Conselho Nacional de Desenvolvimento Científico e Tecnológico / A diminuição do aporte de oxigênio e nutrientes na vida perinatal resulta em danos, como astrogliose, morte de neurônios e de células proliferativas. Déficits cognitivos podem estar relacionados a danos no hipocampo. Neste trabalho avaliamos a citoarquitetura do giro dentado (DG) durante o desenvolvimento e a memória de ratos submetidos à HI. Para tal, utilizamos a técnica de imunohistoquímica para marcador de proliferação celular (KI67), neurônio jovem (DCX), de astrócitos (GFAP) e de óxido nítrico sintase neuronal (NOSn). Para avaliar a memória de curta e de longa duração foi utilizado o teste de reconhecimento de objetos (RO). Ratas Wistar grávidas em E18 foram anestesiadas (tribromoetanol) e as quatro artérias uterinas foram ocluídas com grampos de aneurisma (Grupo HI). Após 45 minutos, os grampos foram removidos e foi feita a sutura por planos anatômicos. Os animais do grupo controle (SHAM) sofreram o mesmo procedimento, excetuando a oclusão das artérias. Os animais nasceram a termo. Animais com idades de 7 a 90 dias pós-natal (P7 a P90), foram anestesiados e perfundido-fixados com paraformaldeído a 4%, e os encéfalos submetidos ao processamento histológico. Cortes coronais do hipocampo (20m) foram submetidos à imunohistoquímica para KI67, DCX, GFAP e NOSn. Animais P90 foram submetidos ao RO. Os procedimentos foram aprovados pelo comitê de ética (CEA/019/2010). Observamos menor imunomarcação para KI67 no giro dentado de animais HI em P7. Para a marcação de DCX nesta idade não foi observada diferença entre os grupos. Animais HI em P15, P20 e P45 tiveram menor imunomarcação para DCX e Ki67 na camada granular. Animais P90 de ambos os grupos não apresentaram marcação para KI67 e DCX. Vimos aumento da imunomarcação para GFAP nos animais HI em todas as idades. A imunomarcação para NOSn nos animais HI foi menor em todas as idades. O maior número de células NOSn positivas foi visto em animais P7 em ambos os grupos na camada polimórfica. Em P15, animais HI apresentam células NOSn+ em todo o DG. Em P30 animais HI apresentam células NOSn+ nas camadas polimórfica e sub-granular. Animais adultos (P90) de ambos os grupos apresentam células NOSn positivas apenas nas camadas granular e sub-granular. Embora animais HI P90 não apresentaram déficits de memória, estes apresentaram menor tempo de exploração do objeto. Comportamento correspondente a déficits de atenção em humanos. Nossos resultados sugerem que HI perinatal diminui a população de células proliferativas, de neurônios jovens, de neurônios NOSn+, além de causar astrogliose e possivelmente déficits de atenção. O modelo demonstrou ser útil para a compreensão dos mecanismos celulares das lesões hipóxico-isquêmicas e pode ser usado para testar estratégias terapêuticas. / The supply of oxygen and nutrients decreasing in perinatal life may results in CNS damage such as deficits in memory and attention and increased susceptibility to epileptic disorders in adulthood. Perinatal hypoxia-ischemia ( HI ) results in astrogliosis in white matter and loss of cortical neurons (Robinson et al, 2005). Cognitive deficits may be related to hippocampal damage. In this study we evaluate the cytoarchitecture of the dentate gyrus (DG) during development and memory in rats submeted to HI. We used the immunohistochemistry marker of cell proliferation (Ki67), young neuron (DCX), astrocytes (GFAP) and neuronal nitric oxide synthase (nNOS). To evaluate the short-memory and long-lasting the recognition of objects (RO) test was used. Pregnant Wistar rats on E18 were anesthetized (tribromoethanol) and the four uterine arteries were occluded with aneurysm clips (Group HI). After 45 minutes, the clips were removed and the incision was sutured to the anatomical planes. The control group (SHAM) underwent the same procedure, except the occlusion of arteries. The animals were born at term. Animals aged 7 to 90 days postnatal (P7 to P90) were anesthetized and perfused-fixed with 4% paraformaldehyde, and their brains were subjected to histological processing. Coronal sections of the hippocampus (20μm) were subjected to immunohistochemistry for Ki67, DCX, GFAP and nNOS. Animals were subjected to RO P90. The procedures were approved by the ethics committee ( CEA/019/2010 ). We observed lower Ki67 immunostaining in the dentate gyrus of animals HI at P7. For marking DCX at this age is no difference between the groups was observed. HI animals at P15, P20 and P45 had less immunostaining for DCX and Ki67 in the granular layer. Animals P90 in both groups showed no labeling for Ki67 and DCX. We have seen an increase in GFAP immunostaining HI in animals at any age. The immunostaining for nNOS in HI animals was lower at all ages. The greater number of positive cells was seen in nNOS P7 animals in both groups in the polymorphic layer. In P15 animals HI nNOS + cells present in the whole DG. In P30 animals HI feature nNOS + cells in the polymorphic layer and sub-granular. Adult animals (P90) of both groups have positive nNOS granular cell layers, and only in the sub-granular. Although HI P90 animals showed no memory deficits, these patients had shorter holding the object. Corresponding to attention deficits in human behavior. Our results suggest that perinatal HI decreases the population of proliferative cells, young neurons, nNOS+ neurons, and astrocytic and possibly cause attention deficits. The model proved to be useful for understanding the cellular mechanisms of hypoxic- ischemic injury and can be used to test therapeutic strategies.

