Alpha-1 antitrypsin deficiency in a French General Hospital: fortuitous detection rather than efficient screening

Introduction: We studied the characteristics of the screening procedure for alpha-1 antitrypsin at Nevers Hospital (France), together with the performance of serum protein gel electrophoresis for the fortuitous detection of patients with deficiency. Material and methods: We carried out a retrospective study of requests for alpha-1 antitrypsin determination referred to the laboratory during 3 years. We compared these requests with the numbers of patients seen at the hospital and requiring screening according to international recommendations. In parallel, we reviewed all the serum protein gel electrophoresis results obtained during the same period. Results: The laboratory received 102 direct requests for alpha-1 antitrypsin determination, whereas more than 1397 patients presented an indication for screening. No case of alpha-1 antitrypsin deficiency was detected among the 102 patients screened. In parallel, 5551 serum protein gel electrophoresis analyses were carried out at the laboratory. A decrease in the size of the alpha-1 globulin fraction was detected in 68 patients. Seventeen of these patients underwent alpha-1 antitrypsin determinations and 14 were found to have alpha-1 antitrypsin deficiency. Conclusion: Alpha-1 antitrypsin deficiency was more frequently detected fortuitously, by electrophoresis, than through efficient screening. The exploration of alpha-1 globulin deficiencies by serum protein gel electrophoresis thus appears to be still a particularly efficient approach to the detection of alpha-1 antitrypsin deficiency and should be carried out systematically. Furthermore, the testing of all patients with an indication for screening according to international recommendations should be encouraged

Assessing the potential of crop model to reproduce Thinopyrum intermedium agro-ecosystems functioning and support knowledge acquisition about perennial grain crops.

Perennial crops are gaining increasing attention in recent years as they are proposed as a potential solution to address several challenges encountered with annual crops productions in the global context of agroecological transition. Indeed, it has been promoted to enhance carbon storage, microbiological activity and it could prevent issues such as fertilizing nutrients leaching or soil erosion. Worldwide, several selection programs are thus taking place to develop perennial crops or to create perennial versions of annual cereals (such as rice, rye and wheat). Regarding perenniality and grain production, one of the best foreseen candidates to produce perennial grain is Thinopyrum intermedium ((Host) Barkworth & D.R. Dewey), commercialized under the name of Kernza®. Its recent selection history is notably turned towards the increase of thousand kernels weight and the ease of thershing. Additionally, its original use as a forage crop makes it possible to consider a dual purpose of grain and fodder production during the same cropping year. The emergence of this relativelynew crop brings now questions and challenges regarding its management practices, its impact on soils and agronomic potentials or its integration into current cropping systems. Crop modeling is a powerful tool used in support of field experiments to improve our understanding of plants physiology, to test new technical itineraries or to assess crop response toward climate change. Developing relevant models remains important to accelerate and support knowledge acquisition about these new crops as well as assess their potentials, limitations and improvement path. The mechanistic STICS crop model was chosen to simulate Th. intermedium growth and development because of its proven ability to simulate various plants including wheat, vine, forage grasses or tomato.Due to the original behavior of Th. intermedium as a grassland producing grain, the plant was simulated using similar formalisms as the ones used for annual cereal crop. The perenniality of the plant was simulated by an external algorithm which kept values of state variables from the end of a simulation and use them as starting values for the next one. Field data were collected under Belgian conditions (temperate area, deep loamy soil) during 4 years and under multiple fertilization management schemes. After a parametrization and a calibration/validation process, the model showed very good results regarding the simulation of phenology, biomass production, grain yield and nitrogen nutrition. Multi simulations were then run over twenty past meteorological dataset in order to determine the optimal nitrate fertilization scheme for the crop. Results showed that a total application of 100 kgN/ha separated in two fractions allowed to maximize high grain yield probability. A first fraction should ideally be applied at the stem elongation stage with an amount of 75 kgN/ha and a second during autumn, with an additional amount of 25 kgN/ha. These results are consistent with the findings of Jungers et al. (2017) who showed that an application of nitrogen fertilizer in the form of urea at rates ranging from 60 kgN/ha and 100 kgN/ha in spring allowed to achieve the best yields by maximizing fertile tillers. These early results are encouraging and support the idea that crop modeling can be a powerful tool to support and accelerate knowledge acquisition about these new types of crops. Further investigations will be done in order to evaluate the robustness of the model in various agroclimatic regions. In addition, new formalism will be tested regarding the modeling of bellowground biomass dynamics. Jungers, J.M., DeHaan, L.R., Betts, K.J., Sheaffer, C.C. and Wyse, D.L. (2017), Intermediate Wheatgrass Grain and Forage Yield Responses to Nitrogen Fertilization. Agronomy Journal, 109: 462-472. https://doi.org/10.2134/agronj2016.07.0438Nature-based perennial grain cropping as a model to safeguard functional biodiversity towards future-proof agriculture12. Responsible consumption and productio

Diagnostyka niedoboru alfa-1-antytrypsyny we francuskim szpitalu ogólnym — przypadkowe rozpoznania czy systematyczny skrining?

