Glial contribution to excitatory and inhibitory synapse loss in neurodegeneration

Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40-1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective NaV1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective NaV1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid

The Secret Life of the Anthrax Agent Bacillus anthracis: Bacteriophage-Mediated Ecological Adaptations

Ecological and genetic factors that govern the occurrence and persistence of anthrax reservoirs in the environment are obscure. A central tenet, based on limited and often conflicting studies, has long held that growing or vegetative forms of Bacillus anthracis survive poorly outside the mammalian host and must sporulate to survive in the environment. Here, we present evidence of a more dynamic lifecycle, whereby interactions with bacterial viruses, or bacteriophages, elicit phenotypic alterations in B. anthracis and the emergence of infected derivatives, or lysogens, with dramatically altered survival capabilities. Using both laboratory and environmental B. anthracis strains, we show that lysogeny can block or promote sporulation depending on the phage, induce exopolysaccharide expression and biofilm formation, and enable the long-term colonization of both an artificial soil environment and the intestinal tract of the invertebrate redworm, Eisenia fetida. All of the B. anthracis lysogens existed in a pseudolysogenic-like state in both the soil and worm gut, shedding phages that could in turn infect non-lysogenic B. anthracis recipients and confer survival phenotypes in those environments. Finally, the mechanism behind several phenotypic changes was found to require phage-encoded bacterial sigma factors and the expression of at least one host-encoded protein predicted to be involved in the colonization of invertebrate intestines. The results here demonstrate that during its environmental phase, bacteriophages provide B. anthracis with alternatives to sporulation that involve the activation of soil-survival and endosymbiotic capabilities

A Reduced Astrocyte Response to β-Amyloid Plaques in the Ageing Brain Associates with Cognitive Impairment

Aims β-amyloid (Aβ) plaques are a key feature of Alzheimer’s disease pathology but correlate poorly with dementia. They are associated with astrocytes which may modulate the effect of Aβ-deposition on the neuropil. This study characterised the astrocyte response to Aβ plaque subtypes, and investigated their association with cognitive impairment. Methods Aβ plaque subtypes were identified in the cingulate gyrus using dual labelling immunohistochemistry to Aβ and GFAP+ astrocytes, and quantitated in two cortical areas: the area of densest plaque burden and the deep cortex near the white matter border (layer VI). Three subtypes were defined for both diffuse and compact plaques (also known as classical or core-plaques): Aβ plaque with (1) no associated astrocytes, (2) focal astrogliosis or (3) circumferential astrogliosis. Results In the area of densest burden, diffuse plaques with no astrogliosis (β = -0.05, p = 0.001) and with focal astrogliosis (β = -0.27, p = 0.009) significantly associated with lower MMSE scores when controlling for sex and age at death. In the deep cortex (layer VI), both diffuse and compact plaques without astrogliosis associated with lower MMSE scores (β = -0.15, p = 0.017 and β = -0.81, p = 0.03, respectively). Diffuse plaques with no astrogliosis in layer VI related to dementia status (OR = 1.05, p = 0.025). In the area of densest burden, diffuse plaques with no astrogliosis or with focal astrogliosis associated with increasing Braak stage (β = 0.01, p<0.001 and β = 0.07, p<0.001, respectively), and ApoEε4 genotype (OR = 1.02, p = 0.001 and OR = 1.10, p = 0.016, respectively). In layer VI all plaque subtypes associated with Braak stage, and compact amyloid plaques with little and no associated astrogliosis associated with ApoEε4 genotype (OR = 1.50, p = 0.014 and OR = 0.10, p = 0.003, respectively). Conclusions Reactive astrocytes in close proximity to either diffuse or compact plaques may have a neuroprotective role in the ageing brain, and possession of at least one copy of the ApoEε4 allele impacts the astroglial response to Aβ plaques

