Electrochemical Doping of Halide Perovskites by Noble Metal Interstitial Cations.

Metal halide perovskites are an attractive class of semiconductors, but it has proven difficult to control their electronic doping by conventional strategies due to screening and compensation by mobile ions or ionic defects. Noble-metal interstitials represent an under-studied class of extrinsic defects that plausibly influence many perovskite-based devices. In this work, doping of metal halide perovskites is studied by electrochemically formed Au+ interstitial ions, combining experimental data on devices with a computational analysis of Au+ interstitial defects based on density functional theory (DFT). Analysis suggests that Au+ cations can be easily formed and migrate through the perovskite bulk via the same sites as iodine interstitials (Ii + ). However, whereas Ii + compensates n-type doping by electron capture, the noble-metal interstitials act as quasi-stable n-dopants. Experimentally, voltage-dependent, dynamic doping by current density-time (J-t), electrochemical impedance, and photoluminescence measurements are characterized. These results provide deeper insight into the potential beneficial and detrimental impacts of metal electrode reactions on long-term performance of perovskite photovoltaic and light-emitting diodes, as well as offer an alternative doping explanation for the valence switching mechanism of halide-perovskite-based neuromorphic and memristive devices.

Controversies in cerebrovascular disease: high or low doses of recombinant tissue plasminogen activator to treat acute stroke? A literature review.

INTRODUCTION: The use of low doses of recombinant tissue plasminogen activator (rt-PA) was initially proposed in Asian countries in response to racial peculiarities related to the functionality of fibrinogen and coagulation factors that potentially increased the risk of intracerebral haemorrhage, and with a view to saving costs. In view of the controversy over the use of rt-PA below the standard dose, we conducted a literature review of studies promoting the use of low doses or comparing different doses of rt-PA. DEVELOPMENT: We reviewed 198 abstracts related to the search terms and the full texts of 52 studies published in the last 30 years. We finally included 13 randomised clinical trials aiming to determine the efficacy and safety of the use of rt-PA at different doses in acute stroke, 14 observational cohort studies, 5 meta-analyses, and 3 systematic reviews. CONCLUSIONS: There is insufficient evidence to classify low doses of rt-PA as superior or at least not inferior to the standard treatment in the management of acute stroke in western populations. More clinical trials are required to determine whether the use of low doses is beneficial in patients with relative contraindications for thrombolytic therapy or other particular circumstances that may increase the risk of intracerebral haemorrhage.

Controversias en enfermedad cerebrovascular: rt-PA a dosis bajas vs. dosis estándar en el tratamiento del ictus agudo. Una revisión de la literatura / Controversies in cerebrovascular disease: High or low doses of recombinant tissue plasminogen activator to treat acute stroke? A literature review

Introducción: El uso de activador tisular del plasminógeno (rt-PA) a dosis bajas fue propuesto inicialmente en países asiáticos en atención a particularidades raciales relacionadas con la funcionalidad del fibrinógeno y factores de coagulación que contribuyen al riesgo de hemorragias intracerebrales, así como a la intención de ahorrar costos. Ante la controversia sobre el uso de rt-PA por debajo de la dosis estándar, realizamos una revisión de la literatura sobre los estudios que motivaron su uso y aquellos dirigidos a comparar diferentes dosis de rt-PA. Desarrollo: Se revisaron 198 resúmenes relacionados con los términos de búsqueda. Se revisaron 52 publicaciones de texto completo de los últimos 30 años. Se incluyeron 13 ensayos clínicos aleatorizados dirigidos a determinar la eficacia y seguridad del uso de rt-PA a diferentes dosis en el ictus agudo, 14 estudios de cohorte observacionales, 5 metaanálisis y 3 revisiones sistemáticas. Conclusiones: No se cuenta con evidencia suficiente para catalogar la dosis baja de alteplase como superior o al menos no inferior que el tratamiento estándar en el manejo del ictus agudo en población occidental. Se requieren más ensayos clínicos para determinar, si el uso de dosis bajas es beneficioso en pacientes con contraindicaciones relativas de terapia trombolítica u otras circunstancias particulares que eleven el riesgo de hemorragias intracerebrales. (AU)

