KRASG12D inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8+ T cells.

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of KRASG12D in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8+ T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.

Oncogenic Kras G12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 + T cells dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRAS G12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras G12D mutant protein. Here we explore the impact of Kras G12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8 + T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8 + T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.

Herramientas de evaluación de actividades de la vida diaria instrumentales en población adulta: revisión sistemática / Tools for the evaluation of daily life activities instrumental in adults: systematic review

Introducción: La transición al modelo biopsicosocial implica que las herramientas de evaluación se adapten a esta nueva visión de la salud. Las herramientas usadas en Chile para medir la funcionalidad en las actividades de la vida diaria instrumentales (AVDI) son las mismas desde los años 50, por lo que se requiere hacer una revisión de la literatura a fin de conocer nuevas metodologías de evaluación en la materia. Objetivo: Identificar las herramientas de evaluación en AVDI, qué ítems son considerados, metodología de puntuación (rangos, puntajes, categorización de resultados), tiempo y contexto de aplicación, creadores de las herramientas y propiedades psicométricas de los mismos. Diseño: Revisión sistemática. Fuentes de datos: PubMed, BIREME y Epistemonikos. Se realizaron tres búsquedas: dos el 2018 (marzo y septiembre) y una el 2020 (diciembre). Selección de estudios: Estudios observacionales (estudios de cohorte y estudios de corte transversal) y revisiones sistemáticas que contemplaron la valoración de AVDI en mayores de 18 años, en inglés o español, publicados desde 1998 y de libre acceso. Extracción de datos: Se realizó lectura de títulos y resúmenes como primer filtro, y posteriormente el texto completo. Una vez seleccionados los estudios que cumplen con los criterios de inclusión, se les aplicó la pauta "Strengthening The Reporting of Observational studies in Epidemiology (STROBE)" y la pauta "Critical Appraisal Skills Programme Spanish (CASPe)" para evaluar la calidad metodológica. Se estableció, a través de un consenso de las investigadoras, que cada estudio seleccionado debía cumplir con al menos 13 de los 22 ítems de la pauta STROBE. Resultados: De los 27.606 artículos encontrados, 15 cumplieron con los criterios de inclusión y el punto de corte establecido de la pauta. Sólo un artículo era en idioma español y 14 en inglés; y fueron publicados principalmente en EE.UU. y España. De los 20 instrumentos encontrados en los artículos seleccionados, el 60% corresponde a la "Escala Lawton y Brody", el 10% a la de "The Performance Assessment of Self-Care Skills (PASS)" y el porcentaje restante otras herramientas. Conclusiones: A nivel internacional se han creado nuevas herramientas de evaluación de AVDI en respuesta a necesidades locales, dificultando la posibilidad de ser generalizadas a otros contextos sin contar previamente con un proceso de validación transcultural y estadística que resguarde la confiabilidad de su aplicación y data. La "Escala de Lawton y Brody", pese a las limitaciones ni sesgos, sigue siendo un patrón de oro a nivel internacional.