Subjective memory complaints in an elderly sample: a cross-sectional study

Background Community based studies show that neurological or psychiatric symptoms are very frequent among the elderly population, with poor memory complaints being the most common. However, the relationship between poor memory complaints and objective memory performance is unclear. We designed this study to evaluate whether subjective memory complaints (SMC) are associated with objective cognitive performance or depression amongst the elderly Brazilian generation.Methods A cross-sectional study was carried out in 114 patients who were 50+, with or without SMC having no obvious cognitive impairment at its baseline (this was screened by the Mini-Mental State Examination with cut-off values adapted according to the subjects' educational background). Subjects were assessed regarding memory difficulty complaints, demographic data and underwent a neuropsychological assessment made up of nine cognitive tests (Rey Auditory Verbal Learning Test, Visual Reproduction Test, Logic Memory-History A, Free and Cued Selective Reminding Test, Stroop Test, Digit Span, Digit Symbol, Trail Making Test, fluency tests: naming animals and fruits) and the Geriatric Depression Scale.Results Twenty-one percent of the subjects had subjective memory complaints. the scores in the. cognitive assessment of subjects with SMC did not differ from the scores of subjects without SMC. However, patients with subjective memory complaints had lower scores in the fluency test - category animals and the Geriatric Depression Scale.Conclusions These results support the finding from other cross-sectional studies showing that subjective memory complaints are associated with depressive symptoms rather than objective cognitive performance. Copyright (C) 2007 John Wiley & Sons, Ltd.Universidade Federal de São Paulo, Sector Behav Neurol, Dept Neurol & Neurosurg, Escola Paulista Med, São Paulo, BrazilUniversidade Federal de São Paulo, Sector Behav Neurol, Dept Neurol & Neurosurg, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

Effects of negative pressure and directed ducted cooling systems on the performance of lactating sows

The objective of the present study was to evaluate the effects of cooling systems by negative pressure versus directed ducts on the performance of lactating sows and their litter. The experiment was conducted in a tropical climatic region in Brazil. Ninety-four lactating sows during 26.2±1.7 days of lactation were included with their 1,236 piglets. Sows were distributed using a completely randomized block design into two treatments: a negative pressure cooling (NPC) system and a directed duct cooling (DDC) system. We adopted sow parity as blocking criterion. During the experimental period, environmental temperatures inside the farrowing rooms were 22.9±1.5 and 25.4±2.5 °C, respectively, using the NPC and DDC systems. Sow daily feed intake, litter weight at weaning, piglet weight at weaning, litter daily weight gain, piglet daily gain, and daily milk production per sow were greater in the NPC system than in the DDC system. The type of cooling system did not affect piglet weight after standardization, mortality, number of piglets weaned per sow, and estrus return. The use of an NPC system can reduce the effects of higher environmental temperatures better than the DDC system. The NPC system allowed for greater feed intake, piglet and litter weight gain, weight of piglets and litter at weaning, and milk production compared with the DDC syste

Noninvasive Determination of Fetal Rh Blood Group, D Antigen Status by Cell-Free DNA Analysis in Maternal Plasma: Experience in a Brazilian Population

We evaluated the diagnostic accuracy of Rh blood group, D antigen (RHD) fetal genotyping, using real-time polymerase chain reaction in maternal blood samples, in a racially mixed population. We performed a prospective study conducted between January 2006 and December 2007, analyzing fetal RHD genotype in the plasma of 102 D-pregnant women by real-time polymerase chain reaction, targeting exons 7 and 10 of the RHD gene. Genotype results were compared with cord blood phenotype obtained after delivery or before the first intrauterine transfusion when necessary. Most of the participants (75.5%) were under 28 weeks of pregnancy, and 87.5% had at least one relative of black ancestry. By combining amplification of two exons, the accuracy of genotyping was 98%, sensitivity was 100%, and specificity was 92%. the positive likelihood ratio was 12.5, and the negative likelihood ratio was 0. the two false-positive cases were confirmed to be pseudogene RHD by real-time polymerase chain reaction. There were no differences between the patients with positive or negative Coombs test (p = 0.479). Determination of fetal RHD status in maternal peripheral blood was highly sensitive in this racially mixed population and was not influenced by the presence of antierythrocyte antibodies.Fed Univ São Paulo UNIFESP, Dept Obstet, São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Prevent Med, São Paulo, BrazilRDO Med Diag, São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Obstet, São Paulo, BrazilFed Univ São Paulo UNIFESP, Dept Prevent Med, São Paulo, BrazilWeb of ScienceFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES