Gene targeting approaches to complex genetic diseases: atherosclerosis and essential hypertension.

Gene targeting allows precise, predetermined changes to be made in a chosen gene in the mouse genome. To date, targeting has been used most often for generation of animals completely lacking the product of a gene of interest. The resulting "knockout" mice have confirmed some hypotheses, have upset others, but have rarely been uninformative. Models of several human genetic diseases have been produced by targeting--including Gaucher disease, cystic fibrosis, and the fragile X syndrome. These diseases are primarily determined by defects in single genes, and their modes of inheritance are well understood. When the disease under study has a complex etiology with multiple genetic and environmental components, the generation of animal models becomes more difficult but no less valuable. The problems associated with dissecting out the individual genetic factors also increases substantially and the distinction between causation and correlation is often difficult. To prove causation in a complex system requires rigorous adherence to the principle that the experiments must allow detection of the effects of changing only a single variable at one time. Gene targeting experiments, when properly designed, can test the effects of a precise genetic change completely free from the effects of differences in any other genes (linked or unlinked to the test gene). They therefore allow proofs of causation.

Local nitric oxide production in viral and autoimmune diseases of the central nervous system.

Because of the short half-life of NO, previous studies implicating NO in central nervous system pathology during infection had to rely on the demonstration of elevated levels of NO synthase mRNA or enzyme expression or NO metabolites such as nitrate and nitrite in the infected brain. To more definitively investigate the potential causative role of NO in lesions of the central nervous system in animals infected with neurotropic viruses or suffering from experimental allergic encephalitis, we have determined directly the levels of NO present in the central nervous system of such animals. Using spin trapping of NO and electron paramagnetic resonance spectroscopy, we confirm here that copious amounts of NO (up to 30-fold more than control) are elaborated in the brains of rats infected with rabies virus or borna disease virus, as well as in the spinal cords of rats that had received myelin basic protein-specific T cells.

Stability and sensitivity analysis of Be-CoDiS, an epidemiological model to predict the spread of human diseases between countries. Validation with data from the 2014-16 West African Ebola Virus Disease epidemic.

Ebola virus disease is a lethal human and primate disease that requires a particular attention from the international health authorities due to important recent outbreaks in some Western African countries and isolated cases in European and North-America continents. Regarding the emergency of this situation, various decision tools, such as mathematical models, were developed to assist the authorities to focus their efforts in important factors to eradicate Ebola. In a previous work, we have proposed an original deterministic spatial-temporal model, called Be-CoDiS (Between-Countries Disease Spread), to study the evolution of human diseases within and between countries by taking into consideration the movement of people between geographical areas. This model was validated by considering numerical experiments regarding the 2014-16 West African Ebola Virus Disease epidemic. In this article, we propose to perform a stability analysis of Be-CoDiS. Our first objective is to study the equilibrium states of simplified versions of this model, limited to the cases of one an two countries, and to determine their basic reproduction ratios. Then, in order to give some recommendations for the allocation of resources used to control the disease, we perform a sensitivity analysis of those basic reproduction ratios regarding the model parameters. Finally, we validate the obtained results by considering numerical experiments based on data from the 2014-16 West African Ebola Virus Disease epidemic.

Structural Polymorphism in Tau Filaments: An Implication for Neurodegenerative Diseases