Introduction: The use of low doses of recombinant tissue plasminogen activator (rt-PA) was initially proposed in Asian countries in response to racial peculiarities related to the functionality of fibrinogen and coagulation factors that potentially increased the risk of intracerebral haemorrhage, and with a view to saving costs. In view of the controversy over the use of rt-PA below the standard dose, we conducted a literature review of studies promoting the use of low doses or comparing different doses of rt-PA. Development: We reviewed 198 abstracts related to the search terms and the full texts of 52 studies published in the last 30 years. We finally included 13 randomised clinical trials aiming to determine the efficacy and safety of the use of rt-PA at different doses in acute stroke, 14 observational cohort studies, 5 meta-analyses, and 3 systematic reviews. Conclusions: There is insufficient evidence to classify low doses of rt-PA as superior or at least not inferior to the standard treatment in the management of acute stroke in western populations. More clinical trials are required to determine whether the use of low doses is beneficial in patients with relative contraindications for thrombolytic therapy or other particular circumstances that may increase the risk of intracerebral haemorrhage. (AU)

Mechanism and Timescales of Reversible p-Doping of Methylammonium Lead Triiodide by Oxygen.

Understanding and controlling the energy level alignment at interfaces with metal halide perovskites (MHPs) is essential for realizing the full potential of these materials for use in optoelectronic devices. To date, however, the basic electronic properties of MHPs are still under debate. Particularly, reported Fermi level positions in the energy gap vary from indicating strong n- to strong p-type character for nominally identical materials, raising serious questions about intrinsic and extrinsic defects as dopants. ​In this work, photoemission experiments demonstrate that thin films of the prototypical methylammonium lead triiodide (MAPbI3 ) behave like an intrinsic semiconductor in the absence of oxygen. Oxygen is then shown to be able to reversibly diffuse into and out of the MAPbI3 bulk, requiring rather long saturation timescales of ≈1 h (in: ambient air) and over 10 h (out: ultrahigh vacuum), for few 100 nm thick films. Oxygen in the bulk leads to pronounced p-doping, positioning the Fermi level universally ≈0.55 eV above the valence band maximum. The key doping mechanism is suggested to be molecular oxygen substitution of iodine vacancies, supported by density functional theory calculations. This insight rationalizes previous and future electronic property studies of MHPs and calls for meticulous oxygen exposure protocols.

Dietary Intervention Reverses Fatty Liver and Altered Gut Microbiota during Early-Life Undernutrition.

Nonalcoholic fatty liver disease (NAFLD), largely studied as a condition of overnutrition, also presents in undernourished populations. Like NAFLD, undernutrition disrupts systemic metabolism and has been linked to gut microbiota dysbiosis. Indeed, chronic exposures to fecal microbes contribute to undernutrition pathology in regions with poor sanitation. Despite a growing prevalence of fatty liver disease, the influence of undernutrition and the gut microbiota remain largely unexplored. Here, we utilize an established murine model (C57BL/6J mice placed on a malnourished diet that received iterative Escherichia coli/Bacteroidales gavage [MBG mice]) that combines a protein/fat-deficient diet and iterative exposure to specific, fecal microbes. Fecal-oral contamination exacerbates triglyceride accumulation in undernourished mice. MBG livers exhibit diffuse lipidosis accompanied by striking shifts in fatty acid, glycerophospholipid, and retinol metabolism. Multiomic analyses revealed metabolomic pathways linked to the undernourished gut microbiome and hepatic steatosis, including phenylacetate metabolism. Intriguingly, fatty liver features were observed only in the early-life, but not adult, MBG model despite similar liver metabolomic profiles. Importantly, we demonstrate that dietary intervention largely mitigates aberrant metabolomic and microbiome features in MBG mice. These findings indicate a crucial window in early-life development that, when disrupted by nutritional deficiency, may significantly influence liver function. Our work provides a multifaceted study of how diet and gut microbes inform fatty liver progression and reversal during undernutrition.IMPORTANCE Nonalcoholic fatty liver disease (NAFLD) remains a global epidemic, but it is often studied in the context of obesity and aging. Nutritional deficits, however, also trigger hepatic steatosis, influencing health trajectories in undernourished pediatric populations. Here, we report that exposure to specific gut microbes impacts fatty liver pathology in mice fed a protein/fat-deficient diet. We utilize a multiomics approach to (i) characterize NAFLD in the context of early undernutrition and (ii) examine the impact of diet and gut microbes in the pathology and reversal of hepatic steatosis. We provide compelling evidence that an early-life, critical development window facilitates undernutrition-induced fatty liver pathology. Moreover, we demonstrate that sustained dietary intervention largely reverses fatty liver features and microbiome shifts observed during early-life malnutrition.

