Diversity of LEI0258 microsatellite locus in indigenous Ethiopian chickens

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Loss of function of RIMS2 causes a syndromic congenital cone-rod synaptic disease with neurodevelopmental and pancreatic involvement

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD

Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU)

Purpose Thrombocytopenia (platelet count < 150 × 109/L) is common in intensive care unit (ICU) patients and is likely associated with worse outcomes. In this study we present international contemporary data on thrombocytopenia in ICU patients. Methods We conducted a prospective cohort study in adult ICU patients in 52 ICUs across 10 countries. We assessed frequencies of thrombocytopenia, use of platelet transfusions and clinical outcomes including mortality. We evaluated pre-selected potential risk factors for the development of thrombocytopenia during ICU stay and associations between thrombocytopenia at ICU admission and 90-day mortality using pre-specified logistic regression analyses. Results We analysed 1166 ICU patients; the median age was 63 years and 39.5% were female. Overall, 43.2% (95% confidence interval (CI) 40.4–46.1) had thrombocytopenia; 23.4% (20–26) had thrombocytopenia at ICU admission, and 19.8% (17.6–22.2) developed thrombocytopenia during their ICU stay. Non-AIDS-, non-cancer-related immune deficiency, liver failure, male sex, septic shock, and bleeding at ICU admission were associated with the development of thrombocytopenia during ICU stay. Among patients with thrombocytopenia, 22.6% received platelet transfusion(s), and 64.3% of in-ICU transfusions were prophylactic. Patients with thrombocytopenia had higher occurrences of bleeding and death, fewer days alive without the use of life-support, and fewer days alive and out of hospital. Thrombocytopenia at ICU admission was associated with 90-day mortality (adjusted odds ratio 1.7; 95% CI 1.19–2.42). Conclusion Thrombocytopenia occurred in 43% of critically ill patients and was associated with worse outcomes including increased mortality. Platelet transfusions were given to 23% of patients with thrombocytopenia and most were prophylactic.publishedVersio

Actions menées en France suite à l’accident de Three Mile Island

L’accident de TMI a conduit à travers le monde nucléaire à de nombreuses actions d’amélioration de la Sûreté des tranches : - introduction de l’approche accidents graves et renforcement de l’organisation de crise, - amélioration de design comme les soupapes du pressuriseur, - développement des Etudes Probabilistes de Sûreté et de leur utilisation, - meilleure exploitation du Retour d’Expérience, - et enfin, renforcement de la conduite, avec des progrès importants dans la prise en compte du facteurs humains

Genetic variation of LEI0258 locus at major histocompatibility complex (MHC) region in Ethiopian indigenous village chicken

Indigenous chickens are locally adapted to environmental challenges and provide subsistence to millions of farmers in Africa. However, their productivity remains low compared to exotic strains. Efforts are being made to combine the local adaptation of indigenous chicken with productive traits of exotic chicken. Understanding the link between genetic diversity and environmental challenges leads to marker-assisted breed improvement programs for sustainable chicken production at smallholder level. Genetic variation at LEI0258 VNTR locus located within the MHC region has been linked to infectious disease resistance/susceptibility in commercial breeds. The aim of this study was to investigate allelic variability, genetic diversity and genetic relationships of 24 chicken populations in Ethiopia. Here, the diversity at LEI0258 in 236 chickens from 24 Ethiopian indigenous chicken populations using the major Histo-compatibility Complex linked LEI0258 marker is reported. A total of 236 DNA samples were genotyped by capillary electrophoresis from 24 chicken populations. The number of alleles, allele frequency, and heterozygosity levels were used to measure genetic variation at LEI0258 locus in Ethiopian indigenous village chicken. Twenty-nine LEI0258 alleles were observed using capillary electrophoresis that ranged from 185 to 569 bp with no significant difference in allele frequencies between populations. The number of alleles ranged from 179 (Meseret) to 569 (Batambie), with an average of 9.6 alleles per population. Allelic polymorphism was further evaluated through genotyping by Sanger sequencing. Twenty-three DNA samples with different fragment sizes were re-amplified and their alleles sequenced to depict polympormisms based on the combination of two repeat regions at 12 bp and 13 bp, respectively, and flanking regions with SNP and indels. The repeat region at 12 bp appeared 2 to 18 times, whereas the region at 13 bp appeared invariant in all populations. Sequence relationships revealed two distinct groups of alleles. The number of indels and mutations were 33 and 17, respectively. From capillary electrophoresis, the fixation coefficient of the sub-population within the total population (FST), inbreeding/fixation/ coefficient of an individual in a sub population (FIS) and total inbreeding /heterozygosity deficit/ coefficient of an individual within the total population (FIT) in the locus was 0.03, 0.08 and 0.11, respectively. Three percent of the genetic diversity was due to differences among populations, where as 8% and 89% were variations among individuals and variations within individuals, respectively. Despite the overall low genetic differentiation, both fragment and sequencing analysis revealed high allelic and genetic variability across the 24 populations. The high diversity at LEI0258 in Ethiopian indigenous village chicken populations supports the importance of the MHC region in relation to the disease challenges faced by smallholder poultry farmers across Ethiopia. We recommend that breed improvement programs ensure the maintenance of this diversity by selecting breeding stock as diverse as possible at the LEI0258 locus

Autoimmune Lymphoproliferative Syndrome-FAS Patients Have an Abnormal Regulatory T Cell (Treg) Phenotype but Display Normal Natural Treg-Suppressive Function on T Cell Proliferation

ObjectiveAutoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS.ResultsThe proportion of CD25highCD127low Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3+CD4+ T cells from ALPS patients and thus an abnormally low proportion of CD25highFOXP3+ Helios+ T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3lowCD45RA+) and an unusual subpopulation (CD4+CD127lowCD15s+CD45RA+). Despite this abnormal phenotype, the CD25highCD127low Tregs’ suppressive function was unaffected. Furthermore, conventional T cells from FAS-mutated patients showed normal levels of sensitivity to Treg suppression.ConclusionAn abnormal Treg phenotype is observed in circulating lymphocytes of ALPS patients. However, these Tregs displayed a normal suppressive function on T effector proliferation in vitro. This is suggesting that lymphoproliferation observed in ALPS patients does not result from Tregs functional defect or T effector cells insensitivity to Tregs suppression

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Objective<p>Autoimmune lymphoproliferative syndrome (ALPS) with FAS mutation (ALPS-FAS) is a nonmalignant, noninfectious, lymphoproliferative disease with autoimmunity. Given the central role of natural regulatory T cells (nTregs) in the control of lymphoproliferation and autoimmunity, we assessed nTreg-suppressive function in 16 patients with ALPS-FAS.</p>Results<p>The proportion of CD25^highCD127^low Tregs was lower in ALPS-FAS patients than in healthy controls. This subset was correlated with a reduced CD25 expression in CD3⁺CD4⁺ T cells from ALPS patients and thus an abnormally low proportion of CD25^highFOXP3⁺ Helios⁺ T cells. The ALPS patients also displayed a high proportion of naïve Treg (FOXP3^lowCD45RA⁺) and an unusual subpopulation (CD4⁺CD127^lowCD15s⁺CD45RA⁺). Despite this abnormal phenotype, the CD25^highCD127^low Tregs’ suppressive function was unaffected. Furthermore, conventional T cells from FAS-mutated patients showed normal levels of sensitivity to Treg suppression.</p>Conclusion<p>An abnormal Treg phenotype is observed in circulating lymphocytes of ALPS patients. However, these Tregs displayed a normal suppressive function on T effector proliferation in vitro. This is suggesting that lymphoproliferation observed in ALPS patients does not result from Tregs functional defect or T effector cells insensitivity to Tregs suppression.</p