Innate immune basis for rift valley fever susceptibility in mouse models

Rift Valley fever virus (RVFV) leads to varied clinical manifestations in animals and in humans that range from moderate fever to fatal illness, suggesting that host immune responses are important determinants of the disease severity. We investigated the immune basis for the extreme susceptibility of MBT/Pas mice that die with mild to acute hepatitis by day 3 post-infection compared to more resistant BALB/cByJ mice that survive up to a week longer. Lower levels of neutrophils observed in the bone marrow and blood of infected MBT/Pas mice are unlikely to be causative of increased RVFV susceptibility as constitutive neutropenia in specific mutant mice did not change survival outcome. However, whereas MBT/Pas mice mounted an earlier inflammatory response accompanied by higher amounts of interferon (IFN)-α in the serum compared to BALB/cByJ mice, they failed to prevent high viral antigen load. Several immunological alterations were uncovered in infected MBT/Pas mice compared to BALB/cByJ mice, including low levels of leukocytes that expressed type I IFN receptor subunit 1 (IFNAR1) in the blood, spleen and liver, delayed leukocyte activation and decreased percentage of IFN-γ-producing leukocytes in the blood. These observations are consistent with the complex mode of inheritance of RVFV susceptibility in genetic studies

How the mouse has become, timidly, a model for animal and human genetic research

Depuis le début du vingtième siècle, le modèle souris est l’un des plus communément utilisés par les généticiens. Cet article retrace les origines des recherches en Génétique de la Souris, et présente ses liens avec les travaux les plus actuels en Biologie expérimentale. Après les premières analyses formelles par Lucien Cuénot, William E. Castle, Clarence C. Little, et John B. S. Haldane, les généticiens se sont lancés dans la production de lignées consanguines. Cette histoire se prolonge jusqu’à nos jours avec la production de nouvelles populations de référence présentant une diversité génétique très élevée : le Collaborative Cross, et le Diversity Outbred. Dans le même temps, Leroy Stevens, Martin Evans, Gail Martin, et Barry Pierce réalisent une série d’expériences cruciales sur une tumeur rare : le tératocarcinome. Ces tumeurs vont être placées au coeur de recherches passionnantes qui se poursuivent de nos jours encore avec les travaux qui visent à comprendre les mécanismes de la reprogrammation des cellules somatiques adultes en cellules pluripotentes.From the early twentieth century onwards, the mouse is one the most popular model amongst geneticists. This article dedicates the origins of scientific work on mouse genetics and reports their links with current research in experimental biology. Following the first formal analyses by Lucien Cuénot, William E. Castle, Clarence C. Little, and John B. S. Haldane, geneticists plunged into the production of inbred strains. This history continues today with the development of new resource populations with high levels of genetic diversity: the Collaborative Cross, and the Diversity Outbred. At the same time, Leroy Stevens, Martin Evans, Gail Martin, and Barry Pierce performed a series of crucial experiments on a rare tumour: testicular teratocarcinoma. These tumours became the focus of a great deal of research that continues today through the works aimed at understanding the mechanisms of somatic adult cell reprogramming into pluripotent cells

Control of organ sizes : genetics andpathophysiology of intestinal lengthening in mouse strains

The mechanisms controlling the body size of adult mammals are well known. By contrast, even though zoologists have examined this question since the 19th century, little is still known on the mechanisms controlling the size of organs or tissues. The study of variants in mice, obtained either spontaneously or generated on purpose, could provide a lead to understand and dissect these mechanisms. This paper shows through a few chosen examples the conceptual and practical difficulties associated with this strategy.Les mécanismes qui contrôlent la taille du corps des mammifères adultes sont aujourd'hui bien connus. Par comparaison, peu de choses sont connues sur les mécanismes qui contrôlent la taille des organes et des tissus, bien que cette question intéresse les zoologistes depuis le XIXe siècle. L'étude de variants, spontanés ou fabriqués à façon chez la souris, pourrait fournir un fil d'Ariane pour identifier et disséquer les mécanismes sous-jacents. Cet article montre, à travers quelques exemples choisis, les difficultés conceptuelles et pratiques posées par cette approche

Initial clinical experience with the pulsed solid-state thulium YAG laser from Dornier during RIRS: first 25 cases

Introduction Holmium:yttrium–aluminium–garnet (Ho:YAG) and thulium fiber (TFL) lasers are currently the two laser sources recommended for endocorporeal laser lithotripsy (ELL). Recently, the pulsed-thulium:YAG (Tm:YAG) laser was also proposed for ELL, as an answer to both Ho:YAG and TFL limitations. We aimed to evaluate the efficiency, safety, and laser settings of Tm:YAG laser in ELL during retrograde intrarenal surgery (RIRS). Methods A prospective study of the first 25 patients with ureteral and renal stones who underwent RIRS using the Thulio (pulsed-Tm:YAG, Dornier©, Germany) was performed in a single center. 272 μm laser fibers were used. Stone size, stone density, laser-on time (LOT) and laser settings were recorded. We also assessed the ablation speed (mm 3 /s), Joules/mm 3 and laser power (W) values for each procedure. Postoperative results, such as stone-free rate (SFR) and zero fragments rate (ZFR) were also recorded. Results A total of 25 patients were analyzed (Table 1). The median (IQR) age was 55 (44–72) years old. Median (IQR) stone volume was 2849 (916–9153)mm3 . Median (IQR) stone density was 1000 (600–1174)HU. Median (IQR) pulse energy, pulse rate and total power were 0.6 (0.6–0,8)J, 15(15–20)Hz and 12(9–16)W, respectively. All procedures used “Captive Frag- menting” pulse modulation (Table 2). The median (IQR) J/mm 3 was 14,8 (6–21). The median (IQR) ablation rate was 0,75 (0,46–2)mm 3 /s. One postoperative complications occurred (streinstrasse). SFR and ZFR were 95% and 55%, respectively. Conclusion The pulsed-Tm:YAG laser is a safe and effective laser source for lithotripsy during RIRS, using low pulse energy and low pulse frequency

