Impact Of Pregabalin Treatment On Synaptic Plasticity And Glial Reactivity During The Course Of Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for studying MS is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins from myelin. The present study investigated the evolution of EAE in pregabalin treated animals up to the remission phase. The results demonstrated a delay in the onset of the disease with statistical differences at the 10th and the 16th day after immunization. Additionally, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of putative synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and the glial reaction was downregulated during the course of the disease. qRT-PCR data did not show immunomodulatory effects of pregabalin, indicating that the positive effects were restricted to the CNS environment. Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction.

Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice

Background: Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrP(sc)) of the natural cellular prion protein (PrP(c)) encoded by the Prnp gene. Although several roles have been attributed to PrP(c), its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrP(c) studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Principal Findings: Here we explore the role of PrP(c) expression in neurotransmission and neural excitability using wild-type, Prnp -/- and PrP(c)-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp -/- mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp -/- and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABA(A) and AMPA-kainate receptors are co-regulated in both Prnp -/- and Tg20 mice. Conclusions/Significance: Present results demonstrate that PrP(c) is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABA(A) and AMPA-Kainate neurotransmission. New PrP(c) functions have recently been described, which point to PrP(c) as a target for putative therapies in Alzheimer's disease. However, our results indicate that a "gain of function" strategy in Alzheimer's disease, or a "loss of function" in prionopathies, may impair PrP(c) function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.

Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice

Background: Prionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrP(sc)) of the natural cellular prion protein (PrP(c)) encoded by the Prnp gene. Although several roles have been attributed to PrP(c), its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrP(c) studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation. Principal Findings: Here we explore the role of PrP(c) expression in neurotransmission and neural excitability using wild-type, Prnp -/- and PrP(c)-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp -/- mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp -/- and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABA(A) and AMPA-kainate receptors are co-regulated in both Prnp -/- and Tg20 mice. Conclusions/Significance: Present results demonstrate that PrP(c) is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABA(A) and AMPA-Kainate neurotransmission. New PrP(c) functions have recently been described, which point to PrP(c) as a target for putative therapies in Alzheimer's disease. However, our results indicate that a "gain of function" strategy in Alzheimer's disease, or a "loss of function" in prionopathies, may impair PrP(c) function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.

Synaptic plasticity and sensory-motor improvennent following fibrin sealant dorsal root reimplantation and mononuclear cell therapy

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Reconfiguration of distribution networks to minimize loss and disruption costs using genetic algorithms

In this paper a computational implementation of an evolutionary algorithm (EA) is shown in order to tackle the problem of reconfiguring radial distribution systems. The developed module considers power quality indices such as long duration interruptions and customer process disruptions due to voltage sags, by using the Monte Carlo simulation method. Power quality costs are modeled into the mathematical problem formulation, which are added to the cost of network losses. As for the EA codification proposed, a decimal representation is used. The EA operators, namely selection, recombination and mutation, which are considered for the reconfiguration algorithm, are herein analyzed. A number of selection procedures are analyzed, namely tournament, elitism and a mixed technique using both elitism and tournament. The recombination operator was developed by considering a chromosome structure representation that maps the network branches and system radiality, and another structure that takes into account the network topology and feasibility of network operation to exchange genetic material. The topologies regarding the initial population are randomly produced so as radial configurations are produced through the Prim and Kruskal algorithms that rapidly build minimum spanning trees. (C) 2009 Elsevier B.V. All rights reserved.

TIME COURSE OF SKELETAL MUSCLE LOSS AND OXIDATIVE STRESS IN RATS WITH WALKER 256 SOLID TUMOR

Reactive oxygen species oxidize proteins and modulate the proteasomal system in muscle-wasting cancer cachexia. On day 5 (D5), day 10 (D10), and day 14 (D14) after tumor implantation, skeletal muscle was evaluated. Carbonylated proteins and thiobarbituric acid reactive substances were measured. Chemiluminescence was employed for lipid hydroperoxide estimation. Glutathione, superoxide dismutase, and total radical antioxidant capacity were evaluated. The proteasomal system was assessed by mRNA atrogin-1 expression. Increased muscle wasting, lipid hydroperoxide, and superoxide dismutase, and decreased glutathione levels and total radical antioxidant capacity, were found on D5 in accordance with increased mRNA atrogin-1 expression. All parameters were significantly modified in animals treated with alpha-tocopherol. The elevation in aldehylde levels and carbonylated proteins observed on D10 were reversed by cc-tocopherol treatment. Oxidative stress may trigger signal transduction of the proteasomal system and cause protein oxidation. These pathways may be associated with the mechanism of muscle wasting that occurs in cancer cachexia. Muscle Nerve 42: 950-958, 2010

