Netherton syndrome: skin inflammation and allergy by loss of protease inhibition

Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect and constant allergic manifestations. NS is caused by loss-of-function mutations in SPINK5 (serine protease inhibitor of kazal type 5) encoding LEKTI-1 (lympho-epithelial kazal type related inhibitor type 5) expressed in stratified epithelia. In vitro and in vivo studies in murine models and in NS patients have cast light on the pathogenesis of the disease and shown that LEKTI deficiency results in unopposed kallikrein-related peptidase 5 (KLK5) and KLK7 activities and to the overactivity of a new epidermal protease, elastase 2 (ELA2). Two main cascades initiated by KLK5 activity have emerged. One results in desmoglein 1 degradation and desmosome cleavage leading to stratum corneum detachment. KLK5 also activates KLK7 and ELA2, which contribute to a defective skin barrier. This facilitates allergen and microbe penetration and generates danger signals leading to caspase 1 activation and the production of active interleukin-1β. In parallel, KLK5 activates a specific cascade of allergy and inflammation by activating protease-activated receptor-2 (PAR-2) receptors. PAR-2 activation triggers the production of the major pro-Th2 cytokine TSLP (thymic stromal lymphopoietin) and several inflammatory cytokines, including tumour necrosis factor-α. Levels of thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) also contribute to allergy in a PAR-2-independent manner. Patient investigations have confirmed these abnormalities and revealed a wide spectrum of disease expression, sometimes associated with residual LEKTI expression. These results have demonstrated that the tight regulation of epidermal protease activity is essential for skin homeostasis and identified new targets for therapeutic intervention. They also provide a link with atopic dermatitis through deregulated protease activity, as recently supported by functional studies of the E420K LEKTI variant.     

La dysfonction érectile, un marqueur précoce d’atteinte cardio-vasculaire

Erectile dysfunction (ED) affects approximately 100 million men in the world and 50% of men between the ages of 40 and 70 years. The commonest cause is a vascular disorder of penile arteries. ED may therefore be a an early marker of cardiovascular disease (CVD). The main arguments in favour of this assertion are primarily epidemiological, but also pathophysiological, as control of cardiovascular risk factors such as smoking, obesity and hypertension may prevent not only CVD, but also ED. This relationship is particularly strong in diabetic patients, in whom ED can be considered to be an element able to identify patients at risk of asymptomatic heart disease. From a pathophysiological point of view, small calibre penile vessels present signs of obstruction earlier than larger vessels because they are more sensitive to even minor haemodynamic changes. There is also a significant correlation between the severity of ED and the number of vessels affected in patients with coronary artery disease. Endothelial dysfunction is the common denominator underlying these diseases and therefore represents a major cause of ED. Preliminary studies have shown that PDE-5 inhibitors can reduce symptoms, improve exercise tolerance, and reduce endothelial dysfunction in patients after cardiac arrest and in diabetics. In the years to come, ED may therefore be added to the classical cardiovascular risk factors and could characterize a population with an increased risk of coronary artery disease.     

Cancer incidence estimation at a district level without a national registry: A validation study for 24 cancer sites using French health insurance and registry data

Background: District-level cancer incidence estimation is an important issue in countries without a national cancer registry. This study aims to both evaluate the validity of district-level estimations in France for 24 cancer sites, using health insurance data (ALD demands – Affection de Longue Durée) and to provide estimations when considered valid. Incidence is estimated at a district-level by applying the ratio between the number of first ALD demands and incident cases (ALD/I ratio), observed in those districts with cancer registries, to the number of first ALD demands available in all districts. These district-level estimations are valid if the ratio does not vary greatly across the districts or if variations remain moderate compared with variations in incidence rates. Methods: Validation was performed in the districts covered by cancer registries over the period 2000–2005. The district variability of the ALD/I ratio was studied, adjusted for age (mixed-effects Poisson model), and compared with the district variability in incidence rate. The epidemiological context is also considered in addition to statistical analyses. Results: District-level estimation using the ALD/I ratio was considered valid for eight cancer sites out of the 24 studied (lip–oral cavity–pharynx, oesophagus, stomach, colon–rectum, lung, breast, ovary and testis) and incidence maps were provided for these cancer sites. Conclusion: Estimating cancer incidence at a sub-national level remains a difficult task without a national registry and there are few studies on this topic. Our validation approach may be applied in other countries, using health insurance or hospital discharge data as correlate of incidence.     