Breakdown of the Static Picture of Defect Energetics in Halide Perovskites: The Case of the Br Vacancy in CsPbBr3.

We consider the Br vacancy in CsPbBr3 as a prototype for the impact of structural dynamics on defect energetics in halide perovskites (HaPs). Using first-principles molecular dynamics based on density functional theory, we find that the static picture of defect energetics breaks down; the energy level associated with a Br vacancy is found to be intrinsically dynamic, oscillating by as much as 1 eV on the picosecond time scale at room temperature. These significant energy fluctuations are correlated with the distance between the neighboring Pb atoms across the vacancy and with the electrostatic potential at these Pb atomic sites. We expect this unusually strong coupling of structural dynamics and defect energetics to bear important implications for both experimental and theoretical analyses of defect characteristics in HaPs. It may also hold significant ramifications for carrier transport and defect tolerance in this class of photovoltaic materials.

Controversies in cerebrovascular disease: High or low doses of recombinant tissue plasminogen activator to treat acute stroke? A literature review. / Controversias en enfermedad cerebrovascular: rt-PA a dosis bajas vs. dosis estándar en el tratamiento del ictus agudo. Una revisión de la literatura.

INTRODUCTION: The use of low doses of recombinant tissue plasminogen activator (rt-PA) was initially proposed in Asian countries in response to racial peculiarities related to the functionality of fibrinogen and coagulation factors that potentially increased the risk of intracerebral haemorrhage, and with a view to saving costs. In view of the controversy over the use of rt-PA below the standard dose, we conducted a literature review of studies promoting the use of low doses or comparing different doses of rt-PA. DEVELOPMENT: We reviewed 198 abstracts related to the search terms and the full texts of 52 studies published in the last 30 years. We finally included 13 randomised clinical trials aiming to determine the efficacy and safety of the use of rt-PA at different doses in acute stroke, 14 observational cohort studies, 5 meta-analyses, and 3 systematic reviews. CONCLUSIONS: There is insufficient evidence to classify low doses of rt-PA as superior or at least not inferior to the standard treatment in the management of acute stroke in western populations. More clinical trials are required to determine whether the use of low doses is beneficial in patients with relative contraindications for thrombolytic therapy or other particular circumstances that may increase the risk of intracerebral haemorrhage.

Evaluation of a psychoeducation programme for parents of children and adolescents with ADHD: immediate and long-term effects using a blind randomized controlled trial.

Recent guidelines for the diagnosis and treatment of attention deficit hyperactivity disorder (ADHD) have claimed the possible benefits of psychoeducational techniques in the comprehensive management of ADHD. To evaluate the efficacy of a psychoeducation programme for parents of children and adolescents with ADHD in a clinical setting using a blind randomized trial. 81 children/adolescents with ADHD were randomly assigned for their families to receive either a well-structured psychoeducation programme (intervention group, n = 44), or a parent counselling and support intervention (control group, n = 37). Measures of child ADHD symptoms, psychopathology, quality of life and family stress were taken before and after intervention and after a year follow-up. Parents and evaluators were unaware of the condition received. Compared to the support control group, the psychoeducation group showed ADHD Index and cognitive/inattention levels significantly reduced after the intervention ended (Mann-Whitney U = 3.34; p = 0.001; Mann-Whitney U = 3.47; p = 0.001). An improvement in the pro-social domain was also observed after 1 year follow-up (Mann-Whitney U = -2.37; p = 0.018), and clinical global impression found a statistically significant effect for severity over the time. Differences were initially found for the impact of the disorder in the family in different domains, including emotional and social functioning; these differences were no longer significant after alpha correction. No significant differences in quality of life or family stress were found in comparison with the control group. This psychoeducation programme is a valuable treatment for parents/carers of children/adolescents with ADHD, which needs to be considered when evaluating different non-pharmacological treatment options. Psychoeducation and other kind of non-pharmacological approaches need to be regarded not as a substitute, but as a complementary treatment to medications; these approaches might help other very crucial aspects of ADHD including social and familiar outcomes.

Skeletal muscle uncoupling-induced longevity in mice is linked to increased substrate metabolism and induction of the endogenous antioxidant defense system.