Protein Intake during Weight Loss Influences the Energy Required for Weight Loss and Maintenance in Cats

The effects of 2 diets with different protein contents on weight loss and subsequent maintenance was assessed in obese cats. The control group [Cc; n = 8; body condition score (BCS) = 8.6 +/- 0.2] received a diet containing 21.4 g crude protein (CP)/MJ of metabolizable energy and the high-protein group (HP; n = 7; BCS = 8.6 +/- 0.2) received a diet containing 28.4 g CP/MJ until the cats achieved a 20% controlled weight loss (0.92 +/- 0.2%/wk). After the weight loss, the cats were all fed a diet containing 28.0 g CP/MJ at an amount sufficient to maintain a constant body weight (MAIN) for 120 d. During weight loss, there was a reduction of lean mass in Cc (P < 0.01) but not in HIP cats and a reduction in leptinemia in both groups (P < 0.01). Energy intake per kilogram of metabolic weight (kg(-0.40)) to maintain the same rate of weight loss was lower (P < 0.04) in the Co (344 +/- 15.9 kJ.kg(-0.40).d(-1)) than in the HP group (377 +/- 12.4 kJ.kg-(0.40).d(-1)). During the first 40 d of MAIN, the energy requirement for weight maintenance was 398.7 +/- 9.7 kJ.kg(-0.40).d(-1) for both groups, corresponding to 73% of the NRC recommendation. The required energy gradually increased in both groups (P < 0.05) but at a faster rate in HP; therefore, the energy consumption during the last 40 d of the MAIN was higher (P < 0.001) for the HP cats (533.8 +/- 7.4 kJ.kg(-0.40).d(-1)) than for the control cats (462.3 +/- 9.6 kJ.kg(-0.40).d(-1)). These findings suggest that HIP diets allow a higher energy intake to weight loss in cats, reducing the intensity of energy restriction. Protein intake also seemed to have long-term effects so that weight maintenance required more energy after weight loss. J. Nutr, 139: 855-860, 2009.

Saethre-Chotzen Syndrome, Pro136His TWIST Mutation, Hearing Loss, and External and Middle Ear Structural Anomalies: Report on a Brazilian Family

Objective: To describe the clinical, speech, hearing, and imaging findings in three members of a Brazilian family with Saethre-Chotzen syndrome (SCS) who presented some unusual characteristics within the spectrum of the syndrome. Design: Clinical evaluation was performed by a multidisciplinary team. Direct sequencing of the polymerase chain reaction amplified coding region of the TWIST1 gene, routine and electrophysiological hearing evaluation, speech evaluation, and imaging studies through computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed. Results: TWIST1 gene analysis revealed a Pro136His mutation in all patients. Hearing evaluation showed peripherial and mixed hearing loss in two of the patients, one of them with severe unilateral microtia. Computed tomography scan showed structural middle ear anomalies, and MRI showed distortion of the skull contour as well as some of the brain structures. Conclusions: We report a previously undescribed TWIST1 gene mutation in patients with SCS. There is evidence that indicates hearing loss (conductive and mixed) can be related both with middle ear (microtia, high jugular bulb, and enlarged vestibules) as well as with brain stem anomalies. Here we discuss the relationship between the gene mutation and the clinical, imaging, speech, and hearing findings.

