Animal Models of Friedreich Ataxia

Friedreich ataxia (FRDA) is the most common form of autosomal-recessive ataxia. Common nonmotor features include cardiomyopathy and diabetes mellitus. At present, no effective treatments are available to prevent disease progression. Age of onset varies from infancy to adulthood. In the majority of patients, FRDA is caused by intronic GAA expansions in FXN, which encodes a highly-conserved small mitochondrial matrix protein, frataxin. A mouse model of FRDA has been difficult to generate because complete loss of frataxin causes early embryonic lethality. Although there are some controversies about the function of frataxin, recent biochemical and structural studies have confirmed that it is a component of the multiprotein complex that assembles iron-sulfur clusters in the mitochondrial matrix. The main consequences of frataxin deficiency are energy deficit, altered iron metabolism, and oxidative damage.

The European union

Introduction An overview of media markets shows that rapid growth and the integration of some of the most dynamic market segments are characteristics of this fast-moving industry. The main players are the established incumbents upstream and the delivery segments of media downstream. The presence of incumbents, inheritors of previous public monopolies, has led Member States to use regulation in a complementary role with competition. In these markets, strategies to deliver new products and services and to serve new geographic markets focus less on organic growth than on alliances and mergers in order to create multi-media offshoots, bid for control of content rights, increase the diffusion of products and services, and develop technologies for conditional access and transmission standards to capture advantages through proprietary technology. As a result, vertically integrated dominant positions either upstream or downstream have tended to emerge. There is nothing wrong with vertical integration except when there is market power at one stage of the vertical chain. Indeed, as far as the media industry is concerned, there are some specific challenges at the European level. The new EU regulatory framework grants some specific competition principles which can be integrated into ex ante regulation. EU merger control may also prevent potential distortion of competition resulting from the creation or the strengthening of a single or collective dominant position in the media sector at a horizontal level, or from foreclosure effects at a vertical level.

CMS Collaboration

SCOPUS: ar.j

ESR/ERS white paper on lung cancer screening

Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low-dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low-dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and a quality assurance plan. The establishment of a central registry, including a biobank and an image bank, and preferably on a European level, is strongly encouraged. Key points: • Lung cancer screening using low dose computed tomography reduces mortality. • Leading US medical societies recommend large scale screening for high-risk individuals. • There are no lung cancer screening recommendations or reimbursed screening programmes in Europe as of yet. • The European Society of Radiology and the European Respiratory Society recommend lung cancer screening within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. • High risk, eligible individuals should be enrolled in comprehensive, quality-controlled longitudinal programmes.

Ronald Aronson, Sartre's second Critique. Chicago: the university of Chicago Press, 1987. 252 p.

info:eu-repo/semantics/published

Protoporphyrin treatment modulates susceptibility to experimental autoimmune encephalomyelitis in miR-155-deficient mice

We previously identified heme oxygenase 1 (HO-1) as a specific target of miR-155, and inhibition of HO-1 activity restored the capacity of miR-155-/- CD4+ T cells to promote antigendriven inflammation after adoptive transfer in antigen-expressing recipients. Protoporphyrins are molecules recognized for their modulatory effect on HO-1 expression and function. In the present study, we investigated the effect of protoporphyrin treatment on the development of autoimmunity in miR-155-deficient mice. MiR-155-mediated control of HO-1 expression in promoting T cell-driven chronic autoimmunity was confirmed since HO-1 inhibition restored susceptibility to experimental autoimmune encephalomyelitis (EAE) in miR-155- deficient mice. The increased severity of the disease was accompanied by an enhanced T cell infiltration into the brain. Taken together, these results underline the importance of miR- 155-mediated control of HO-1 expression in regulating the function of chronically-stimulated T cells in EAE.

Friedreich Ataxia

Friedreich's ataxia (FRDA) is the most common autosomal recessive hereditary ataxia in Caucasians. Neurological symptoms dominate the clinical picture. The underlying neuropathology affects the dorsal root ganglia, the spinal cord, and the deep cerebellar nuclei. In addition, most cases present a hypertrophic cardiomyopathy that may cause premature death. Other problems include a high risk of diabetes, skeletal abnormalities such as kyphoscoliosis, and pes cavus. Most patients carry a homozygous expansion of GAA trinucleotide repeat within the first intron of the FXN gene, leading to repressed transcription through epigenetic mechanisms. The encoded protein, frataxin, is localized in mitochondria and participates in the biogenesis of iron-sulfur clusters. Frataxin deficiency leads to mitochondrial dysfunction, altered iron metabolism, and oxidative damage. Thanks to progress in understanding pathogenesis and to the development of animal and cellular models, therapies targeted to correct frataxin deficiency or its downstream consequences are being developed and tested in clinical trials.