Multiple Sclerosis (MS), an autoimmune disorder marked by inflammation of the central nervous system, is associated with a myriad of symptoms. Individuals with MS are more likely to experience depressive symptoms, perhaps due to perceived cognitive impairments. Thus, we aimed to explore perceived stress and sleep deficits as potential mediators of the association between perceived cognitive deficits and depressive symptoms. We recruited a sample of 77 MS participants from an outpatient, university-based MS clinic in the United States. Participants ranged in age between 30 and 75 years old (M = 51.12; SD = 9.6), with more females than males (83% female; n = 64). Participants completed the Perceived Deficits Questionnaire, the Pittsburgh Sleep Quality Index, the Perceived Stress Scale, and the Center for Epidemiological Studies Depression Scale – Revised. Correlation analyses and mediation analyses were conducted with bootstrapping technique. Statistical analyses revealed that higher levels of perceived cognitive deficits were associated with lower quality of sleep, more perceived stress, and higher levels of depressive symptoms. Additionally, both perceived stress and sleep quality served as a significant mediator in the perceived cognitive impairments and depressive symptoms linkage. Our novel findings demonstrate the importance of underlying mechanisms (e.g., sleep quality and perceived stress) in the conceptualization of MS. Perceived stress and sleep quality are potentially modifiable factors, perhaps serving as a target for future treatment, to buffer risk of MS patients developing depression.

Psychosocial problems are exceedingly common following moderate-to-severe traumatic brain injury (TBI), and are thought to be the major predictor of long-term functional outcome. However, current rehabilitation protocols have shown little success in improving interpersonal and social abilities of individuals with TBI, revealing a critical need for new and more effective treatments. Recent research has shown that neuro-modulatory treatments (e.g., non-invasive brain stimulation, lifestyle interventions) targeting the functionality of specific brain systems—as opposed to focusing on re-teaching individuals with TBI the impaired behaviors— hold the potential to succeed where past behavioral protocols have failed. However, in order to implement such treatments it is crucial to gain a better knowledge of the neural systems underlying social functioning secondary to TBI. It is well established that in TBI populations the inability to identify and interpret social cues, and in particular to engage in successful recognition of facial affects, is one of the factors driving impaired social functioning following TBI. The aims of the work here described were threefold: (1) to determine the degree of impairment in individuals with moderate-to-severe TBI on tasks measuring different sub-types of facial affect recognition skills, (2) to determine the relationship between white matter integrity and different facial affect recognition ability in individuals with TBI by using diffusion tensor imaging, and (3) to determine the patterns of brain activation associated with facial affect recognition ability in individuals with TBI by using task-related functional magnetic resonance imaging (MRI). Our results revealed that individuals with TBI are impaired at both perceptual and verbal categorization facial affect recognition tasks, although they are significantly more impaired in the latter. Moreover, performance on tasks tapping into different types of emotion recognition abilities showed different white-matter neural correlates, with more individuals with TBI showing more extensive damage in the left inferior fronto-occipital fasciculus, uncinate fasciculus and inferior longitudinal fasciculus more likely to perform poorly on verbal categorization tasks. Lastly, our functional MRI study suggests an involvement of left dorsolateral prefrontal regions in the disruption of more perceptual emotion recognition skills, and involvement on the fusiform gyrus and of the ventromedial prefrontal cortex in more interpretative facial affect recognition deficits. The findings here presented further out understanding of the neurobiological mechanisms underlying facial affect impairment following TBI, and have the potential to inform the development of new and more effective treatments.