WSTĘP: Poddano analizie procedurę badania przesiewowego w kierunku niedoboru alfa-1-antytrypsyny (A1AT) w Szpitalu w Nevers (Francja) oraz badań elektroforezy białek surowicy wykonanych w celu wykrycia niedoboru A1AT. MATERIAŁ I METODY: Badanie miało charakter retrospektywny. Przeanalizowano wyniki oznaczenia niedoboru alfa-1-antytrypsyny wykonanych na bezpośrednie zlecenie w okresie 3 lat oraz wyniki badań przesiewowych w kierunku niedoboru A1AT realizowanych zgodnie z międzynarodowymi rekomendacjami. Oceniono również wyniki elektroforezy białek surowicy uzyskane w tym samym okresie. WYNIKI: Na bezpośrednie badanie stężenia alfa-1-antytrypsyny skierowano 102 pacjentów, podczas gdy 1392 pacjentów spełniało wskazania do badania przesiewowego. Nie wykryto żadnego przypadku niedoboru wśród zbadanych 102 pacjentów. W tym czasie w laboratorium wykonano 5551 badań elektroforezy białek surowicy. Obniżenie frakcji alfa-1 globulin stwierdzono u 68 badanych. U 17 pacjentów oznaczono stężenie alfa-1-antytrypsyny i u 14 stwierdzono niedobór. WNIOSKI: Niedobór alfa-1-antytrypsyny częściej wykrywa się przypadkowo w badaniu elektroforezy białek surowicy niż w wyniku badania przesiewowego. Badanie niedoboru alfa-1 globulin za pomocą elektroforezy białek surowicy wydaje się wciąż najbardziej skuteczną metodą detekcji i powinno być wykonywane systematycznie. Co więcej, badaniem tą metodą powinni być objęci wszyscy pacjenci poddani badaniu skriningowemu, realizowanemu zgodnie z międzynarodowymi wytycznymi.WSTĘP: Poddano analizie procedurę badania przesiewowego w kierunku niedoboru alfa-1-antytrypsyny (A1AT) w Szpitalu w Nevers (Francja) oraz badań elektroforezy białek surowicy wykonanych w celu wykrycia niedoboru A1AT. MATERIAŁ I METODY: Badanie miało charakter retrospektywny. Przeanalizowano wyniki oznaczenia niedoboru alfa-1-antytrypsyny wykonanych na bezpośrednie zlecenie w okresie 3 lat oraz wyniki badań przesiewowych w kierunku niedoboru A1AT realizowanych zgodnie z międzynarodowymi rekomendacjami. Oceniono również wyniki elektroforezy białek surowicy uzyskane w tym samym okresie. WYNIKI: Na bezpośrednie badanie stężenia alfa-1-antytrypsyny skierowano 102 pacjentów, podczas gdy 1392 pacjentów spełniało wskazania do badania przesiewowego. Nie wykryto żadnego przypadku niedoboru wśród zbadanych 102 pacjentów. W tym czasie w laboratorium wykonano 5551 badań elektroforezy białek surowicy. Obniżenie frakcji alfa-1 globulin stwierdzono u 68 badanych. U 17 pacjentów oznaczono stężenie alfa-1-antytrypsyny i u 14 stwierdzono niedobór. WNIOSKI: Niedobór alfa-1-antytrypsyny częściej wykrywa się przypadkowo w badaniu elektroforezy białek surowicy niż w wyniku badania przesiewowego. Badanie niedoboru alfa-1 globulin za pomocą elektroforezy białek surowicy wydaje się wciąż najbardziej skuteczną metodą detekcji i powinno być wykonywane systematycznie. Co więcej, badaniem tą metodą powinni być objęci wszyscy pacjenci poddani badaniu skriningowemu, realizowanemu zgodnie z międzynarodowymi wytycznymi

Sleep and wake disturbances following traumatic brain injury

Traumatic brain injury (TBI) is a major health concern in industrialised countries. Sleep and wake disturbances are among the most persistent and disabling sequelae after TBI. Yet, despite the widespread complaints of post-TBI sleep and wake disturbances, studies on their etiology, pathophysiology, and treatments remain inconclusive. This narrative review aims to summarise the current state of knowledge regarding the nature of sleep and wake disturbances following TBI, both subjective and objective, spanning all levels of severity and phases postinjury. A second goal is to outline the various causes of post-TBI sleep-wake disturbances. Globally, although sleep-wake complaints are reported in all studies and across all levels of severity, consensus regarding the objective nature of these disturbances is not unanimous and varies widely across studies. In order to optimize recovery in TBI survivors, further studies are required to shed light on the complexity and heterogeneity of post-TBI sleep and wake disturbances, and to fully grasp the best timing and approach for intervention

A Pitfall in the Diagnosis of Unresectable Liver Metastases: Multiple Bile Duct Hamartomas (von Meyenburg Complexes)

Von Meyenburg complexes (VMC) are a cluster of benign liver malformations including biliary cystic lesions, with congenital fibrocollagenous stroma. This rare entity can mimick multiple secondary hepatic lesions. We report a case of a 56-year-old woman who had multiples liver lesions 12 years after operation for breast cancer. Biopsy of the hepatic lesion confirmed the diagnosis of VMC. Preoperative discovery of multiple gray-white nodular lesions scattered on the surface of the liver should not always contraindicate curative liver resection. The diagnosis of VMC should be known and confirmed with liver biopsy

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers