Greater Europe and the Euro A Window of Opportunity

Ao longo dos fins do Verão e do Outono de 1998 foi-se tomando cada vez mais evidente que as virtudes proclamadas aos quatro ventos do nascente Banco Central Europeu e seu esperado filho, o Euro, tinham sido enaltecidas um pouco para além do credível. Os cenários descritos pelos seus protagonistas pareceram ignorar as armadilhas que as circunstâncias económicas poderão fazer surgir. Circunstâncias essas que tomarão muito difícil aos governos nacionais cumprir os termos do Pacto de Estabilidade de Amesterdão. Este curto artigo apresentou um cenário que seria possível como resultado dum forte arranque inicial do Euro e, como alternativa, outro mais apropriado que surgiria menos robusto, por várias razões, algumas das quais poderiam facilmente ter sido imprevisívei

Economic Development and Social Cohesion At the Heart ofthe Matter

Without Economic Development there can be no freedom from the scourge of mass unemployment. There can be no freedom from want. There is no freedom from want unless there is a chance to earn a competency for a life that is worth while. Across Europe there are around 36 million souls who do not have any such chance. They are ‘The Unemployed”. Possibly 12 million ofthem are already called The Long Term Unemployed. More people will join them unless we can manage to generate economic development. Meanwhile, maybe it is reasonable for us to postulate that: 1. A stagnant economy will remain in that State until a dynamic force changes it. 2. The dynamic force provided by technical innovation is directly proportional to the economic growth it induces, the constant ofthe proportionality being the inertia ofthe stagnant economy, and 3. For every instance ofself-induced economic growth there will be a parallel positive multiplying effect on the creation ofplaces of employment. There is little or no economic progress when growth occurs without development. Economic Development only occurs when the underlying rate ofeconomic growth is both self-induced andself-sustaining, so that changes in the structures ofmanufacturing, technological and Services industries yield higher productivity and higherreal income per working person. To induce the desired kind of economic growth, there has to be a steady supply of new initiative, innovation and enterprise that accepts a hopefully properly calculated amount of risk. There have to be many such start-ups on a continued basis. Each European nation will have to make its own decisions and enact measures to cope with its own particular set of problems. Structural and Cohesion Funds may help but they do not bring an economy to life with the wave of a wand. The nations’ economies need to become vibrant as the result ofthe joint human endeavour oftheir young people. Their efforts have to be recognised, encouraged and properly rewarded on an ongoing basis

The New BARBARIAN MANIFESTO: How to survive the Information age by lan Angel

Whether we agree with the conclusions lan Angell proposes or not, this book assuredly deserves our attention. It is provocative and, for the open-minded, it is food for considerable thought. It shocks and yet it doesn’t. It wams us, if we accept his evaluation of the consequences of the advent of the Information Age. Above all, it challenges our complacency and calls on us to reassess the context of the near future

Heat shock-induced phosphorylation of TAR DNA-binding protein 43 (TDP-43) by MAPK/ERK kinase regulates TDP-43 function

TAR DNA-binding protein (TDP-43) is a highly conserved and essential DNA- and RNA-binding protein that controls gene expression through RNA processing, in particular, regulation of splicing. Intracellular aggregation of TDP-43 is a hallmark of amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration. This TDP-43 pathology is also present in other types of neurodegeneration including Alzheimer's disease. We report here that TDP-43 is a substrate of MEK, a central kinase in the MAPK/ERK signaling pathway. TDP-43 dual phosphorylation by MEK, at threonine 153 and tyrosine 155 (p-T153/Y155), was dramatically increased by the heat shock response (HSR) in human cells. HSR promotes cell survival under proteotoxic conditions by maintaining protein homeostasis and preventing protein misfolding. MEK is activated by HSR and contributes to the regulation of proteome stability. Phosphorylated TDP-43 was not associated with TDP-43 aggregation, and p-T153/Y155 remained soluble under conditions that promote protein misfolding. We found that active MEK significantly alters TDP-43-regulated splicing and that phosphomimetic substitutions at these two residues reduce binding to GU-rich RNA. Cellular imaging using a phospho-specific p-T153/Y155 antibody showed that phosphorylated TDP-43 was specifically recruited to the nucleoli, suggesting that p-T153/Y155 regulates a previously unappreciated function of TDP-43 in the processing of nucleolar-associated RNA. These findings highlight a new mechanism that regulates TDP-43 function and homeostasis through phosphorylation and, therefore, may contribute to the development of strategies to prevent TDP-43 aggregation and to uncover previously unexplored roles of TDP-43 in cell metabolism