Autism Spectrum Disorder (ASD) refers to a heterogeneous neurological condition characterized by repetitive and restrictive behaviors and social communication deficits. ASD diagnoses are at a record high, at approximately 1 in 59 children according to the US Center for Disease Control. Currently, there are no available interventions that effectively treat the core symptoms of ASD. All pharmaceutical options address comorbid side effects of ASD but not core deficits and are particularly associated with negative side effects. Additionally, there are economic and geographic barriers that can prevent families of individuals with ASD from seeking or receiving effective interventions. Many of the available interventions are extremely costly, time-consuming, and age dependent. These factors, as well as others, have led to an increase in families independently utilizing complementary and alternative interventions. Due to the large amount of misinformation available on the Internet, families have become more susceptible to trying alternative forms of interventions that have not been scientifically proven as effective, and in some cases, are significantly detrimental. Thus, the need for accessible and inexpensive evidence-based nonpharmaceutical interventions is critical and must be addressed. Fortunately, recent groundbreaking research has discovered two strains of probiotics, Bacteroides fragilis and Lactobacillus reuteri, that have been shown to ameliorate behavioral and social deficits respectively, in validated ASD mouse models in a non-age-dependent manner. Probiotic intervention with a combination of these specific strains would effectively target both repetitive behaviors and social deficits, core ASD symptoms, and provide families with an accessible and inexpensive form of intervention. The mechanisms underlying the efficacy of these probiotics are thought to be associated with the gastrointestinal (GI) system and the oxytocin pathway. This study seeks to examine the necessity of accessible nonpharmaceutical interventions and to provide an effective intervention that is neither expensive or age dependent. This study also aims to provide greater insight into the pathways and systems in which these probiotics operate.

The relationship between feeding development and early speech production has received increasing interest over the past 30 years. If a relationship between the motor control systems for feeding and communication is present, it could have implications for the early identification of communication deficits in children. Theoretical support exists for a relationship between the feeding and speech motor systems based on evolutionary theory (Blanchard, 1963), and anatomical similarities in oral motor function (Morris, 1985, 1990, 1991, 1998). However, the existence of a causal relationship between early feeding and communication development remains uncertain due to a lack of empirical research. A model proposed by Carpendale and Lewis (2004) encompasses the triadic interaction between the environment, maternal factors, and infant factors, which can influence both feeding and communication development. Clinical feeding assessments typically employed by clinicians and researchers are most often carried out with observational checklists. Data reflecting the theoretical foundation, validity, and reliability for these tools are limited. Observation tools assess specific aspects of feeding and oral motor control from a modular perspective, without regard for the infant’s total feeding system. Rogers and Arvedson (2005) highlighted the need for a single standardised assessment tool to assess infant feeding descriptively and objectively. The primary aim of the project was to determine whether the same motor control mechanisms are utilised for oral feeding and communication. The first stage of the study involved the development of a theoretically informed assessment protocols to document systematically the development of feeding skills from birth, the Feeding Assessment Observation (FAO) and the Feeding Assessment Questionnaire (FAQ). / The assessment protocol was piloted on 10 term and 10 preterm infants at 1 to 2 weeks, 4, 8 and 12 months corrected age (CA) for preterm infants and chronological age for term infants. The second stage of the project examined the progression of feeding and communication development in a group of term and preterm infants over a 12 month period. The progression of 8 preterm and 7 term infants was observed at 1-2 weeks, 4, 8 and 12 months CA and chronological age for term infants. The mean gestational age for preterm infants was 30 weeks, 6 days (SD = 6.8 days), and term infants was 39 weeks, 5 days (SD = 9.4 days). Assessment of the infants’ feeding and communication skills, environmental and maternal influences was conducted using the initial questionnaire, Feeding Assessment Observation (FAO), Feeding Assessment Questionnaire (FAQ), Home Screening Questionnaire (HSQ), Receptive Expressive Emergent Language Scale, second edition (REEL-2), and the infant-toddler checklist of the Communication and Symbolic Behavior Scales Developmental Profile (CSBS-DP), to determine the nature and impact of environmental and social factors on feeding and/or communication development. Preliminary reliability testing of the FAO was conducted. Sixty seven percent (10/15) of observation items achieved greater than 90% inter-observer agreement. There was no significant difference in feeding and communication development between term and preterm infants. The negative linear trend for the development of feeding efficiency on liquids for infants was opposed to the positive linear trend for communication development. Infant feeding efficiency on solids showed parallel positive linear developmental trends with communication development. / Comprehensive data were collected on influencing factors from infant, maternal and environmental domains during the initial assessment, and the 4, 8 and 12 month CA developmental reviews. The data revealed significant differences between the term and preterm groups for infant and environmental factors, but no significant differences were found for maternal influences. The study provided some support for the hypothesis of integrative motor control and co-development of feeding and communication. The prediction that infant, maternal, and environmental factors would significantly influence feeding and communication development was not supported. In addition, there was no difference in the impact of influencing factors for the term and preterm groups. The feeding and communication skills of preterm infants developed at corrected age levels, and were not significantly slower than term infants. Furthermore, predicted delays in feeding development were not associated with concomitant delays in communication development for term and preterm infants. Further investigation of the subsequent communication development of infants with definitive feeding difficulties and with a larger sample is suggested.