Tau filaments are the pathological hallmark of >20 neurodegenerative diseases including Alzheimer's disease, Pick's disease, and progressive supranuclear palsy. In the adult human brain, six isoforms of tau are expressed that differ by presence or absence of the second of the four semiconserved repeats. As a consequence, half of the tau isoforms have three repeats (3R tau), whereas the other half has four repeats (4R tau). Site-directed spin labeling of recombinant tau in conjunction with electron paramagnetic resonance spectroscopy was used to obtain structural insights into tau filaments. The studies showed that the filaments of 4R tau and 3R tau share a highly ordered core structure in the third repeat with parallel, in-register arrangement of beta-strands. This structure in 3R and 4R is conserved regardless of whether full-length isoforms (htau40 and htau23) or truncated constructs (K18 and K19) are used. When mixed, 3R tau and 4R tau coassembled into heterogeneous filaments. Hence, these findings indicate that there are at least three compositionally distinct types of filaments: homogeneous 3R tau, homogeneous 4R tau, and heterogeneous 3R/4R tau. In vitro experiments show that the seeded filament growth, a prerequisite for tau spreading in tissue culture and brain, is crucially dependent on the isoform composition of individual seeds. Seeds of 3R tau and 3R/4R tau recruit both types of isoforms whereas seeds of 4R tau can recruit 4R tau, but not 3R tau, establishing an asymmetric barrier. Conformational templating of 4R tau onto 3R tau seeds eliminates this barrier, giving rise to a new type of tau filament. Conformational studies at the molecular level of tau filaments were done using Double electron-electron resonance spectroscopy, which allows the determination of distances between pairs of spin labels. These studies revealed structural differences between filaments of 3R tau and 4R tau. Furthermore, they indicated that 4R tau assumed the conformation of 3R tau when templated on 3R tau seeds. Our measurements have also provided insights into the heterogeneity of tau filament structure. Conformational differences due to variation in filament composition and seeding properties of tau filaments have shown that they are structurally polymorphic in nature. This structural polymorphism of tau filaments has widespread implications in understanding and treatment of neurodegenerative diseases.

Functional outcomes after stabilization with Dynesys in patients with spinal degenerative diseases

Objective: To know the impact of the Dynesys system on the functional outcomes in patients with spinal degenerative diseases. Summary of background data: Dynesys system has been proposed as an alternative to vertebral fusion for several spinal degenerative diseases. The fact that it has been used in people with different diagnosis criteria using different tools to measure clinical outcomes makes very difficult unifying the results available nowadays. Methods: The data base of Medlars Online International Literature (MEDLINE) via PubMed©, EMBASE©, and the Cochrane Library Plus were reviewed in search of all the studies published until November 2012 in which an operation with Dynesys in patients with spinal degenerative diseases and an evaluation of the results by an analysis of functional outcomes had taken place. No limits were used to article type, date of publication or language. Results: A total of 134 articles were found, 26 of which fulfilled the inclusion criteria after being assessed by two reviewers. All of them were case series, except for a multicenter randomized clinical trial (RCT) and a prospective case-control study. The selected articles made a total of 1507 cases. The most frequent diagnosis were lumbar spinal canal stenosis (LSCS), degenerative disc disease (DDD), degenerative spondylolisthesis (DS) and lumbar degenerative scoliosis (LDS). In cases of lumbar spinal canal stenosis Dynesys was associated to surgical decompression. Several tools to measure the functional disability and general health status were found. Oswestry Disability Index (ODI), the ODI Korean version (K-Odi), Prolo, Sf-36, Sf-12, Roland-Morris disability questionnaire (RMDQ), and the pain Visual Analogue Scale (VAS) were the most used. They showed positive results in all cases series reviewed. In most studies the ODI decreased about 25% (e.g. from a score of 85% to 60%). Better results when dynamic fusion was combined with nerve root decompression were found. Functional outcomes and leg pain scores with Dynesys were statistically non-inferior to posterolateral spinal fusion using autogenous bone. When Dynesys and decompression was compared with posterior interbody lumbar fixation (PLIF) and decompression, differences in ODI and VAS were not statistically significant. Conclusions: In patients with spinal degenerative diseases due to degenerative disc disorders, spinal canal stenosis and degenerative spondylolisthesis, surgery with Dynesys and decompression improves functional outcomes, decreases disability, and reduces back and leg pain. More studies are needed to conclude that dynamic stabilization is better than posterolateral and posterior interbody lumbar fusion. Studies comparing Dynesys with decompression against decompression alone should be done in order to isolate the effect of the dynamic stabilization.

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.

The natural history of Aleppo: containing a description of the city, and the principal natural productions in its neighbourhood : together with an account of the climate, inhabitants, and diseases, particularly of the plague

by Alex. Russell.