Friedreich Ataxia

Friedreich ataxia (FRDA) is an autosomal recessive disease characterized by progressive neurological and cardiac abnormalities. It has a prevalence of around 2×10⁵ in whites, accounting for more than one-third of the cases of recessively inherited ataxia in this ethnic group. FRDA may not exist in nonwhite populations.The first symptoms usually appear in childhood, but age of onset may vary from infancy to adulthood. Atrophy of sensory and cerebellar pathways causes ataxia, dysarthria, fixation instability, deep sensory loss, and loss of tendon reflexes. Corticospinal degeneration leads to muscular weakness and extensor plantar responses. A hypertrophic cardiomyopathy may contribute to disability and cause premature death. Other common problems include kyphoscoliosis, pes cavus, and, in 10% of patients, diabetes mellitus.The FRDA gene (FXN) encodes a small mitochondrial protein, frataxin, which is produced in insufficient amounts in the disease, as a consequence of the epigenetic silencing of the gene triggered by a GAA triplet repeat expansion in the first intron of the gene. Frataxin deficiency results in impaired iron-sulfur cluster biogenesis in mitochondria, in turn leading to widespread dysfunction of iron-sulfur center containing enzymes (in particular respiratory complexes I, II and III, and aconitase), impaired iron metabolism, oxidative stress, and mitochondrial dysfunction. Therapy aims to restore frataxin levels or to correct the consequences of its deficiency.

Editorial Introductions

SCOPUS: ed.j

Pulmonary vascular resistance: A meaningless variable?

Almost 20 years ago, Adriaan Versprille published an editorial in this journal to explain why, in his opinion, the calculation of pulmonary vascular resistance (PVR) is meaningless [1]. The uncertainties of PVR were underscored a year later by McGregor and Sniderman in the American Journal of Cardiology [2]. Obviously, both papers failed to convince. A Medline search from 1985 to the end of 2002 reveals no less than 7,158 papers with PVR calculations. What is it that could be wrong in all this literature?.

Red blood cell rheology in sepsis

Changes in red blood cell (RBC) function can contribute to alterations in microcirculatory blood flow and cellular dysoxia in sepsis. Decreases in RBC and neutrophil deformability impair the passage of these cells through the microcirculation. While the role of leukocytes has been the focus of many studies in sepsis, the role of erythrocyte rheological alterations in this syndrome has only recently been investigated. RBC rheology can be influenced by many factors, including alterations in intracellular calcium and adenosine triphosphate (ATP) concentrations, the effects of nitric oxide, a decrease in some RBC membrane components such as sialic acid, and an increase in others such as 2,3 diphosphoglycerate. Other factors include interactions with white blood cells and their products (reactive oxygen species), or the effects of temperature variations. Understanding the mechanisms of altered RBC rheology in sepsis, and the effects on blood flow and oxygen transport, may lead to improved patient management and reductions in morbidity and mortality.

Commentary

SCOPUS: no.j

A double blind trial of ketoprofen in the treatment of osteoarthritis of the hip

In a double blind study of ketoprofen and placebo in the treatment of osteoarthritis of the hip, ketoprofen was shown to be significantly more effective. Analysis of results was made using the sequential technique. Major intolerance occurred in two cases and minor intolerance in five cases. Newly diagnosed cases were treated more readily with ketoprofen than chronic cases treated for several months with other drugs which had proved ineffective. There were no changes in biological parameters. Age and sex did not affect the result. The further study of ketoprofen in large open trials appears to be indicated.

Charles De Coster: les noces de Thyl et Nele

info:eu-repo/semantics/published

One Person, Many Votes: Divided Majority and Information Aggregation

In elections, majority divisions pave the way to focal manipulations and coordination failures, which can lead to the victory of the wrong candidate. This paper shows how this flaw can be addressed if voter preferences over candidates are sensitive to information. We consider two potential sources of divisions: majority voters may have similar preferences but opposite information about the candidates, or opposite preferences. We show that when information is the source of majority divisions, Approval Voting features a unique equilibrium with full information and coordination equivalence. That is, it produces the same outcome as if both information and coordination problems could be resolved. Other electoral systems, such as Plurality and Two-Round elections, do not satisfy this equivalence. The second source of division is opposite preferences. Whenever the fraction of voters with such preferences is not too large, Approval Voting still satisfies full information and coordination equivalence.