Testing landscape metrics as indicators of habitat loss and fragmentation in continuous eucalypt forests (Queensland, Australia)

Landscape metrics are widely applied in landscape ecology to quantify landscape structure. However, many are poorly tested and require rigorous validation if they are to serve as reliable indicators of habitat loss and fragmentation, such as Montreal Process Indicator 1.1e. We apply a landscape ecology theory, supported by exploratory and confirmatory statistical techniques, to empirically test landscape metrics for reporting Montreal Process Indicator 1.1e in continuous dry eucalypt forests of sub-tropical Queensland, Australia. Target biota examined included: the Yellow-bellied Glider (Petaurus australis); the diversity of nectar and sap feeding glider species including P. australis, the Sugar Glider P. breviceps, the Squirrel Glider P. norfolcensis, and the Feathertail Glider Acrobates pygmaeus; six diurnal forest birds species; total diurnal bird species diversity; and the density of nectar-feeding diurnal bird species. Two scales of influence were considered: the stand-scale (2 ha), and a series of radial landscape extents (500 m - 2 km; 78 - 1250 ha) surrounding each fauna transect. For all biota, stand-scale structural and compositional attributes were found to be more influential than landscape metrics. For the Yellow-bellied Glider, the proportion of trace habitats with a residual element of old spotted-gum/ironbark eucalypt trees was a significant landscape metric at the 2 km landscape extent. This is a measure of habitat loss rather than habitat fragmentation. For the diversity of nectar and sap feeding glider species, the proportion of trace habitats with a high coefficient of variation in patch size at the 750 m extent was a significant landscape metric. None of the landscape metrics tested was important for diurnal forest birds. We conclude that no single landscape metric adequately captures the response of the region's forest biota per se. This poses a major challenge to regional reporting of Montreal Process Indicator 1.1e, fragmentation of forest types.

Association between tooth loss and obesity in Brazilian adults: a population-based study

OBJECTIVE: To examine the association between tooth loss and general and central obesity among adults. METHODS: Population-based cross-sectional study with 1,720 adults aged 20 to 59 years from Florianópolis, Southern Brazil. Home interviews were performed and anthropometric measures were taken. Information on sociodemographic data, self-reported diabetes, self-reported number of teeth, central obesity (waist circumference [WC] > 88 cm in women and > 102 cm in men) and general obesity (body mass index [BMI] ≥ 30 kg/m²) was collected. We used multivariable Poisson regression models to assess the association between general and central obesity and tooth loss after controlling for confounders. We also performed simple and multiple linear regressions by using BMI and WC as continuous variables. Interaction between age and tooth loss was also assessed. RESULTS: The mean BMI was 25.9 kg/m² (95%CI 25.6;26.2) in men and 25.4 kg/m2 (95%CI 25.0;25.7) in women. The mean WC was 79.3 cm (95%CI 78.4;80.1) in men and 88.4 cm (95%CI 87.6;89.2) in women. A positive association was found between the presence of less than 10 teeth in at least one arch and increased mean BMI and WC after adjusting for education level, self-reported diabetes, gender and monthly per capita income. However, this association was lost when the variable age was included in the model. The prevalence of general obesity was 50% higher in those with less than 10 teeth in at least one arch when compared with those with 10 or more teeth in both arches after adjusting for education level, self-reported diabetes and monthly per capita family income. However, the statistical significance was lost after controlling for age. CONCLUSIONS: Obesity was associated with number of teeth, though it depended on the participants' age groups.

Gender differences in the association between tooth loss and obesity among older adults in Brazil

OBJECTIVE To analyze if differences according to gender exists in the association between tooth loss and obesity among older adults.METHODS We analyzed data on 1,704 older adults (60 years and over) from the baseline of a prospective cohort study conducted in Florianopolis, SC, Southern Brazil. Multivariable logistic regression models were used to assess the association between tooth loss and general and central obesity after adjustment for confounders (age, gender, skin color, educational attainment, income, smoking, physical activity, use of dentures, hypertension, and diabetes). Linear regressions were also assessed with body mass index and waist circumference as continuous outcomes. Interaction between gender and tooth loss was further assessed.RESULTS Overall mean body mass index was 28.0 kg/m2. Mean waist circumference was 96.8 cm for males and 92.6 cm for females. Increasing tooth loss was positively associated with increased body mass index and waist circumference after adjustment for confounders. Edentates had 1.4 (95%CI 1.1;1.9) times higher odds of being centrally obese than individuals with a higher number of teeth; however, the association lost significance after adjustment for confounders. In comparison with edentate males, edentate females presented a twofold higher adjusted prevalence of general and central obesity. In the joint effects model, edentate females had a 3.8 (95%CI 2.2;6.6) times higher odds to be centrally obese in comparison with males with more than 10 teeth present in both the arches. Similarly, females with less than 10 teeth in at least one arch had a 2.7 (95%CI 1.6;4.4) times higher odds ratio of having central obesity in comparison with males with more than 10 teeth present in both the arches.CONCLUSIONS Central obesity was more prevalent than general obesity among the older adults. We did not observe any association between general obesity and tooth loss. The association between central obesity and tooth loss depends on gender – females with tooth loss had greater probability of being obese.

