Mechanisms underlying functional recovery after in vivo focal cerebral ischemia : from preconditioning to diffusion MRI

Version abregée L'ischémie cérébrale est la troisième cause de mort dans les pays développés, et la maladie responsable des plus sérieux handicaps neurologiques. La compréhension des bases moléculaires et anatomiques de la récupération fonctionnelle après l'ischémie cérébrale est donc extrêmement importante et représente un domaine d'intérêt crucial pour la recherche fondamentale et clinique. Durant les deux dernières décennies, les chercheurs ont tenté de combattre les effets nocifs de l'ischémie cérébrale à l'aide de substances exogènes qui, bien que testées avec succès dans le domaine expérimental, ont montré un effet contradictoire dans l'application clinique. Une approche différente mais complémentaire est de stimuler des mécanismes intrinsèques de neuroprotection en utilisant le «modèle de préconditionnement» : une brève insulte protège contre des épisodes d'ischémie plus sévères à travers la stimulation de voies de signalisation endogènes qui augmentent la résistance à l'ischémie. Cette approche peut offrir des éléments importants pour clarifier les mécanismes endogènes de neuroprotection et fournir de nouvelles stratégies pour rendre les neurones et la glie plus résistants à l'attaque ischémique cérébrale. Dans un premier temps, nous avons donc étudié les mécanismes de neuroprotection intrinsèques stimulés par la thrombine, un neuroprotecteur «préconditionnant» dont on a montré, à l'aide de modèles expérimentaux in vitro et in vivo, qu'il réduit la mort neuronale. En appliquant une technique de microchirurgie pour induire une ischémie cérébrale transitoire chez la souris, nous avons montré que la thrombine peut stimuler les voies de signalisation intracellulaire médiées par MAPK et JNK par une approche moléculaire et l'analyse in vivo d'un inhibiteur spécifique de JNK (L JNK) .Nous avons également étudié l'impact de la thrombine sur la récupération fonctionnelle après une attaque et avons pu démontrer que ces mécanismes moléculaires peuvent améliorer la récupération motrice. La deuxième partie de cette étude des mécanismes de récupération après ischémie cérébrale est basée sur l'investigation des bases anatomiques de la plasticité des connections cérébrales, soit dans le modèle animal d'ischémie transitoire, soit chez l'homme. Selon des résultats précédemment publiés par divers groupes ,nous savons que des mécanismes de plasticité aboutissant à des degrés divers de récupération fonctionnelle sont mis enjeu après une lésion ischémique. Le résultat de cette réorganisation est une nouvelle architecture fonctionnelle et structurelle, qui varie individuellement selon l'anatomie de la lésion, l'âge du sujet et la chronicité de la lésion. Le succès de toute intervention thérapeutique dépendra donc de son interaction avec la nouvelle architecture anatomique. Pour cette raison, nous avons appliqué deux techniques de diffusion en résonance magnétique qui permettent de détecter les changements de microstructure cérébrale et de connexions anatomiques suite à une attaque : IRM par tenseur de diffusion (DT-IR1V) et IRM par spectre de diffusion (DSIRM). Grâce à la DT-IRM hautement sophistiquée, nous avons pu effectuer une étude de follow-up à long terme chez des souris ayant subi une ischémie cérébrale transitoire, qui a mis en évidence que les changements microstructurels dans l'infarctus ainsi que la modification des voies anatomiques sont corrélés à la récupération fonctionnelle. De plus, nous avons observé une réorganisation axonale dans des aires où l'on détecte une augmentation d'expression d'une protéine de plasticité exprimée dans le cône de croissance des axones (GAP-43). En appliquant la même technique, nous avons également effectué deux études, rétrospective et prospective, qui ont montré comment des paramètres obtenus avec DT-IRM peuvent monitorer la rapidité de récupération et mettre en évidence un changement structurel dans les voies impliquées