Background: The transition to the biopsychosocial model implies that the assessment tools are adapted to this new vision of health. In Chile, the evaluations to measure functionality on Instrumental Activities of Daily Living (IADL), have been the same since the 1950s, so a review of the literature is required to know new evaluation tools in the matter. Aim: To identify the evaluation tools that exist to assess the functionality in AVDI, what items are considered, scoring methodology (rank, score, categorization of results), time and in which contexts they are applied, assessment creators and psychometric properties. Design: Systematic review. Data sources: PubMed, BIREME and Epistemonikos. Three searches were carried out: two in 2018 (March and September) and one in 2020 (December). Study selection: Observational studies (cohort studies and cross-sectional studies) and Systematic Reviews that contemplated the assessment of IADL in people over 18 years of age, in English or Spanish, published since 1998 and open access. Data extraction: Titles and abstracts were read as a first filter, followed by the full text. Once the studies that met the inclusion criteria had been selected, the "Strengthening The Reporting of Observational studies in Epidemiology (STROBE)" and "Critical Appraisal Skills Programme Spanish (CASPe)" guideline was applied to assess methodological quality. It was established, through a consensus of the researchers, that each selected study had to comply with at least 13 of the 22 items of STROBE guideline. Results: Of the 27.606 articles found, 15 met the inclusion criteria and the established cut-off point of the guideline. One article was written in Spanish and 14 in English, which were carried out mainly in the United States and Spain (3 out of 15 respectively). Of the 20 instruments found in the selected articles, 60% correspond to "Lawton & Brody Scale", 10% to "The Performance Assessment of Self-Care Skills (PASS)" and the remaining percentage other tools. Conclusions: At an international level, new IADL assessment tools have been created in response to local needs, making it difficult to generalize to other contexts without previously having a cross-cultural and statistical validation process that safeguards the reliability of its application and data. The "Lawton s Brody Scale", despite its limitations and biases, remains an international gold standard.

Surgical Outcome in Extratemporal Epilepsies Based on Multimodal Pre-Surgical Evaluation and Sequential Intraoperative Electrocorticography.

OBJECTIVE: to present the postsurgical outcome of extratemporal epilepsy (ExTLE) patients submitted to preoperative multimodal evaluation and intraoperative sequential electrocorticography (ECoG). SUBJECTS AND METHODS: thirty-four pharmaco-resistant patients with lesional and non-lesional ExTLE underwent comprehensive pre-surgical evaluation including multimodal neuroimaging such as ictal and interictal perfusion single photon emission computed tomography (SPECT) scans, subtraction of ictal and interictal SPECT co-registered with magnetic resonance imaging (SISCOM) and electroencephalography (EEG) source imaging (ESI) of ictal epileptic activity. Surgical procedures were tailored by sequential intraoperative ECoG, and absolute spike frequency (ASF) was calculated in the pre- and post-resection ECoG. Postoperative clinical outcome assessment for each patient was carried out one year after surgery using Engel scores. RESULTS: frontal and occipital resection were the most common surgical techniques applied. In addition, surgical resection encroaching upon eloquent cortex was accomplished in 41% of the ExTLE patients. Pre-surgical magnetic resonance imaging (MRI) did not indicate a distinct lesion in 47% of the cases. In the latter number of subjects, SISCOM and ESI of ictal epileptic activity made it possible to estimate the epileptogenic zone. After one- year follow up, 55.8% of the patients was categorized as Engel class I-II. In this study, there was no difference in the clinical outcome between lesional and non lesional ExTLE patients. About 43.7% of patients without lesion were also seizure- free, p = 0.15 (Fischer exact test). Patients with satisfactory seizure outcome showed lower absolute spike frequency in the pre-resection intraoperative ECoG than those with unsatisfactory seizure outcome, (Mann- Whitney U test, p = 0.005). CONCLUSIONS: this study has shown that multimodal pre-surgical evaluation based, particularly, on data from SISCOM and ESI alongside sequential intraoperative ECoG, allow seizure control to be achieved in patients with pharmacoresistant ExTLE epilepsy.

Efectos de las Técnicas Manuales Orofaciales en la Disminución del Dolor Cervical. Una Revisión Bibliográfica / Effects of Orofacial Manual Techniques in the Reduction of Cervical Pain. A Bibliographic Review

