptotic actions. In contrast, oxidized LDL, at oxidation levels that did not modify these actions by themselves, significantly reduced the mitogenic and survival effects of IGF-I by 40% and 60%, respectively. These observations correlated with opposite changes exerted by native and oxidized LDL on the insulin receptor substrate-1 (IRS)-associated PI3 kinase/Akt response to IGF-I. The extracellular signal-regulated kinase (ERK) signaling response was not affected. CONCLUSIONS: Our study demonstrates a previously unidentified modulation of the actions of IGF-I on A10 VSMC by LDL, dependent on their extent of oxidative modification. Our findings suggest that the differential modulation of the PI3 kinase/Akt response to IGF-I play a pivotal role.

Los nefrólogos que elegimos el laboratorio / The nefrologists who choosed the laboratory

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Glutathionylation of the p50 subunit of NF-kappaB: a mechanism for redox-induced inhibition of DNA binding.

The cellular redox status can modify the function of NF-kappaB, whose DNA-binding activity can be inhibited by oxidative, nitrosative, and nonphysiological agents such as diamide, iodoacetamide, or N-ethylmaleimide. This inhibitory effect has been proposed to be mediated by the oxidation of a conserved cysteine in its DNA-binding domain (Cys62) through unknown biochemical mechanisms. The aim of this work was to identify new oxidative modifications in Cys62 involved in the redox regulation of the NF-kappaB subunit p50. To address this problem, we exposed p50, both the native form (p50WT) and its corresponding mutant in Cys62 (C62S), to changes in the redox pair glutathione/glutathione disulfide (GSH/GSSG) ratio ranging from 100 to 0.1, which may correspond to intracellular (patho)physiological states. A ratio between 1 and 0.1 resulted in a 40-70% inhibition of the DNA binding of p50WT, having no effect on the C62S mutant. Mass spectrometry studies, molecular modeling, and incorporation of (3)H-glutathione assays were consistent with an S-glutathionylation of p50WT in Cys62. Maximal incorporation of (3)H-glutathione to the p50WT and C62S was of 0.4 and 0.1 mol of (3)H-GSH/mol of protein, respectively. Because this covalent glutathione incorporation did not show a perfect correlation with the observed inhibition in the DNA-binding activity of p50WT, we searched for other modifications contributing to the maximal inhibition. MALDI-TOF and nanospray-QIT studies revealed the formation of sulfenic acid as an alternative or concomitant oxidative modification of p50. In summary, these data are consistent with new oxidative modifications in p50 that could be involved in redox regulatory mechanisms for NF-kappaB. These postranslational modifications could represent a molecular basis for the coupling of pro-oxidative stimuli to gene expression.

Cooperation between low density lipoproteins and IGF-I in the promotion of mitogenesis in vascular smooth muscle cells.

Low density lipoproteins (LDL) are an independent risk factor for atherosclerosis and show synergism with some growth factors in vascular smooth muscle cell (VSMC) proliferation. IGF-I has mitogenic actions on VSMC, which, in turn, show enhanced expression of IGF-I and its receptor when exposed to hypercholesterolemic diets in vivo. To investigate the molecular basis of a possible interaction between LDL and the IGF-I signaling system in VSMC, we used A10 cells, where synergism between both factors in DNA synthesis was demonstrated. IGF-I activates phosphatidylinositol 3-kinase (PI3 kinase) and extracellular signal-regulated MAPK pathways in A10 cells, although insulin receptor substrate-1 (IRS-1)-associated PI3 kinase is more closely linked to IGF-I induced proliferation. LDL, in pathophysiological concentrations, affect the IGF-I signaling pathway at multiple levels: 1) they induce phosphorylation of IGF-I receptor beta and IRS-1 in a time- and dose-dependent manner; 2) they up-regulate IRS-1-associated PI3 kinase/Akt activation in response to IGF-I at early times; and 3) they show additive effects with IGF-I on extracellular signal-regulated MAPK 1/2 phosphorylation. These actions are not present in very low density lipoprotein treatments. Taken together, these results indicate specific cooperation between LDL and the IGF-I signaling pathways and may represent a more general mechanism through which proatherogenic lipoproteins modulate VSMC response to growth factors.

Regulation of cyclooxygenase-2 expression by nitric oxide in cells.

Two different cyclooxygenases (COXs) are functional in mammals: COX-1 and COX-2. COX-2 is mainly an inducible isoform that shares significant features with inducible nitric oxide synthase (iNOS) in terms of its tissue distribution and participation in pathophysiological phenomena. Furthermore, the product of iNOS catalysis, nitric oxide (NO), is an important regulator of COX-2 activity and expression, and the products of COX-1 and COX-2 (diverse prostanoids) may also influence iNOS expression. Both positive and negative effects of NO on COX-2 expression have been encountered in experimental systems, showing that the outcome of the NO-COX-2 interaction is exquisitely dependent upon the temporal frame and the cell type studied. The pathophysiological significance of NO-COX cross-talk also arises from in vivo studies, in which most evidence points to a positive effect of NO on COX-2 activity and/or expression. This emphasizes the need to understand the underlying mechanisms. Among these, the capacity of NO and its effector cyclic GMP to modulate the function of several target proteins, including transcription factors such as nuclear factor-kappaB and activator protein-1, appears as the key pathway by which NO may regulate COX-2 expression. Given the capacity of some prostanoids to modulate the inflammatory response, the interplay between NO synthase and COX pathways stands at the center of the pathophysiological basis of inflammatory diseases.