Ectopic expression of uncoupling protein 1 (UCP1) in skeletal muscle (SM) mitochondria increases lifespan considerably in high-fat diet-fed UCP1 Tg mice compared with wild types (WT). To clarify the underlying mechanisms, we investigated substrate metabolism as well as oxidative stress damage and antioxidant defense in SM of low-fat- and high-fat-fed mice. Tg mice showed an increased protein expression of phosphorylated AMP-activated protein kinase, markers of lipid turnover (p-ACC, FAT/CD36), and an increased SM ex vivo fatty acid oxidation. Surprisingly, UCP1 Tg mice showed elevated lipid peroxidative protein modifications with no changes in glycoxidation or direct protein oxidation. This was paralleled by an induction of catalase and superoxide dismutase activity, an increased redox signaling (MAPK signaling pathway), and increased expression of stress-protective heat shock protein 25. We conclude that increased skeletal muscle mitochondrial uncoupling in vivo does not reduce the oxidative stress status in the muscle cell. Moreover, it increases lipid metabolism and reactive lipid-derived carbonyls. This stress induction in turn increases the endogenous antioxidant defense system and redox signaling. Altogether, our data argue for an adaptive role of reactive species as essential signaling molecules for health and longevity.

Utilidad de la colonoscopia en la colitis isquémica / Usefulness of colonoscopy in ischemic colitis

Introducción: la colitis isquémica es la causa más frecuentede isquemia intestinal. Realizamos un estudio con el objetivo deanalizar las características demográficas, clínicas y la utilidad de lacolonoscopia en los pacientes diagnosticados de colitis isquémicaen nuestro centro en relación a un cambio de actitud terapéutica.Método: estudio retrospectivo en el que se seleccionaron 112pacientes diagnosticados de colitis isquémica mediante colonoscopiay biopsia, en un periodo de tiempo de cinco años. Se analizaron:edad, sexo, motivo de exploración, factores de riesgo cardiovascular,grado endoscópico de isquemia, cambio en la actitudterapéutica, tratamiento y evolución.Resultados: la edad media de nuestros pacientes fue de 73,6± 12,1 años con una incidencia similar en ambos sexos (50,9%mujeres y 49,1% hombres). Los factores de riesgo asociados fueronla hipertensión arterial (61,1%), el tabaco (37,2%) y antecedentede accidente cardiovascular previo (52,2%). El motivo másfrecuente de realización de colonoscopia fue rectorragia (53,6%)seguido de dolor abdominal (30,4%), realizándose de forma urgenteen el 65,3% de los casos. La colonoscopia permitió uncambio en la actitud terapéutica en el 50% de los casos, aumentandoen la urgente al 65,75%. La mortalidad global fue del27,67%. La colitis isquémica grave (25%) fue más frecuente envarones (64,3%), y cuando la indicación de colonoscopia fue urgente(85,71%) y cursó con mortalidad alta (53,57%). En estos serealizó tratamiento quirúrgico en el 57,14% de los casos con unaevolución favorable en el 50%, mientras que los pacientes con colitisisquémica leve o moderada tuvieron un pronóstico mejor, conevolución favorable en el 80,95% de los casos y con menor requerimientode tratamiento quirúrgico (4,76%, p < 0,05).Conclusión: la colitis isquémica es más frecuente en la edadavanzada. La sintomatología más común es la rectorragia y el dolorabdominal...(AU)

Background: the ischemic colitis is intestinal the most frequentcause of ischemia. With this work we determine the demographicand clinical characteristics, and the usefulness of thecolonoscopy in the patients with ischemic colitis diagnosed in ourcentre in relation to a change of therapeutic attitude.Method: retrospective study in which were selected 112 patientsdiagnosed with ischemic colitis by colonoscopy and biopsy,in a period of five years. It was analyzed: age, sex, reason for examination,factors of cardiovascular risk, endoscopic degree of ischemia,change in the therapeutic attitude, treatment and outcome.Results: the average age was of 73.64 ± 12.10 years with anequal incidence in women (50.9%) and the men (49.1%). The associatedfactors were the HTA (61.1%), tobacco (37.2%) and antecedentsof cardiovascular episode (52.2%). The most frequentreason for colonoscopy was rectorrhagia (53.6%) followed of theabdominal pain (30.4%), being urgent the 65.3%. Colonoscopyallowed a change in the therapeutic attitude in the 50 increasingin the urgent one to the 65.75%. Global mortality was of27.67%. The serious ischemic colitis (25%) was more frequent inmen (64.3%) in urgent indication (85.71%) and attends with highmortality (53.57%). Surgical treatment in the 57.14% was madewith a good evolution in the 50%, whereas the patients with mildor moderate ischemic colitis had a better prognosis (favourableevolution in 80.95%) with smaller requirement of the surgicaltreatment (4.76%), p < 0.05.Conclusion: the colitis ischemic are more frequent in the olderage. The most frequent symptoms are the rectorrhagia and theabdominal pain. The colonoscopy is a useful technique to evaluatethe gravity and it induces a change of attitude according to the resultof the same one. The evidence of a serious colitis supposedan increase of the necessity of surgery and worse prognosis(AU)

Usefulness of colonoscopy in ischemic colitis.

BACKGROUND: the ischemic colitis is intestinal the most frequent cause of ischemia. With this work we determine the demographic and clinical characteristics, and the usefulness of the colonoscopy in the patients with ischemic colitis diagnosed in our centre in relation to a change of therapeutic attitude. METHOD: retrospective study in which were selected 112 patients diagnosed with ischemic colitis by colonoscopy and biopsy, in a period of five years. It was analyzed: age, sex, reason for examination, factors of cardiovascular risk, endoscopic degree of ischemia, change in the therapeutic attitude, treatment and outcome. RESULTS: the average age was of 73.64 + or - 12.10 years with an equal incidence in women (50.9%) and the men (49.1%). The associated factors were the HTA (61.1%), tobacco (37.2%) and antecedents of cardiovascular episode (52.2%). The most frequent reason for colonoscopy was rectorrhagia (53.6%) followed of the abdominal pain (30.4%), being urgent the 65.3%. Colonoscopy allowed a change in the therapeutic attitude in the 50 increasing in the urgent one to the 65.75%. Global mortality was of 27.67%. The serious ischemic colitis (25%) was more frequent in men (64.3%) in urgent indication (85.71%) and attends with high mortality (53.57%). Surgical treatment in the 57.14% was made with a good evolution in the 50%, whereas the patients with mild or moderate ischemic colitis had a better prognosis (favourable evolution in 80.95%) with smaller requirement of the surgical treatment (4.76%), p < 0.05. CONCLUSION: the colitis ischemic are more frequent in the older age. The most frequent symptoms are the rectorrhagia and the abdominal pain. The colonoscopy is a useful technique to evaluate the gravity and it induces a change of attitude according to the result of the same one. The evidence of a serious colitis supposed an increase of the necessity of surgery and worse prognosis.

Boundary lipids in the nicotinic acetylcholine receptor microenvironment.

The structural and functional properties of the nicotinic acetylcholine receptor (AChR), the archetype molecule in the superfamily of Cys-looped ligand-gated ion channels, are strongly dependent on the lipids in the vicinal microenvironment. The influence on receptor properties is mainly exerted by the AChR-vicinal ("shell" or "annular") lipids, which occur in the liquid-ordered phase as opposed to the more disordered and "fluid" bulk membrane lipids. Fluorescence studies from our laboratory have identified discrete sites for fatty acids, phospholipids, and cholesterol on the AChR protein, and electron-spin resonance spectroscopy has enabled the establishment of the stoichiometry and selectivity of the shell lipid for the AChR and the disclosure of lipid sites in the AChR transmembrane region. Experimental evidence supports the notion that the interface between the protein moiety and the adjacent lipid shell is the locus of a variety of pharmacologically relevant processes, including the action of steroids and other lipids. I surmise that the outermost ring of M4 helices constitutes the boundary interface, most suitable to convey the signals from the lipid microenvironment to the rest of the transmembrane region, and to the channel inner ring in particular.

Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord.

Several studies have reported the neuroprotective effects of lithium (Li) suggesting its potential in the treatment of neurological disorders, among of them amyotrophic lateral sclerosis (ALS). Although the cause of motoneuron (MN) death in ALS remains unknown, there is evidence that glutamate-mediated excitotoxicity plays an important role. In the present study we used an organotypic culture system of chick embryo spinal cord to explore the presumptive neuroprotective effects of Li against kainate-induced excitotoxic MN death. We found that chronic treatment with Li prevented excitotoxic MN loss in a dose dependent manner and that this effect was mediated by the inhibition of glycogen synthase kinase-3beta (GSK-3beta) signaling pathway. This neuroprotective effect of Li was potentiated by a combined treatment with riluzole. Nevertheless, MNs rescued by Li displayed structural changes including accumulation of neurofilaments, disruption of the rough endoplasmic reticulum and free ribosome loss, and accumulation of large dense core vesicles and autophagic vacuoles. Accompanying these changes there was an increase in immunostaining for (a) phosphorylated neurofilaments, (b) calcitonin gene-related peptide (CGRP) and (c) the autophagic marker LC3. Chronic Li treatment also resulted in a reduction in the excitotoxin-induced rise in intracellular Ca(2+) in MNs. In contrast to the neuroprotection against excitotoxicity, Li was not able to prevent normal programmed (apoptotic) MN death in the chick embryo when chronically administered in ovo. In conclusion, these results show that although Li is able to prevent excitotoxic MN death by targeting GSK-3beta, this neuroprotective effect is associated with conspicuous cytopathological changes.

Evaluación de un programa de intervención breve motivacional para fumadores: resultados de un estudio piloto / Evaluation of a brief motivational intervention program for smokers: results of a pilot study

Tobacco consumption is a world-wide public health problem that has been associated with different types of cancer, cardiovascular and respiratory diseases, alterations in the reproductive system, dental problems and some eye diseases. In Mexico the National Survey of Addictions (2002) reported that 26.4% of the urban population between 12 and 65 years and 14.3% of the rural population are smokers. The Secretary of Health indicated that more than 53000 people died from diseases related to tobacco consumption. The consumption of tobacco stands among the ten first causes of morbidity and mortality in Mexico. In this sense, smoking is considered as one of the main public health problems in Mexico. Several organisms and institutions have undertaken actions in an attempt to solve it, such as the development of educative programs directed to the general population and programs to help smokers to quit this habit. Some of the main strategies to reduce cigarette consumption include nicotine replacement therapy, therapy not based on nicotine (antidepressants, some opiate antagonists and anxiolytic drugs), psychological programs, and the combination of some of them. Regarding psychological treatments, behavioral and cognitive behavioral techniques for smoking cessation hold empirical evidence about their efficacy for reducing the abuse of substances. In Mexico, psychological, nicotinic and non-nicotinic treatments to stop smoking are used. Nevertheless, the methodological and theoretical grounds of the psychological interventions are not well-established and there are no specific data about the changes in the consumption pattern after the application of the interventions and whether the effects of the treatment stay through the time. Specifically, the information about the efficacy of the brief interventions on smokers in the Mexican population is scarce. Although different studies have demonstrated that the brief motivational interventions are more effective to reduce the abuse of different substances than intensive interventions or no interventions at all, the techniques are not widely used in the treatment of tobacco consumption in Mexican population. With this evidence, the National Autonomous University of Mexico (UNAM) developed the Brief Motivational Intervention Program to treat smokers. The Brief Motivational Intervention is based in the Social Cognitive Theory, the Prevention of Relapses Model, in techniques of motivational interview and self-control techniques. Therefore, the goal of the present research is to evaluate a brief motivational intervention program for smokers. In order to achieve this aim, 10 individuals between 19 and 55 years old participated in the program; five individuals showed low nicotine dependence and five severe nicotine dependence according to the Questionnaire of Fagerström Tolerance. There was a public invitation and the participants consent to participate voluntarily in the <

Glial fibrillary acidic protein is a major target of glycoxidative and lipoxidative damage in Pick's disease.

Pick's disease is a subset of fronto-temporal dementia characterised by severe atrophy of the temporal and frontal lobes due to marked neuronal loss accompanied by astrocytic gliosis enriched in glial acidic protein. The remaining neurones have intracytoplasmic inclusions composed of hyperphosphorylated tau, called Pick bodies, in addition to hyperphosphorylated tau in astrocytes and oligodendrocytes. Gel electrophoresis and western blotting using markers of glycoxidation (advanced glycation end products, N-carboxyethyl-lysine and N-carboxymethyl-lysine: AGE, CEL, CML, respectively) and lipoxidation (4-hydroxy-2-nonenal: HNE, and malondialdehyde-lysine: MDAL) were used in the frontal and occipital cortex in three Pick's disease cases and three age-matched controls. In Pick's disease, increased AGE, CML, CEL, HNE and MDAL bands of about 50 kDa were observed in the frontal cortex (but not in the occipital cortex) in association with increased density of glial acidic protein bands. Bi-dimensional gel electrophoresis and western blotting also disclosed increased amounts and numbers of glial acidic protein isoforms in the frontal cortex in Pick's disease. Moreover, redox proteomics showed glycoxidation, as revealed with anti-CEL antibodies and lipoxidation using anti-HNE antibodies, of at least three glial acidic protein isoforms. The present results demonstrate that glial acidic protein is a target of oxidative damage in the frontal cortex in Pick's disease.