Innate immune basis for rift valley fever susceptibility in mouse models

Rift Valley fever virus (RVFV) leads to varied clinical manifestations in animals and in humans that range from moderate fever to fatal illness, suggesting that host immune responses are important determinants of the disease severity. We investigated the immune basis for the extreme susceptibility of MBT/Pas mice that die with mild to acute hepatitis by day 3 post-infection compared to more resistant BALB/cByJ mice that survive up to a week longer. Lower levels of neutrophils observed in the bone marrow and blood of infected MBT/Pas mice are unlikely to be causative of increased RVFV susceptibility as constitutive neutropenia in specific mutant mice did not change survival outcome. However, whereas MBT/Pas mice mounted an earlier inflammatory response accompanied by higher amounts of interferon (IFN)-α in the serum compared to BALB/cByJ mice, they failed to prevent high viral antigen load. Several immunological alterations were uncovered in infected MBT/Pas mice compared to BALB/cByJ mice, including low levels of leukocytes that expressed type I IFN receptor subunit 1 (IFNAR1) in the blood, spleen and liver, delayed leukocyte activation and decreased percentage of IFN-γ-producing leukocytes in the blood. These observations are consistent with the complex mode of inheritance of RVFV susceptibility in genetic studies

Centronuclear myopathy in labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide

Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA<sup>cnm</sup> mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA<sup>cnm</sup> carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA<sup>cnm</sup> allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM

Comparaison in vitro de l’efficacité statique ou dynamique des lasers Holmium :YAG et thulium fibré pour la lithotritie endocorporelle : impact de la vitesse de déplacement

La vitesse optimale de déplacement (VOD) de la fibre laser pour réaliser la pulvérisation lithiasique est une variable inconnue à ce jour, autant pour le laser thulium fibré (TFL) que pour le laser Holmium :YAG (Ho :YAG). L’objectif était de déterminer in vitro la VOD de la fibre laser lors d’une lithotritie endocorporelle en fonction des paramètres laser avec le TFL et l’Ho :YAG, au moyen des volumes d’ablation (VA).Bourse de Recherche AFU 201

Analyse in vitro de l’efficacité de la lithotritie laser : quel modèle utiliser ?

L’étude in vitro de la lithotritie laser (LL) utilise des calculs humains (CH) ou synthétiques (CS). Devant l’augmentation de la pulvérisation laser (Dusting), peu d’échantillons humains sont disponibles. Les CS sont donc privilégiés, confectionnés par mélange d’eau et de plâtre, avec la problématique de leur réhydratation lors des LL. L’objectif était de comparer les volumes d’ablation (VA) entre CS homogènes (CSHo) ou hétérogènes(CSHe), et par rapport au poids ablaté (PA).Bourse de Recherche AFU 201

Medium to long term follow up study of the efficacy of cessation of eye-rubbing to halt progression of keratoconus

PurposeTo study the progression of keratoconus after cessation of eye rubbing with a minimum follow up of three-years.DesignRetrospective, monocentric, longitudinal cohort study of keratoconus patients with a minimum of 3 years follow-up.ParticipantsOne hundred fifty three eyes of seventy-seven consecutive patients with keratoconus were included.MethodsInitial examination consisted of anterior and posterior segment evaluation using slit-lamp biomicroscopy. At the initial visit, patients were thoroughly informed of their pathology and instructed to stop rubbing their eyes. Eye rubbing cessation was assessed at all the follow-up visits at 6 months, 1 year, 2 years, 3 years, and yearly afterward. Corneal topography using the Pentacam® (Oculus®, Wetzlar, Germany) was used to obtain maximum and average anterior keratometry readings (Kmax and Kmean), as well as thinnest pachymetry (Pachymin, μm) in both eyes.Main outcome measuresThe main outcomes measured were maximum keratometry (Kmax), mean keratometry (Kmean), and thinnest pachymetry (Pachymin) values at various time points to assess for keratoconus progression. Keratoconus progression was defined as a significant augmentation of Kmax (>1D), Kmean (>1D), or significant diminution of Pachymin (>5%) throughout the total follow-up duration.ResultsOne hundred fifty three eyes of seventy-seven patients (75.3% males) aged 26.4 years old, were followed for an average of 53 months. Over the course of the follow-up, there was no statistically significant variation of ∆Kmax (+0.04 ± 0.87; p = 0.34), ∆ Kmean (+0.30 ± 0.67; p = 0.27) nor ∆Pachymin (−4.36 ± 11.88; p = 0.64). Among the 26 of the 153 eyes which had at least one criterion of KC progression, 25 admitted continuing eye rubbing, or other at-risk behaviors.ConclusionThis study suggests that a significant proportion of keratoconus patients are likely to remain stable if close monitoring and strict ARB cessation are achieved, without the need for further intervention