Effect of hydrocephalus on rat brain extracellular compartment

<p>Abstract</p> <p>Background</p> <p>The cerebral cortex may be compressed in hydrocephalus and some experiments suggest that movement of extracellular substances through the cortex is impaired. We hypothesized that the extracellular compartment is reduced in size and that the composition of the extracellular compartment changes in rat brains with kaolin-induced hydrocephalus.</p> <p>Methods</p> <p>We studied neonatal (newborn) onset hydrocephalus for 1 or 3 weeks, juvenile (3 weeks) onset hydrocephalus for 3–4 weeks or 9 months, and young adult (10 weeks) onset hydrocephalus for 2 weeks, after kaolin injection. Freeze substitution electron microscopy was used to measure the size of the extracellular compartment. Western blotting and immunohistochemistry with quantitative image densitometry was used to study the extracellular matrix constituents, phosphacan, neurocan, NG2, decorin, biglycan, and laminin.</p> <p>Results</p> <p>The extracellular space in cortical layer 1 was reduced significantly from 16.5 to 9.6% in adult rats with 2 weeks duration hydrocephalus. Western blot and immunohistochemistry showed that neurocan increased only in the periventricular white matter following neonatal induction and 3 weeks duration hydrocephalus. The same rats showed mild decorin increases in white matter and around cortical neurons. Juvenile and adult onset hydrocephalus was associated with no significant changes.</p> <p>Conclusion</p> <p>We conclude that compositional changes in the extracellular compartment are negligible in cerebral cortex of hydrocephalic rats at various ages. Therefore, the functional change related to extracellular fluid flow should be reversible.</p

Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation

BACKGROUND: The chemokine CCL2 has an important role in the recruitment of inflammatory cells into the central nervous system (CNS). A transgenic mouse model that overexpresses CCL2 in the CNS shows an accumulation of leukocytes within the perivascular space surrounding vessels, and which infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx). METHODS: This study used contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood–brain barrier (BBB) disruption in this model pre- and post-PTx administration compared to wild-type mice. Contrast-enhanced MR images were obtained before and 1, 3, and 5 days after PTx injection in each animal. After the final imaging session fluorescent dextran tracers were administered intravenously to each mouse and brains were examined histologically for cellular infiltrates, BBB leakage and tight junction protein. RESULTS: BBB breakdown, defined as a disruption of both the endothelium and glia limitans, was found only in CCL2 transgenic mice following PTx administration and seen on MR images as focal areas of contrast enhancement and histologically as dextrans leaking from blood vessels. No evidence of disruption in endothelial tight junctions was observed. CONCLUSION: Genetic and environmental stimuli were needed to disrupt the integrity of the BBB in this model of neuroinflammation

Low levels of amyloid-beta and its transporters in neonatal rats with and without hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Previous studies in aging animals have shown that amyloid-beta protein (Aβ) accumulates and its transporters, low-density lipoprotein receptor-related protein-1 (LRP-1) and the receptor for advanced glycation end products (RAGE) are impaired during hydrocephalus. Furthermore, correlations between astrocytes and Aβ have been found in human cases of normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD). Because hydrocephalus occurs frequently in children, we evaluated the expression of Aβ and its transporters and reactive astrocytosis in animals with neonatal hydrocephalus.</p> <p>Methods</p> <p>Hydrocephalus was induced in neonatal rats by intracisternal kaolin injections on post-natal day one, and severe ventriculomegaly developed over a three week period. MRI was performed on post-kaolin days 10 and 21 to document ventriculomegaly. Animals were sacrificed on post-kaolin day 21. For an age-related comparison, tissue was used from previous studies when hydrocephalus was induced in a group of adult animals at either 6 months or 12 months of age. Tissue was processed for immunohistochemistry to visualize LRP-1, RAGE, Aβ, and glial fibrillary acidic protein (GFAP) and with quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) to quantify expression of LRP-1, RAGE, and GFAP.</p> <p>Results</p> <p>When 21-day post-kaolin neonatal hydrocephalic animals were compared to adult (6–12 month old) hydrocephalic animals, immunohistochemistry demonstrated levels of Aβ, RAGE, and LRP-1 that were substantially lower in the younger animals; in contrast, GFAP levels were elevated in both young and old hydrocephalic animals. When the neonatal hydrocephalic animals were compared to age-matched controls, qRT-PCR demonstrated no significant changes in Aβ, LRP-1 and RAGE. However, immunohistochemistry showed very small increases or decreases in individual proteins. Furthermore, qRT-PCR indicated statistically significant increases in GFAP.</p> <p>Conclusion</p> <p>Neonatal rats with and without hydrocephalus had low expression of Aβ and its transporters when compared to adult rats with hydrocephalus. No statistical differences were observed in Aβ and its transporters between the control and hydrocephalic neonatal animals.</p