Differential effects of experimental and cold-induced hyperthyroidism on factors inducing rat liver oxidative damage.

Thyroid hormone-induced increase in metabolic rates is often associated with increased oxidative stress. The aim of the present study was to investigate the contribution of iodothyronines to liver oxidative stress in the functional hyperthyroidism elicited by cold, using as models cold-exposed and 3,5,3'-triiodothyronine (T3)- or thyroxine (T4)-treated rats. The hyperthyroid state was always associated with increases in both oxidative capacity and oxidative damage of the tissue. The most extensive damage to lipids and proteins was found in T3-treated and cold-exposed rats, respectively. Increase in oxygen reactive species released by mitochondria and microsomes was found to contribute to tissue oxidative damage, whereas the determination of single antioxidants did not provide information about the possible contribution of a reduced effectiveness of the antioxidant defence system. Indeed, liver oxidative damage in hyperthyroid rats was scarcely related to levels of the liposoluble antioxidants and activities of antioxidant enzymes. Conversely, other biochemical changes, such as the degree of fatty acid unsaturation and hemoprotein content, appeared to predispose hepatic tissue to oxidative damage associated with oxidative challenge elicited by hyperthyroid state. As a whole, our results confirm the idea that T3 plays a key role in metabolic changes and oxidative damage found in cold liver. However, only data concerning changes in glutathione peroxidase activity and mitochondrial protein content favour the idea that dissimilarities in effects of cold exposure and T3 treatment could depend on differences in serum levels of T4.

Lesión oxidativa de proteínas de hígado y corazón de rata durante el proceso de envejecimiento / Protein oxidative damage in rat liver and heart during the ageing process

Objetivos: el proceso de envejecimiento afecta a todos los organismos y es de suponer que sus mecanismos básicos esten conservados entre especies. La oxidación de proteínas se ha propuesto como uno de estos mecanismos básicos enlazando los radicales derivados del oxígeno con el proceso básico de envejecimiento. Así, si la lesión oxidativa de proteínas esta implicada en el envejecimiento, los animales con edades avanzadas deberían presentar valores basales elevados de lesión proteínica en comparación con animales más jóvenes. Sin embargo, la información disponible sobre esta predicción es limitada considerando la utilización de marcadores químicos específicos. Material y método: en este estudio, la concentración basal de diferentes marcadores de lesión proteínica (oxidación [semialdehídos glutámico y aminoadípico], glucoxidación [carboxietil-lisina], mixto de gluco y lipoxidación [carboximetil-lisina] y lipoxidación [malondialdehído-lisina]), así como el perfil de ácidos grasos de membrana, han sido determinados en el hígado y corazón de ratas macho adultas jóvenes (8 meses) y edad avanzada (30 meses). Resultados: los resultados mostraron incrementos significativos de los marcadores de oxidación y glucoxidación en el grupo de animales de 30 meses tanto en hígado como en corazón. Con relación a la lesión lipoxidativa, también se detectó un aumento significativo de ésta en el grupo de edad avanzada, probablemente asociado al incremento del índice de dobles enlaces y peroxidabilidad mostrados por las membranas celulares del hígado y corazón. Comparativamente, el corazón mostró grados de lesión oxidativa y lipoxidativa significativamente superiores a los del hígado. Los niveles de lesión glucoxidativa fueron superiores en hígado que en corazón. Asimismo, el corazón mostró mayor sensibilidad al envejecimiento, como lo demuestran los mayores incrementos porcentuales en lesión oxidativa, gluco y lipoxidativa. Conclusiones: estos resultados, en el contexto de la teoría del envejecimiento basada en el estrés oxidativo, además de poner de manifiesto las diferencias existentes entre órganos, refuerzan el papel del grado de insaturación de membrana, así como de los mecanismos homeostáticos que regulan el valor basal de modificación oxidativa en dicho proceso biológico