Introducción: La prevalencia anual de dolor cervical oscila entre un 16,7% y un 75,1%, durando alrededor de 6 meses o más en el 14% de los casos, desencadenando en restricción del movimiento y dolor principalmente. Esto podría deberse a la relación entre la cabeza, columna cervical y estructuras relacionadas a la articulación temporomandibular (ATM). El objetivo de esta investigación es describir a través de la evidencia científica el efecto de las técnicas manuales orales en la disminución del dolor cervical. Métodos: Se incluyeron ensayos clínicos aleatorizados y revisiones sistemáticas encontrados en las bases de datos PubMed, Cochrane y PEDro. Realizando la extracción de datos a través de una tabla estructurada para cada tipo de estudio. Resultados: De 10 estudios seleccionados, 3 corresponden a revisiones sistemáticas y 7 a ensayos clínicos, donde la disminución del dolor cervical fue significativa al aplicar la terapia manual con ejercicios por sobre la terapia manual por sí sola. Por otro lado, las técnicas orofaciales fueron beneficiosas al combinarlas con terapia manual en comparación con un tratamiento habitual. No se encontraron diferencias significativas al aplicar ejercicios de Maitland y movilizaciones en comparación con ejercicios de flexibilidad, fortalecimiento, ejercicios de Mulligan y movilizaciones. Conclusión: Los resultados son debatibles, ya que la terapia manual por sí sola o combinada con ejercicios es la técnica más efectiva no solo en la disminución del dolor cervical, también en la mejoría de la calidad de vida.

Introduction: The annual prevalence of cervical pain ranges from 16.7% to 75.1%, lasting about 6 months or more in 14% of cases, triggering mainly movement restriction and pain. This could be due to the relationship between the head, cervical spine and structures related to the temporomandibular joint (TMJ). The objective of this research is to describe through scientific evidence the effect of oral techniques in reducing cervical pain. Methods: Randomized clinical trials and systematic reviews found in the PubMed, Cochrane and PEDro databases were included. Data extraction was done through a structured table for each type of study. Results: Out of 10 selected studies, 3 correspond to systematic reviews and 7 to clinical trials, where the decrease in neck pain was significant when applying manual therapy with exercises over manual therapy alone. On the other hand, orofacial techniques were beneficial when combined with manual therapy compared to an usual treatment. No significant differences were found when applying Maitland exercises and mobilizations compared to flexibility, strengthening, Mulligan exercises, and mobilizations (p<0.05). Conclusion: The results are debatable, as manual therapy alone or combined with exercises is the most effective technique not only in reducing neck pain, but also in improving quality of life.

Motor Coordination Disorders Evaluated through the Grid Test and Changes in the Nigral Nrf2 mRNA Expression in Rats with Pedunculopontine Lesion.

Neurotoxic lesion of the pedunculopontine nucleus (PPN) is known to cause subtle motor dysfunctions. However, motor coordination during advance on a discontinuous and elevated surface has not been studied. It is also not known whether there are changes in the mRNA expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in nigral tissue. METHODS: The effects of the unilateral neurotoxic lesion of the PPN in motor coordination evaluated through grid test and Nrf2 mRNA expression in nigral tissue were evaluated. Two experimental designs (ED) were organized: ED#1 behavioral study (7 and 30 days after PPN lesion) and ED#2 molecular biology study (24 h, 48 h and 7 days) after PPN lesion. RESULTS: ED#1-The number of faults made with left limbs, were significant higher in the lesioned groups (p < 0.01) both 7 and 30 days post-lesion. The number of failures made by the right limbs, was also significantly higher (p < 0.05) vs. control groups. ED#2-Nrf2 mRNA expression showed an increase 24 h after PPN injury (p < 0.01), followed by a peak of expression 48 h post injury (p < 0.001). CONCLUSIONS: Disorders of motor coordination associated with PPN injury are bilateral. The increased Nrf2 mRNA expression could represent an adaptive response to oxidative stress in the nigral tissue following pontine injury.

New Aspects of VEGF, GABA, and Glutamate Signaling in the Neocortex of Human Temporal Lobe Pharmacoresistant Epilepsy Revealed by RT-qPCR Arrays.