ABSTRACT In the modern era, the most common post-operative complications following cardiopulmonary bypass (CPB) are neurocognitive deficits (NCD) and atrial fibrillation (AF). Both morbidities have been linked to inflammation resulting from surgery, anesthesia and CPB. Microemboli, inadequate oxygen delivery and the inflammatory response consequent to blood contacting artificial components of the CPB circuit have all been linked to postoperative NCD and to a lesser extent post-operative AF. The artificial components of the CPB circuit consist of stainless steel, polyvinylchloride (PVC), polycarbonate and other carbon-based plastics. In order to attenuate the negative sequelae of blood-circuit contact related inflammatory response, industry developed the biocompatible circuit (BCC) coating for the disposable CPB circuits. Four such coatings were studied and compared to an uncoated control group in a total of 101 patients undergoing routine CPB-assisted cardiac surgical procedures. Soluble adhesion molecule (SAM) activation was studied at different time points and common clinical outcomes such as white blood cell activation, serum renal function parameters urea and creatinine, postoperative bleeding, transfusion requirements, intensive care and hospital length of stay, CPB pump volume balances, changes in weight, postoperative serum lactate and glucose and the development of AF postoperatively, were compared. Additionally, postoperative neurocognitive testing was performed using a simple bedside neurocognitive test called the antisaccadic eye movement test. The patients in all groups were tested for comparison preoperatively and 72 hr postoperatively. Results: The mandate of BCC coating development and manufacture is to attenuate the well-documented and demonstrated inflammatory response consequent to the contact of blood with artificial CPB surfaces. The studied BCCs significantly decreased platelet transfusions in females. In addition, the BCCs decreased the concentrations of 2 SAMs when measured 6 hours after surgery and CPB. The difference in SAM expression seen between the coated and uncoated groups at 6 hr was no longer apparent at 72 hr. Very little difference was noted between the four BCC groups. Patients who developed AF postoperatively seemed predisposed to do so as the serum levels of soluble vascular cell adhesion molecule was significantly higher at baseline and remained so at 6 and 72 hr. The decreased platelet transfusions in females resulting from BCC use is a highly significant finding within this high-risk group of patients. As most platelet transfusions occur soon after the patient is disconnected from CPB, the short-term decrease in SAM activation can be linked to this improved clinical finding. The studied BCC coatings have achieved limited success in their intended mandate to attenuate inflammatory response in terms of improved clinical and laboratory desired outcomes.

Over the past decade, the European Union has been characterized by an explosion of expenditure, insufficient revenue, high deficits and a lack of budget discipline. Financial markets in Europe are currently dealing with enormous government debts, poor government balance sheets and a weakening banking system. The purpose of this paper is to investigate the origins of the current Euro-crisis and specifically identify the extent to which it will affect the nation of Italy going forward. To understand Italy's stance amid the Euro-crisis, we proceed as follows: First, a historical background section will develop the fundamental issues that have developed in Europe over time leading to the current situation. Next, a discussion about Italian economics and politics will identify Italy's central policy issues placed in the context of the Euro-crisis. Subsequently, Italy's issues with tax evasion will be covered illustrating its history and enforcement addendums going forward. The final section of this paper will present a forward-looking prediction about the fate of Italy and the Euro-zone and will include some of the necessary steps toward avoiding an international economic collapse.