dans les manifestations cliniques. Dans la dernière partie de ce travail, nous avons décrit la manière dont la DS-IRM peut être appliquée dans le domaine expérimental et clinique pour étudier la plasticité cérébrale après ischémie. Abstract Ischemic stroke is the third leading cause of death in developed countries and the disease responsible for the most serious long-term neurological disability. Understanding molecular and anatomical basis of stroke recovery is, therefore, extremely important and represents a major field of interest for basic and clinical research. Over the past 2 decades, much attention has focused on counteracting noxious effect of the ischemic insult with exogenous substances (oxygen radical scavengers, AMPA and NMDA receptor antagonists, MMP inhibitors etc) which were successfully tested in the experimental field -but which turned out to have controversial effects in clinical trials. A different but complementary approach to address ischemia pathophysiology and treatment options is to stimulate and investigate intrinsic mechanisms of neuroprotection using the "preconditioning effect": applying a brief insult protects against subsequent prolonged and detrimental ischemic episodes, by up-regulating powerful endogenous pathways that increase resistance to injury. We believe that this approach might offer an important insight into the molecular mechanisms responsible for endogenous neuroprotection. In addition, results from preconditioning model experiment may provide new strategies for making brain cells "naturally" more resistant to ischemic injury and accelerate their rate of functional recovery. In the first part of this work, we investigated down-stream mechanisms of neuroprotection induced by thrombin, a well known neuroprotectant which has been demonstrated to reduce stroke-induced cell death in vitro and in vivo experimental models. Using microsurgery to induce transient brain ischemia in mice, we showed that thrombin can stimulate both MAPK and JNK intracellular pathways through a molecular biology approach and an in vivo analysis of a specific kinase inhibitor (L JNK1). We also studied thrombin's impact on functional recovery demonstrating that these molecular mechanisms could enhance post-stroke motor outcome. The second part of this study is based on investigating the anatomical basis underlying connectivity remodeling, leading to functional improvement after stroke. To do this, we used both a mouse model of experimental ischemia and human subjects with stroke. It is known from previous data published in literature, that the brain adapts to damage in a way that attempts to preserve motor function. The result of this reorganization is a new functional and structural architecture, which will vary from patient to patient depending on the anatomy of the damage, the biological age of the patient and the chronicity of the lesion. The success of any given therapeutic intervention will depend on how well it interacts with this new architecture. For this reason, we applied diffusion magnetic resonance techniques able to detect micro-structural and connectivity changes following an ischemic lesion: diffusion tensor MRI (DT-MRI) and diffusion spectrum MRI (DS-MRI). Using DT-MRI, we performed along-term follow up study of stroke mice which showed how diffusion changes in the stroke region and fiber tract remodeling is correlating with stroke recovery. In addition, axonal reorganization is shown in areas of increased plasticity related protein expression (GAP 43, growth axonal cone related protein). Applying the same technique, we then performed a retrospective and a prospective study in humans demonstrating how specific DTI parameters could help to monitor the speed of recovery and show longitudinal changes in damaged tracts involved in clinical symptoms. Finally, in the last part of this study we showed how DS-MRI could be applied both to experimental and human stroke and which perspectives it can open to further investigate post stroke plasticity.