Objectives: ageing affects all organisms and its basic mechanisms can be expected to be conserved across species. Protein oxidation has been proposed as one of the basic mechanisms linking oxygen radicals with the basic ageing process. If oxidative damage to proteins is involved in ageing, aged animals should show higher steady-state levels of specific markers of this kind of damage than younger adult animals. However, the evidence available on this prediction is limited when the use of specific chemical markers is considered. Material and method: we measured steady-state levels of markers of different kinds of protein damage-oxidation (glutamic and aminoadipic semialdehydes), glycoxidation (carboxyethyl-lysine), mixed glyco- and lipoxidation (carboxymethyl-lysine), and lipoxidation (malondialdehydelysine)-, as well as fatty acid profile in the livers and hearts of young adult (8 months old) and aged (30 months old) male rats. Results: oxidative and glycoxidative markers were significantly increased in both the liver and heart of aged rats. Lipoxidation damage was also significantly increased in aged rats. This result was probably associated with the significantly increased double bond and peroxidizability indexes found in liver and heart cell membranes. Steady-state levels of oxidation and lipoxidation damage were significantly higher in the heart than in the liver. In contrast, glycoxidation damage was greater in the liver than in the heart. Accumulation rates of protein damage were higher in the heart than in the liver during aging. Conclusions: in the context of the oxidative stress theory of ageing, these results reveal differences between organs and reinforce the role of membrane unsaturation as well as the homeostatic mechanisms that maintain the steady-state level of protein damage in this biological process

Histopathologic features of the vagus nerve after electrical stimulation in swine.

This paper describes the histological features of the vagus nerve after its stimulation with an electrostimulation system that is being developed for morbid obesity treatment. An electrostimulation system was implanted laparoscopically around the ventral vagal trunk of five Large White female pigs (49.63+/-1.94 kg.). Vagal nerve stimulation was performed by continuous constant voltage current pulses. Thoracic samples of both ventral and dorsal vagal trunks were obtained thoracoscopically one month after implantation. Animals were sacrificed one month after thoracoscopic vaguectomy. Tissue samples were then harvested from the vagal nerve at the implantation site, 1cm cranial to it, thoracic portion of ventral and dorsal vagal trunks, sub-diaphragmatic dorsal vagal trunk, left and right vagus nerves. Specimens were analysed with light microscope. The severity of the lesions was graded from 0 to 4 (0: no lesion, 1: mild, 2: moderate, 3: severe and 4: extremely severe), taking into account fibrosis, vascularization, necrosis, fiber degeneration and inflammation. Electrode implantation resulted in thickened epineurium and endoneural connective tissue. The greatest lesion score was evidenced at the leads implantation site in the ventral vagal trunk, followed by, in order of decreasing lesion severity, left vagus nerve, thoracic portion of ventral vagal trunk, subdiaphragmatic dorsal vagal trunk, thoracic portion of dorsal vagal trunk and right vagus nerve. The stimulation device used in this study caused connective tissue growth, greatest in the samples located closer to the implantation site. However, there was no sign of altered vascularization in any studied specimen.

Prebiotic ingestion does not improve gastrointestinal barrier function in burn patients.

Prebiotics increase intestinal levels of health-promoting bacteria implicated in decreasing pathogen colonization, stimulating immune functions and stabilizing gut barrier functions, parameters which are altered in burn patients. We propose that regular intake of a prebiotic, oligofructose (OF), might help to improve the altered gastrointestinal (GI) permeability observed in burn patients. A randomized, double-blind, controlled clinical trial was carried out in 41 burn patients (mean burn surface area=17.1+/-8.2%) who ingested daily 6 g of oligofructose (OF group) or sucrose as placebo (Control group) during 15 days. Gastrointestinal permeability to sucrose and lactulose/mannitol (L/M) was evaluated on days 1 (before treatment) 3, 7, 14 and 21. A permeability test was also performed in 18 healthy subjects as controls. Thirty-one patients completed the protocol (dropout rate=24.4%). Healthy subjects had a basal sucrose excretion of 21.3 mg (14.0-32.5 mg) and a basal L/M ratio of 0.017% (0.009-0.022%). Sucrose excretion increased 5-fold and L/M ratio 4.4-fold in burn patients on day 1 and these high levels of marker excretion decreased significantly throughout the study (p=0.016 and 0.000001, respectively). No differences between the OF and Control groups were observed for sucrose excretion or L/M ratio. In conclusion, the normalization of gastrointestinal permeability is not accelerated by prebiotic intake.