In the epilepsy spectrum, temporal lobe epilepsy (TLE) is the most common and devastating focal and symptomatic epilepsy form in adults, where more than 30% of patients develop pharmacoresistance. It is not fully understood how the gene expression contributes to establishing an epileptic phenotype. Cerebrovascular remodeling directed by VEGF (vascular endothelial growth factor) signaling might modulate the synaptic neurotransmission in the epileptic brain. To address this question, the gene expression was profiled in biopsies of the temporal cortex from diagnosed patients with pharmacoresistant TLE that underwent surgical resection to seizure control. One hundred sixty-eight genes related to VEGF signaling and GABA and glutamate neurotransmissions were evaluated. Genes related to downstream signaling -phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPK), and Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) pathways- and neurotransmitters metabolism were evaluated too. Thirty-nine genes were upregulated. The genes encoding for G protein q polypeptide, serine racemase, gephyrin, and glutamate/cystine antiporter system xCT appeared as novel upregulated genes in the pharmacoresistant TLE. ClueGO, a Cytoscape plugin, was used to build a gene network associated using Gene Ontology (GO) terminology. Enrichment analysis by ClueGO retrieves that positive regulation of endothelial cell proliferation, nerve development, and neuronal apoptosis were over-represented categories. In conclusion, VEGF signaling is confirmed as a relevant mediator in the pharmacoresistant TLE. In addition, the enrichment analysis applied to differentially expressed genes suggests new pharmacological targets to be assessed in the treatment of pharmacoresistant TLE. Results make up an approximation to better understand the epileptic brain and complement the available data.

Relation of Structural and Functional Changes in Auditory and Visual Pathways after Temporal Lobe Epilepsy Surgery.

Auditory and visual pathways may be affected as a consequence of temporal lobe epilepsy surgery because of their anatomical relationships with this structure. The purpose of this paper is to correlate the results of the auditory and visual evoked responses with the parameters of tractography of the visual pathway, and with the state of connectivity between respective thalamic nuclei and primary cortices in both systems after the surgical resection of the epileptogenic zone in drug-resistant epileptic patients. Tractography of visual pathway and anatomical connectivity of auditory and visual thalamus-cortical radiations were evaluated in a sample of eight patients. In general, there was a positive relationship of middle latency response (MLR) latency and length of resection, while a negative correlation was found between MLR latency and the anatomical connection strength and anatomical connection probability of the auditory radiations. In the visual pathway, significant differences between sides were found with respect to the number and length of tracts, which was lower in the operated one. Anatomical connectivity variables and perimetry (visual field defect index) were particularly correlated with the latency of P100 wave which was obtained by quadrant stimulation. These results demonstrate an indirect functional modification of the auditory pathway and a direct traumatic lesion of the visual pathway after anterior temporal lobectomy in patients with drug resistant epilepsy.

Oxidative Stress in Patients with Drug Resistant Partial Complex Seizure.

Oxidative stress (OS) has been implicated as a pathophysiological mechanism of drug-resistant epilepsy, but little is known about the relationship between OS markers and clinical parameters, such as the number of drugs, age onset of seizure and frequency of seizures per month. The current study’s aim was to evaluate several oxidative stress markers and antioxidants in 18 drug-resistant partial complex seizure (DRPCS) patients compared to a control group (age and sex matched), and the results were related to clinical variables. We examined malondialdehyde (MDA), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), nitric oxide (NO), uric acid, superoxide dismutase (SOD), glutathione, vitamin C, 4-hydroxy-2-nonenal (4-HNE) and nitrotyrosine (3-NT). All markers except 4-HNE and 3-NT were studied by spectrophotometry. The expressions of 4-HNE and 3-NT were evaluated by Western blot analysis. MDA levels in patients were significantly increased (p ≤ 0.0001) while AOPP levels were similar to the control group. AGEs, NO and uric acid concentrations were significantly decreased (p ≤ 0.004, p ≤ 0.005, p ≤ 0.0001, respectively). Expressions of 3-NT and 4-HNE were increased (p ≤ 0.005) similarly to SOD activity (p = 0.0001), whereas vitamin C was considerably diminished (p = 0.0001). Glutathione levels were similar to the control group. There was a positive correlation between NO and MDA with the number of drugs. The expression of 3-NT was positively related with the frequency of seizures per month. There was a negative relationship between MDA and age at onset of seizures, as well as vitamin C with seizure frequency/month. We detected an imbalance in the redox state in patients with DRCPS, supporting oxidative stress as a relevant mechanism in this pathology. Thus, it is apparent that some oxidant and antioxidant parameters are closely linked with clinical variables.

Long-Term Electroclinical and Employment Follow up in Temporal Lobe Epilepsy Surgery. A Cuban Comprehensive Epilepsy Surgery Program.

The purpose of this paper is to present a long- term electroclinical and employment follow up in temporal lobe epilepsy (TLE) patients in a comprehensive epilepsy surgery program. Forty adult patients with pharmacoresistant TLE underwent detailed presurgical evaluation. Electroencephalogram (EEG) and clinical follow up assessment for each patient were carried out. The occurrence of interictal epileptiform activity (IEA) and absolute spike frequency (ASF) were tabulated before and after 1, 6, 12, 24 and 72 months surgical treatment. Employment status pre- to post-surgery at the last evaluated period was also examined. Engel scores follow-up was described as follows: at 12 months 70% (28) class I, 10% (4) class II and 19% (8) class III-IV; at 24 months after surgery 55.2% (21) of the patients were class I, 28.9% (11) class II and 15.1% (6) class III-IV. After one- year follow up 23 (57.7%) patients were seizure and aura-free (Engel class IA). These figures changed to 47.3%, and 48.6% respectively two and five years following surgery whereas 50% maintained this condition in the last follow up period. A decline in the ASF was observed from the first year until the sixth year after surgery in relation to the preoperative EEG. The ASF one year after surgery allowed to distinguish "satisfactory" from "unsatisfactory" seizure relief outcome at the last follow up. An adequate social functioning in terms of education and employment in more than 50% of the patients was also found. Results revealed the feasibility of conducting a successful epilepsy surgery program with favorable long term electroclinical and psychosocial functioning outcomes in a developing country as well.

Tyrosine Hydroxylase, Vesicular Monoamine Transporter and Dopamine Transporter mRNA Expression in Nigrostriatal Tissue of Rats with Pedunculopontine Neurotoxic Lesion.

BACKGROUND: The degeneration of the pedunculopontine nucleus (PPN) precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson's disease (PD). Although the literature recognizes that a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function. METHODS: In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA-lesioned rats and Sham-operated rats. RESULTS: Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (p < 0.05); in contrast, VMAT2 mRNA expression showed a significant decrease (p < 0.01). DAT mRNA expression showed a significant decrease (p < 0.001) in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury. CONCLUSIONS: Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells.

Follow-Up of Peripheral IL-1ß and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery.

Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1ß and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1ß and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation.

Motor dysfunction and alterations in glutathione concentration, cholinesterase activity, and BDNF expression in substantia nigra pars compacta in rats with pedunculopontine lesion.

Pedunculopontine nucleus (PPN) has been considered a critically important region in the regulation of some of the physiological functions that fail during the progression of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN [through the injection of N-methyl-d-aspartate (NMDA) solution (concentration: 0.1M; volume: 0.5µL)] in motor execution and gait disorders and the changes in cellular and molecular indicators in rat nigral tissue were evaluated. The motor execution was assessed using the beam test (BT) and the gait disorders by footprint test. Glutathione (GSH) concentrations, acetyl cholinesterase enzymatic activity (AChE EA), and brain-derived neurotrophic factor (BDNF) mRNA expression in nigral tissue were analyzed. NMDA-lesioned rats showed fine motor dysfunction with a significant increase in the slow (p≤0.01) and fast movement (p≤0.01) time and in path deviation (p≤0.01) on the smaller diameter beams. Moreover, NMDA-lesioned rats exhibited an imprecise path with moments of advances and setbacks, alternating with left and right deviations, suspensions, and inverted positions. Footprint test revealed slight gait disorders, which were manifested by a reduction in the left and right stride lengths, the intra-step distance, and the support area (p≤0.01). Biochemical studies showed that 48h after the PPN neurotoxic injury, the GSH concentrations and BDNF expression were significantly increased (p≤0.01). These variables returned to normal values 7days after the PPN lesion; the AChE EA showed a significant increase at this time. These functional changes in nigral tissue could be a plastic responses associated with early PD.

Hotspots of Community Change: Temporal Dynamics Are Spatially Variable in Understory Plant Composition of a California Oak Woodland.

Community response to external drivers such climate and disturbance can lead to fluctuations in community composition, or to directional change. Temporal dynamics can be influenced by a combination of drivers operating at multiple spatial scales, including external landscape scale drivers, local abiotic conditions, and local species pools. We hypothesized that spatial variation in these factors can create heterogeneity in temporal dynamics within landscapes. We used understory plant species composition from an 11 year dataset from a California oak woodland to compare plots where disturbance was experimentally manipulated with the removal of livestock grazing and a prescribed burn. We quantified three properties of temporal variation: compositional change (reflecting the appearance and disappearance of species), temporal fluctuation, and directional change. Directional change was related most strongly to disturbance type, and was highest at plots where grazing was removed during the study. Temporal fluctuations, compositional change, and directional change were all related to intrinsic abiotic factors, suggesting that some locations are more responsive to external drivers than others. Temporal fluctuations and compositional change were linked to local functional composition, indicating that environmental filters can create subsets of the local species pool that do not respond in the same way to external drivers. Temporal dynamics are often assumed to be relatively static at the landscape scale, provided disturbance and climate are continuous. This study shows that local and landscape scale factors jointly influence temporal dynamics creating hotspots that are particularly responsive to climate and disturbance. Thus, adequate predictions of response to disturbance or to changing climate will only be achieved by considering how factors at multiple spatial scales influence community resilience and recovery.

Multimodal imaging in nonlesional medically intractable focal epilepsy.

Identification and localization of epileptogenic zone (EZ) is vital in patients with medically-intractable focal epilepsy, who may be candidates for potentially curative resective epilepsy surgery. Presence of a lesion on magnetic resonance imaging (MRI) influences both diagnostic classification and selection for surgery. However, the implications for MRI-negative cases are not well-defined for such patients. Most of these patients undergo invasive long-term Electroencephalography recordings before a final decision regarding resection is possible. Recent developments in structural and functional neuroimaging which include quali-quantitative MRI, Positron Emission Tomography, Single Photon Emission Computed Tomography, and functional MRI have significantly changed presurgical epilepsy evaluation. Source analysis based on electrophysiological information, using either EEG or magnetoencephalography are also promising in order to noninvasively localize the EZ and to guide surgery in medically-intractable focal epilepsy patients that exhibit nonlesional MRI. This chapter aims to review the value of the combined use of structural and functional imaging techniques, and how this multimodal approach improves both selection of surgical candidates and post-operative outcomes in medically-intractable nonlesional focal epilepsy.

Temporal lobe epilepsy surgery modulates the activity of auditory pathway.