Chemical attributes of a Hapludox soil after nine years of pig slurry application

The objective of this study was to evaluate the pig slurry application effects on chemical attributes of a Hapludox soil managed under no-tillage system. Treatments consisted of 50, 100 and 200 m³ ha-1 per year of pig slurry application, and a control with replacement of P and K exported through harvested grains. Attributes related to soil chemical reaction, exchange complex, and nutrient contents were determined in soil samples collected in the ninth year of experimentation from 0 - 0.025, 0.025 - 0.05, 0.05 - 0.10, 0.10 - 0.20, 0.20 - 0.40 and 0.40 - 0.60 m soil depths. The continuous application of high doses of pig slurry on the Oxisol surface under no-tillage acidifies the soil and increases Al, P, Cu, and Zn contents down to 0.2-m depth, and K levels down to 0.6-m depth.

Adaptability and stability of white oat cultivars in relation to chemical composition of the caryopsis

The objective of this work was to characterize the chemical properties of white oat (Avena sativa) caryopsis and to determine the adaptability and stability of cultivars recommended for cultivation in the state of Rio Grande do Sul, Brazil. The trials were carried out in the 2007, 2008 and 2009 crop seasons, in three municipalities: Augusto Pestana, Capão do Leão, and Passo Fundo. Fifteen cultivars were evaluated in a randomized block design, with four replicates. The contents of protein, lipid, and nitrogen-free extract were evaluated in the caryopsis. Cultivar performances for the measured characters varied according to location and year of cultivation. The cultivar URS Guapa showed high content of nitrogen-free extract and low contents of protein and lipid in the caryopsis. 'FAPA Louise' showed high content of lipid, whereas 'Albasul', 'UPF 15', and 'UPF 18' showed high content of protein and low content of nitrogen-free extract. There is no evidence of an ideal biotype for the evaluated characters, which could simultaneously show high average performance, adaptability to favorable and unfavorable environments, and stability.

Microbiological and chemical attributes of a Hapludalf soil with swine manure fertilization

The objective of this work was to evaluate the microbiological and chemical attributes of a soil with a seven‑year history of urea and swine manure application. In the period from October 2008 to October 2009, soil samples were collected in the 0-10 cm layer and were subjected to the treatments: control, without application of urea or manure; and with the application of urea, pig slurry, and deep pig litter in two doses, in order to supply one or two times the recommended N doses for the maize (Zea mays)/black oat (Avena strigosa) crop succession. The carbon of the microbial biomass (MB‑C) and the basal respiration (C‑CO2) were analyzed, and the metabolic (qCO2) and microbial quotient (qmic) were calculated with the obtained data. Organic matter, pH in water, available P and K, and exchangeable Ca and Mg were also determined. The application of twice the dose of deep pig litter increases the MB‑C and C‑CO2 values. The qmic and qCO2 are little affected by the application of swine manure. The application of twice the dose of deep pig litter increases the values of pH in water and the contents of available P and of exchangeable Ca and Mg in the soil.

Rapid marine recovery after the end-Permian mass-extinction event in the absence of marine anoxia

A new Early Triassic marine fauna is described from the Central Oman Mountains. The fauna is Griesbachian in age, on the basis of abundant conodonts and ammonoids, and was deposited in an oxygenated seamount setting off the Arabian platform margin. It is the first Griesbachian assemblage from a well-oxygenated marine setting and thus provides a test for the hypothesis that widespread anoxia prevented rapid recovery. The earliest Griesbachian (parvus zone) contains a low-diversity benthic fauna dominated by the bivalves Promyalina and Claraia. A similar level of recovery characterizes the immediate postextinction interval worldwide. However, the middle upper Griesbachian sedimentary rocks (isarcica and catinata zones) contain an incredibly diverse benthic fauna of bivalves, gastropods, articulate brachiopods, a new undescribed crinoid, echinoids, and ostracods. This fauna is more diverse and ecologically complex than the typical middle to late Griesbachian faunas described from oxygen-restricted settings worldwide. The level of postextinction recovery observed in the Oman fauna is not recorded elsewhere until the Spathian. These data support the hypothesis that the apparent delay in recovery after the end-Permian extinction event was due to widespread and prolonged benthic oxygen restriction: in the absence of anoxia, marine recovery is much faster.

Chemical composition and fatty acid contents in farmed freshwater prawns

The objective of this work was to evaluate the chemical composition and fatty acid contents of Amazonian and giant river prawns. After four-month farming, with the same diet for both species, palmitic and stearic acids were the main saturated fatty acids. Oleic acid was the main monounsatured fatty acid, and the eicosapentaenoic and docosahexaenoic acids were the most abundant polyunsaturated acids. Amazonian prawn has higher levels of protein and polyunsaturated fatty acids than those of the giant river prawn, which shows its potential for aquaculture.

Laparoscopy in the era of enhanced recovery.