The Fractal Model: a new model to describe the species accumulation process and relative abundance distribution (RAD)

Quantifying a sampled collection of taxa is a widespread problem in ecology. A number of diversity indices have been proposed and used in numerous works in spite of a lack of statistical characteristics and tests of comparison. These Relative Abundance Distributions (RAD) can also be described using graphic representations exhibiting both the number of taxa and the quantitative distribution of the individuals which constitute these taxa. Fitting these RADs to deterministic or stochastic models remains problematic for different reasons like scale dependence or complexity of the numerical procedures. In our study, we introduce a new model to describe RAD and ecological succession. This model is a Fractal Model based on the assumption that during an ecological succession/accumulation process, at each step of the succession, K new species appear which are k times more abundant with K = k ^d (where d is a fractal dimension). We use a Monte-Carlo procedure with a Kolmogorov-Smirnov distance to fit this model and to estimate parameters. Through the study of entomological data from a Mediterranean Man And Biosphere reserve, we demonstrate the qualities of the new Fractal Model. Thus, the Fractal Model was rejected for none of the 13 RADs tested. In addition, the parameters ( K , k and d ) are independent of the Hill family diversity indices and of three evenness indices and are able to provide additional information concerning both the diversity of the sampled ecosystem and development of this biodiversity during the species accumulation process in this ecosystem.     

Recombinant human IL-6 expressed inE. coli undergoes selective N-terminal degradation: Evidence that the protein consists of a stable core and a nonessential flexible N-terminal

A synthetic gene for human interleukin-6 has been expressed inE. coli. The protein has been purified and renatured and has the same activity as natural human IL-6 using the 7TD1 cell proliferation assay. The protein undergoes specific cleavage by a thiol protease, yielding two new N-termini at Arg-9 and His-15. The truncated proteins retain full biological activity. The degradation results in the loss of sharp amide resonances in the¹H-NMR spectrum, and little change to the ultraviolet CD spectrum. Several amino acid type assignments could be made for these sharp amides using a DQF-COSY 2D-NMR experiment. The N-terminal 15 amino acids exist as a flexible, random coil, attached to a central structure.     

The Production of Pyrethrins by Plant Cell and Tissue Cultures of Chrysanthemum cinerariaefolium and Tagetes Species

Pyrethrins, the most economically important natural insecticide, comprise a group of six closely related monoterpene esters. The industrial production is based on their extraction from Chrysanthemum cinerariaefolium (Pyrethrum) capitula. The world production of natural pyrethrins still falls short of global market demand stimulating the research in in vitro production as an alternative to conventional cultivation methods. The different biotechnological alternatives such as callus cultures, shoot and root cultures, plant cell suspension cultures, and bioconversion of precursors by means of enzymatic synthesis or genetically engineered microorganisms, as well as the progress achieved in methods for the identification and quantitation of insecticidal compounds have been reviewed. Although technology for plant cell culture exists, industrial applications have, to date, been limited due to both the low economical viability and technological feasibility at large scale. Bioconversion of readily available precursors looks more attractive, but more research is needed before this technology is used for the industrial production of pyrethrins.     

Development of retinal layers

A noticeable characteristic of nervous systems is the arrangement of synapses into distinct layers. Such laminae are fundamental for the spatial organisation of synaptic connections transmitting different kinds of information. A major example of this is the inner plexiform layer (IPL) of the vertebrate retina, which is subdivided into at least ten sublayers. Another noticeable characteristic of these retina layers is that neurons are displayed in the horizontal plane in a non-random array termed as mosaic patterning. Recent studies of vertebrate and invertebrate systems have identified molecules that mediate these interactions. Here, we review the last mechanisms and molecules mediating retinal layering.