Weight loss and morphometric study of intestinal mucosa in rats after massive intestinal resection: influence of a glutamine-enriched diet

Short-bowel syndrome is responsible for significant metabolic alterations that compromise nutritional status. Glutamine is considered an essential nutrient for enterocytes, so beneficial effects from supplementation of the diet with glutamine are hypothesized. PURPOSE: In this study, the effect of a diet enriched with glutamine was evaluated in rats undergoing extensive small bowel resection, with analysis of postoperative weight loss and intestinal morphometrics of villi height, crypt depth, and thickness of the duodenal and remnant jejunal mucosa. METHODS: Three groups of male Wistar rats were established receiving the following diets: with glutamine, without glutamine, and the standard diet of laboratory ration. All animals underwent an extensive small bowel resection, including the ileocecal valve, leaving a remnant jejunum of only 25 cm from the pylorus that was anastomosed lateral-laterally to the ascendant colon. The animals were weighed at the beginning and end of the experiment (20th postoperative day). Then they were killed and the remnant intestine was removed. Fragments of duodenal and jejunal mucosa were collected from the remnant intestine and submitted to histopathologic exam. The morphometric study of the intestinal mucosa was accomplished using a digital system (KS 300) connected to an optic microscope. Morphometrics included villi height, crypt depth, and the total thickness of intestinal mucosa. RESULTS: The weight loss comparison among the 3 groups showed no significant loss difference. The morphometric studies showed significantly taller duodenal villi in the glutamine group in comparison to the without glutamine group, but not different from the standard diet group. The measurements obtained comparing the 3 groups for villi height, crypt depth, and thickness of the remnant jejunum mucosa were greater in the glutamine-enriched diet group than for the without-glutamine diet group, though not significantly different from with standard-diet group. CONCLUSIONS: In rats with experimentally produced short-bowel syndrome, glutamine-enrichment of an isonitrogenous test diet was associated with an improved adaptation response by the intestinal mucosa but not reduced weight loss. However, the adaptation response in the group receiving the glutamine-enriched diet was not improved over that for the group fed regular chow.

Weight loss and survival of Biomphalaria Glabrata deprived of water

Immature and mature Biomphalaria glabrata are kept out of water at relative humidities varying from 0 to 100%. When snails are submitted to a saturated atmosphere, they show a slow weight loss and survival may be long. If relative humidity (RH) decreases, weight loss becomes important and survival is short. A reduced RH (0 to 65%) produces similar effects. During desiccation, fasting has no noticeable effect; survival depends essentially on weight loss.

Computational quest for understanding the role of astrocyte signaling in synaptic transmission and plasticity.

The complexity of the signaling network that underlies astrocyte-synapse interactions may seem discouraging when tackled from a theoretical perspective. Computational modeling is challenged by the fact that many details remain hitherto unknown and conventional approaches to describe synaptic function are unsuitable to explain experimental observations when astrocytic signaling is taken into account. Supported by experimental evidence is the possibility that astrocytes perform genuine information processing by means of their calcium signaling and are players in the physiological setting of the basal tone of synaptic transmission. Here we consider the plausibility of this scenario from a theoretical perspective, focusing on the modulation of synaptic release probability by the astrocyte and its implications on synaptic plasticity. The analysis of the signaling pathways underlying such modulation refines our notion of tripartite synapse and has profound implications on our understanding of brain function.