Previous research has consistently shown associative deficits in older adults learning and memory (Chalfonte & Johnson 1996; Naveh-Benjamin, 2000; Naveh-Benjamin, Hussain, & Bar-On 2003) that are related to decreases in hippocampal function (Driscoll et al., 2003; Mitchell, Johnson, Raye, & D’Esposito, 2000). However, older adults learn certain simple predictive relationships between events (Mutter & Williams, 2004) that involve basal ganglia dependent error-driven learning. The goal of the current study was to determine whether error-driven learning could reduce the age-related associative deficits that are associated with hippocampal decline. The results did not support the idea that error-driven learning enhanced older adults’ associative memory, although our study supported normal error-driven processing in older adults. Our study confirms prior findings showing that age differences in associative memory are greater following an error-driven learning task than following an observation learning task (Schmitt-Eliassen, Ferstl, Wiesner, Deuschl, & Witt, 2007; Shohamy et al., 2004). Therefore, the results of the study did not support enhanced associative memory for older adults due to errordriven processing.

This dissertation is based on results from an intervention study targeting working memory training. A group of 46 boys and 11 girls (aged 10.7) that were attending special units in 16 regular schools participated in the study. The treatment group (n = 42) trained at school every day for 30-40 minutes with an interactive computer program (Cogmed training) for five weeks. The performances of the treatment group on reading related measures and basic number skills are compared to those of a group of students (n =15) that were attending similar special units and received only ordinary special educational instruction. Working memory measures and non-verbal problem solving were compared to students (n = 25) in a control group from a previous study. In Study I, it was found that reading comprehension and working memory measures correlated and improved at post-tests (T2, T3) for the treatment group to a larger extent than for the comparison group. In Study II, it was found that working memory measures and basic number skills were highly related. The performance of the boys in the treatment group improved more than that of the boys in the comparison group on basic number test at both post-tests. In Study III, basic skills assessed three years later (T4) are reported. The treatment group achieved higher scores in reading comprehension compared to pre-tests and compared to the control group. The treatment group seems to have gained from the cognitive training of working memory with the computer assisted program directly after training, after seven months and at the three year follow-up. The gains were observed on visuo-spatial working memory measure (T2, T3), reading comprehension and on basic number skills in boys (T2, T3, T4). The possible mechanisms that may be involved in and may explain the observed improvements of performances are discussed: executive function, attention, memory, motivation, emotions. The study has some methodological limitations and more research is needed to substantiate the efficacy of the program. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Submitted.</p>

ABSTRACT In the modern era, the most common post-operative complications following cardiopulmonary bypass (CPB) are neurocognitive deficits (NCD) and atrial fibrillation (AF). Both morbidities have been linked to inflammation resulting from surgery, anesthesia and CPB. Microemboli, inadequate oxygen delivery and the inflammatory response consequent to blood contacting artificial components of the CPB circuit have all been linked to postoperative NCD and to a lesser extent post-operative AF. The artificial components of the CPB circuit consist of stainless steel, polyvinylchloride (PVC), polycarbonate and other carbon-based plastics. In order to attenuate the negative sequelae of blood-circuit contact related inflammatory response, industry developed the biocompatible circuit (BCC) coating for the disposable CPB circuits. Four such coatings were studied and compared to an uncoated control group in a total of 101 patients undergoing routine CPB-assisted cardiac surgical procedures. Soluble adhesion molecule (SAM) activation was studied at different time points and common clinical outcomes such as white blood cell activation, serum renal function parameters urea and creatinine, postoperative bleeding, transfusion requirements, intensive care and hospital length of stay, CPB pump volume balances, changes in weight, postoperative serum lactate and glucose and the development of AF postoperatively, were compared. Additionally, postoperative neurocognitive testing was performed using a simple bedside neurocognitive test called the antisaccadic eye movement test. The patients in all groups were tested for comparison preoperatively and 72 hr postoperatively. Results: The mandate of BCC coating development and manufacture is to attenuate the well-documented and demonstrated inflammatory response consequent to the contact of blood with artificial CPB surfaces. The studied BCCs significantly decreased platelet transfusions in females. In addition, the BCCs decreased the concentrations of 2 SAMs when measured 6 hours after surgery and CPB. The difference in SAM expression seen between the coated and uncoated groups at 6 hr was no longer apparent at 72 hr. Very little difference was noted between the four BCC groups. Patients who developed AF postoperatively seemed predisposed to do so as the serum levels of soluble vascular cell adhesion molecule was significantly higher at baseline and remained so at 6 and 72 hr. The decreased platelet transfusions in females resulting from BCC use is a highly significant finding within this high-risk group of patients. As most platelet transfusions occur soon after the patient is disconnected from CPB, the short-term decrease in SAM activation can be linked to this improved clinical finding. The studied BCC coatings have achieved limited success in their intended mandate to attenuate inflammatory response in terms of improved clinical and laboratory desired outcomes.