Laparoscopy is one of the cornerstones in the surgical revolution and transformed outcome and recovery for various surgical procedures. Even if these changes were widely accepted for basic interventions, like appendectomies and cholecystectomies, laparoscopy still remains challenged for more advanced operations in many aspects. Despite these discussion, there is an overwhelming acceptance in the surgical community that laparoscopy did transform the recovery for several abdominal procedures. The importance of improved peri-operative patient management and its influence on outcome started to become a focus of attention 20 years ago and is now increasingly spreading, as shown by the incoming volume of data on this topic. The enhanced recovery after surgery (ERAS) concept incorporates simple measures of general management, and requires multidisciplinary collaboration from hospital staff as well as the patient and the relatives. Several studies have demonstrated a significant decrease in postoperative complication rate, length of hospital stay and reduced overall cost. The key elements of success are fluid restriction, a functioning epidural and preoperative carbohydrate intake. With the expansion of laparoscopic techniques, ERAS increasingly incorporates laparoscopic patients, especially in colorectal surgery. However, the precise impact of laparoscopy on ERAS is still not clearly defined. Increasing evidence suggests that laparoscopy itself is an additional ERAS item that should be considered as routine where feasible in order to obtain the best surgical outcomes.

Chemical and biological attributes of a lowland soil affected by land leveling

The objective of this work was to evaluate the relationship between soil chemical and biological attributes and the magnitude of cuts and fills after the land leveling process of a lowland soil. Soil samples were collected from the 0 - 0.20 m layer, before and after leveling, on a 100 point grid established in the experimental area, to evaluate chemical attributes and soil microbial biomass carbon (MBC). Leveling operations altered the magnitude of soil chemical and biological attributes. Values of Ca, Mg, S, cation exchange capacity, Mn, P, Zn, and soil organic matter (SOM) decreased in the soil profile, whereas Al, K, and MBC increased after leveling. Land leveling decreased in 20% SOM average content in the 0 - 0.20 m layer. The great majority of the chemical attributes did not show relations between their values and the magnitude of cuts and fills. The relation was quadratic for SOM, P, and total N, and was linear for K, showing a positive slope and indicating increase in the magnitude of these attributes in cut areas and stability in fill areas. The relationships between these chemical attributes and the magnitude of cuts and fills indicate that the land leveling map may be a useful tool for degraded soil recuperation through amendments and organic fertilizers.

A performance lower bound for quadratic timing recovery accounting for the symbol transition density

The symbol transition density in a digitally modulated signal affects the performance of practical synchronization schemes designed for timing recovery. This paper focuses on the derivation of simple performance limits for the estimation of the time delay of a noisy linearly modulated signal in the presence of various degrees of symbol correlation produced by the varioustransition densities in the symbol streams. The paper develops high- and low-signal-to-noise ratio (SNR) approximations of the so-called (Gaussian) unconditional Cramér–Rao bound (UCRB),as well as general expressions that are applicable in all ranges of SNR. The derived bounds are valid only for the class of quadratic, non-data-aided (NDA) timing recovery schemes. To illustrate the validity of the derived bounds, they are compared with the actual performance achieved by some well-known quadratic NDA timing recovery schemes. The impact of the symbol transitiondensity on the classical threshold effect present in NDA timing recovery schemes is also analyzed. Previous work on performancebounds for timing recovery from various authors is generalized and unified in this contribution.

Conditional maximum likelihood timing recovery: estimators and bounds

This paper is concerned with the derivation of new estimators and performance bounds for the problem of timing estimation of (linearly) digitally modulated signals. The conditional maximum likelihood (CML) method is adopted, in contrast to the classical low-SNR unconditional ML (UML) formulationthat is systematically applied in the literature for the derivationof non-data-aided (NDA) timing-error-detectors (TEDs). A new CML TED is derived and proved to be self-noise free, in contrast to the conventional low-SNR-UML TED. In addition, the paper provides a derivation of the conditional Cramér–Rao Bound (CRB ), which is higher (less optimistic) than the modified CRB (MCRB)[which is only reached by decision-directed (DD) methods]. It is shown that the CRB is a lower bound on the asymptotic statisticalaccuracy of the set of consistent estimators that are quadratic with respect to the received signal. Although the obtained boundis not general, it applies to most NDA synchronizers proposed in the literature. A closed-form expression of the conditional CRBis obtained, and numerical results confirm that the CML TED attains the new bound for moderate to high Eg/No.