Magnetic resonance imaging indicators of blood-brain barrier and brain water changes in young rats with kaolin-induced hydrocephalus

<p>Abstract</p> <p>Background</p> <p>Hydrocephalus is associated with enlargement of cerebral ventricles. We hypothesized that magnetic resonance (MR) imaging parameters known to be influenced by tissue water content would change in parallel with ventricle size in young rats and that changes in blood-brain barrier (BBB) permeability would be detected.</p> <p>Methods</p> <p>Hydrocephalus was induced by injection of kaolin into the cisterna magna of 4-week-old rats, which were studied 1 or 3 weeks later. MR was used to measure longitudinal and transverse relaxation times (T1 and T2) and apparent diffusion coefficients in several regions. Brain tissue water content was measured by the wet-dry weight method, and tissue density was measured in Percoll gradient columns. BBB permeability was measured by quantitative imaging of changes on T1-weighted images following injection of gadolinium diethylenetriamine penta-acetate (Gd-DTPA) tracer and microscopically by detection of fluorescent dextran conjugates.</p> <p>Results</p> <p>In nonhydrocephalic rats, water content decreased progressively from age 3 to 7 weeks. T1 and T2 and apparent diffusion coefficients did not exhibit parallel changes and there was no evidence of BBB permeability to tracers. The cerebral ventricles enlarged progressively in the weeks following kaolin injection. In hydrocephalic rats, the dorsal cortex was more dense and the white matter less so, indicating that the increased water content was largely confined to white matter. Hydrocephalus was associated with transient elevation of T1 in gray and white matter and persistent elevation of T2 in white matter. Changes in the apparent diffusion coefficients were significant only in white matter. Ventricle size correlated significantly with dorsal water content, T1, T2, and apparent diffusion coefficients. MR imaging showed evidence of Gd-DTPA leakage in periventricular tissue foci but not diffusely. These correlated with microscopic leak of larger dextran tracers.</p> <p>Conclusions</p> <p>MR characteristics cannot be used as direct surrogates for water content in the immature rat model of hydrocephalus, probably because they are also influenced by other changes in tissue composition that occur during brain maturation. There is no evidence for widespread persistent opening of BBB as a consequence of hydrocephalus in young rats. However, increase in focal BBB permeability suggests that periventricular blood vessels may be disrupted.</p

Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis

Neurologic effects of exogenous saccharides: A review of controlled human, animal, and in vitro studies

Objectives: Current research efforts are centered on delineating the novel health benefits of naturally derived saccharides, including growing interest in their abilities to influence neurologic health. We performed a comprehensive review of the literature to consolidate all controlled studies assessing various roles of exogenous saccharide compounds and polysaccharide-rich extracts from plants, fungi, and other natural sources on brain function, with a significant focus on benefits derived from oral intake. Methods: Studies were identified by conducting electronic searches on PubMed and Google Scholar. Reference lists of articles were also reviewed for additional relevant studies. Only articles published in English were included in this review. Results: Six randomized, double-blind, placebo-controlled clinical studies were identified in which consumption of a blend of plant-derived polysaccharides showed positive effects on cognitive function and mood in healthy adults. A separate controlled clinical study observed improvements in well-being with ingestion of a yeast beta-glucan. Numerous animal and in vitro studies have demonstrated the ability of individual saccharide compounds and polysaccharide-rich extracts to modify behavior, enhance synaptic plasticity, and provide neuroprotective effects. Discussion: Although the mechanisms by which exogenous saccharides can influence brain function are not well understood at this time, the literature suggests that certain naturally occurring compounds and polysaccharide-rich extracts show promise, when taken orally, in supporting neurologic health and function. Additional well-controlled clinical studies on larger populations are necessary, however, before specific recommendations can be made