The purpose of this paper is to evaluate the effects of the anterior temporal lobectomy on the functional state of the auditory pathway in a group of drug-resistant epileptic patients, linking the electrophysiological results to the resection magnitude. Twenty-seven patients with temporal lobe epilepsy and a matched control group were studied. Auditory brainstem and middle latency responses (ABR and MLR respectively) were carried out before and after 6, 12 and 24 months surgical treatment. The volume and longitude of temporo-mesial resected structures were estimated on magnetic resonance images taken 6 months after surgery. Before the intervention the patients showed a significant delay of latency in waves III, V, Pa and Nb, with an increase in duration of I-V interval in comparison with healthy subjects (Mann-Whitney U-test, p<0.05). After resection, additional significant differences in waves I and Na latency were observed. Na and Pa waveforms showed a tendency to increase in amplitude, which became statistically significant 12 months after surgery for right hemisphere lobectomized patients in the midline electrode, and in Pa waveform for all patients in the temporal electrodes ipsilateral to resection (Wilcoxon test, p<0.05). In general, latency variations of MLR correlated with resection longitude, while changes in amplitude correlated with the volume of the resection in the middle temporal pole and amygdala (Pearson' correlation test, p<0.05). As a result, we assume that anterior temporal lobectomy provokes functional modifications into the auditory pathway, probably related to an indirect modulation of its activity by the temporo-mesial removed structures.

Determining the effects of cattle grazing treatments on Yosemite toads (Anaxyrus [=Bufo] canorus) in montane meadows.

Amphibians are experiencing a precipitous global decline, and population stability on public lands with multiple uses is a key concern for managers. In the Sierra Nevada Mountains (California, USA), managers have specifically identified livestock grazing as an activity that may negatively affect Yosemite toads due to the potential overlap of grazing with toad habitat. Grazing exclusion from Yosemite toad breeding and rearing areas and/or entire meadows have been proposed as possible management actions to alleviate the possible impact of cattle on this species. The primary objective of this study was to determine if different fencing treatments affect Yosemite toad populations. We specifically examined the effect of three fencing treatments on Yosemite toad breeding pool occupancy, tadpoles, and young of the year (YOY). Our hypothesis was that over the course of treatment implementation (2006 through 2010), Yosemite toad breeding pool occupancy and early life stage densities would increase within two fencing treatments relative to actively grazed meadows due to beneficial changes to habitat quality in the absence of grazing. Our results did not support our hypothesis, and showed no benefit to Yosemite toad presence or early life stages in fenced or partially fenced meadows compared to standard USDA Forest Service grazing levels. We found substantial Yosemite toad variation by both meadow and year. This variation was influenced by meadow wetness, with water table depth significant in both the tadpole and YOY models.

Elementos teóricos sobre la enfermería basada en evidencias y su relación con el proceso de atención de Enfermería / Approaching to Evidence-Based Nursing theoretical aspects and its relation to the nursing process

Resumen:

Los antecedentes de investigación en enfermería están enmarcados a mediados del siglo XIX, cuando surge la figura de Florence Nightingale. Posteriormente, la profesión enfermera se ha caracterizado por el desarrollo de teorías que han aportado conocimiento empírico. Partiendo del principio que desde la teoría se generan los cimientos científicos para ejercer la práctica profesional y que la práctica es el marco en que las teorías son verificadas y validadas, surge el concepto de enfermería basada en evidencias (EBE), que en la actualidad ha evolucionado como una importante herramienta para la toma decisiones. El presente artículo ofrece un acercamiento a aspectos teóricos de la EBE y su relación con el proceso enfermero, a través de la revisión bibliográfica del tema.

Inflammatory mediators in epilepsy.

All common contributing factors to epilepsy such as trauma, malignancies and infections are accompanied by different levels of central nervous system inflammation that in turn have been associated with the occurrence of seizure. Emerging data from human brain tissue and experimental models of epilepsy support the proposed involvement of inflammation in epilepsy. Key mediators of this process include, among others: interleukin (IL) -1ß, IL-6, tumor necrosis factor-α, adhesion molecules and component of complement. Recent advances suggest the involvement of specific inflammatory pathways in the pathogenesis of seizures in patients with pharmacoresistant temporal lobe epilepsy, highlighting the potential for new therapeutic strategies. This review provides an overview of the current knowledge on the relationship between inflammatory mediators and epilepsy. We also describe experimental and clinical evidence of inflammation in epilepsy with special emphasis on clinical aspects once the epileptogenic focus has been resected. Further insight into the complex role of inflammation in epileptogenesis may provide new treatment options.