Impulse response recovery of linear systems through weighted cumulant slice

Identifiability of the so-called ω-slice algorithm is proven for ARMA linear systems. Although proofs were developed in the past for the simpler cases of MA and AR models, they were not extendible to general exponential linear systems. The results presented in this paper demonstrate a unique feature of the ω-slice method, which is unbiasedness and consistency when order is overdetermined, regardless of the IIR or FIR nature of the underlying system, and numerical robustness.

Incidence and management of pulmonary embolism following spinal surgery occurring while under chemical thromboprophylaxis.

Patients undergoing spinal surgery are at risk of developing thromboembolic complications even though lower incidences have been reported as compared to joint arthroplasty surgery. Deep vein thrombosis (DVT) has been studied extensively in the context of spinal surgery but symptomatic pulmonary embolism (PE) has engaged less attention. We prospectively followed a consecutive cohort of 270 patients undergoing spinal surgery at a single institution. From these patients, only 26 were simple discectomies, while the largest proportion (226) was fusions. All patients received both low molecular weight heparin (LMWH) initiated after surgery and compressive stockings. PE was diagnosed with spiral chest CT. Six patients developed symptomatic PE, five during their hospital stay. In three of the six patients the embolic event occurred during the first 3 postoperative days. They were managed by the temporary insertion of an inferior vena cava (IVC) filter thus allowing for a delay in full-dose anticoagulation until removal of the filter. None of the PE patients suffered any bleeding complication as a result of the introduction of full anticoagulation. Two patients suffered postoperative haematomas, without development of neurological symptoms or signs, requiring emergency evacuation. The overall incidence of PE was 2.2% rising to 2.5% after exclusion of microdiscectomy cases. The incidence of PE was highest in anterior or combined thoracolumbar/lumbar procedures (4.2%). There is a large variation in the reported incidence of PE in the spinal literature. Results from the only study found in the literature specifically monitoring PE suggest an incidence of PE as high as 2.5%. Our study shows a similar incidence despite the use of LMWH. In the absence of randomized controlled trials (RCT) it is uncertain if this type of prophylaxis lowers the incidence of PE. However, other studies show that the morbidity of LMWH is very low. Since PE can be a life-threatening complication, LMWH may be a worthwhile option to consider for prophylaxis. RCTs are necessary in assessing the efficacy of DVT and PE prophylaxis in spinal patients.

Chemical characteristics of grape juices from different cultivar and rootstock combinations

The objective of this work was to evaluate the influence of different combinations of grape cultivars and rootstocks on chemical characteristics of grape juices. Six treatments were evaluated, consisting of combinations between the Isabel Precoce and BRS Cora grape cultivars and the 'IAC 766', 'IAC 313', and 'IAC 572' rootstocks. Approximately 10 L of juice were obtained per treatment. Analyses of color, total soluble solids content, pH, anthocyanins, total phenolics, total sugars, and quantification and identification of biogenic amines by HPLC were performed. Biogenic amines, such as putrescine, cadaverine, spermidine, and spermine, were found in all evaluated cultivars. By principal component analysis (PCA), treatments can be divided into two groups, according to the cultivar. Juices obtained from 'Isabel Precoce' are characterized by higher levels of total sugar content and soluble solids; however, juices from 'BRS Cora' are positively correlated with phenolic content, anthocyanins, and color and acidity parameters. The differences found by PCA for juices from the Isabel Precoce and BRS Cora cultivars indicate that, regardless of the rootstock used, the most important factor in the chemical characterization of juices is the grape cultivar.