Flow-mediated-paradoxical vasoconstriction is independently associated with asymptomatic myocardial ischemia and coronary artery disease in type 2 diabetic patients.

International audienceBACKGROUND: To investigate whether flow-mediated dilation (FMD) impairment, which precedes overt atherosclerosis, is associated with silent myocardial ischemia (SMI) and asymptomatic coronary artery disease (CAD) in type 2 diabetes. METHODS: Forearm FMD was measured by ultrasonography in 25 healthy control, 30 non-diabetic overweight or obese patients and 118 asymptomatic type 2 diabetic patients with a high cardiovascular risk profile. SMI (abnormal stress myocardial scintiscan and/or stress dobutamine echocardiogram) and CAD (coronary angiography in the patients with SMI) were assessed in the diabetic cohort. RESULTS: FMD was lower in diabetic patients (median 0.61% (upper limits of first and third quartiles -1.22;3.2)) than in healthy controls (3.95% (1.43;5.25), p < 0.01) and overweight/obese patients (4.25% (1.74;5.56), p < 0.01). SMI was present in 60 diabetic patients, including 21 subjects with CAD. FMD was lower in patients with SMI than in those without (0.12% (-2.3;1.58) vs 1.64% (0;3.69), p < 0.01), with a higher prevalence of paradoxical vasoconstriction (50.0% vs 29.3%, p < 0.05). FMD was also lower in patients with than without CAD (-1.22% (-2.5;1) vs 1.13% (-0.4;3.28), p < 0.01; paradoxical vasoconstriction 61.9% vs 34.4%, p < 0.05). Logistic regression analyses considering the parameters predicting SMI or CAD in univariate analyses with a p value <0.10 showed that paradoxical vasoconstriction (odds ratio 2.7 [95% confidence interval 1.2-5.9], p < 0.05) and nephropathy (OR 2.6 [1.2-5.7], p < 0.05) were independently associated with SMI; and only paradoxical vasoconstriction (OR 3.1 [1.2-8.2], p < 0.05) with CAD. The negative predictive value of paradoxical vasoconstriction to detect CAD was 88.7%. CONCLUSIONS: In diabetic patients, FMD was independently associated with SMI and asymptomatic CAD.Trial registration: Trial registration number NCT00685984

Microevolution of bank voles (Myodes glareolus) at neutral and immune-related genes during multiannual dynamic cycles : Consequences for Puumala hantavirus epidemiology

Understanding howhost dynamics, including variations of population size and dispersal, may affect the epidemiology of infectious diseases through ecological and evolutionary processes is an active research area. Here we focus on a bank vole (Myodes glareolus) metapopulation surveyed in Finland between 2005 and 2009. Bank vole is the reservoir of Puumala hantavirus (PUUV), the agent of nephropathia epidemica (NE, a mild form of hemorrhagic fever with renal symptom) in humans. M. glareolus populations experience multiannual density fluctuations that may influence the level of genetic diversity maintained in bank voles, PUUV prevalence and NE occurrence. We examine bank vole metapopulation genetics at presumably neutral markers and immunerelated genes involved in susceptibility to PUUV (Tnf-promoter, Tlr4, Tlr7 and Mx2 gene) to investigate the links between population dynamics, microevolutionary processes and PUUV epidemiology. We show that genetic drift slightly and transiently affects neutral and adaptive genetic variability within the metapopulation. Gene flow seems to counterbalance its effects during the multiannual density fluctuations. The low abundance phase may therefore be too short to impact genetic variation in the host, and consequently viral genetic diversity. Environmental heterogeneity does not seem to affect vole gene flow, which might explain the absence of spatial structure previously detected in PUUV in this area. Besides, our results suggest the role of vole dispersal on PUUV circulation through sex-specific and density-dependent movements. We find little evidence of selection acting on immune-related genes within this metapopulation. Footprint of positive selection is detected at Tlr-4 gene in 2008 only. We observe marginally significant associations between Mx2 genotype and PUUV genogroups. These results show that neutral processes seem to be the main factors affecting the evolution of these immune-related genes at a contemporary scale, although the relative effects of neutral and adaptive forces could vary temporally with density fluctuations. Immune related gene polymorphism may in turn partly influence PUUV epidemiology in this metapopulation. (C) 2016 Published by Elsevier B.V.Peer reviewe

A 454 multiplex sequencing method for rapid and reliable genotyping of highly polymorphic genes in large-scale studies

Background: High-throughput sequencing technologies offer new perspectives for biomedical, agronomical and evolutionary research. Promising progresses now concern the application of these technologies to large-scale studies of genetic variation. Such studies require the genotyping of high numbers of samples. This is theoretically possible using 454 pyrosequencing, which generates billions of base pairs of sequence data. However several challenges arise: first in the attribution of each read produced to its original sample, and second, in bioinformatic analyses to distinguish true from artifactual sequence variation. This pilot study proposes a new application for the 454 GS FLX platform, allowing the individual genotyping of thousands of samples in one run. A probabilistic model has been developed to demonstrate the reliability of this method. Results: DNA amplicons from 1,710 rodent samples were individually barcoded using a combination of tags located in forward and reverse primers. Amplicons consisted in 222 bp fragments corresponding to DRB exon 2, a highly polymorphic gene in mammals. A total of 221,789 reads were obtained, of which 153,349 were finally assigned to original samples. Rules based on a probabilistic model and a four-step procedure, were developed to validate sequences and provide a confidence level for each genotype. The method gave promising results, with the genotyping of DRB exon 2 sequences for 1,407 samples from 24 different rodent species and the sequencing of 392 variants in one half of a 454 run. Using replicates, we estimated that the reproducibility of genotyping reached 95%. Conclusions: This new approach is a promising alternative to classical methods involving electrophoresis-based techniques for variant separation and cloning-sequencing for sequence determination. The 454 system is less costly and time consuming and may enhance the reliability of genotypes obtained when high numbers of samples are studied. It opens up new perspectives for the study of evolutionary and functional genetics of highly polymorphic genes like major histocompatibility complex genes in vertebrates or loci regulating self-compatibility in plants. Important applications in biomedical research will include the detection of individual variation in disease susceptibility. Similarly, agronomy will benefit from this approach, through the study of genes implicated in productivity or disease susceptibility trait

Role of the cabins as shelters for the lesser horseshoe bat

Dans le cadre d’un programme coordonné par le Parc naturel régional du Luberon, l’expertise présentée ici a porté sur l’inventaire des colonies de Petits Rhinolophes (Rhinolophus hipposideros) présentes dans le petit patrimoine bâti. Au total, sur les 561 cabanons et maisonnettes répertoriés, seuls 120 sont inhabités et présentent un état compatible avec l’accueil de Petits Rhinolophes. Les auteurs ont mis en évidence que seule la toiture en tuile « canal » est une caractéristique architecturale favorable à l’installation d’une colonie de reproduction, mais que cela ne se vérifie pas pour une simple fréquentation de l’espèce. Aucune relation statistiquement signifi cative n’a été découverte pour les critères d’état général du bâti ou le nombre de niveaux. Une relative plasticité écologique du Petit rhinolophe vis-à-vis du choix de son gîte en est déduite, mais lors de la mise-bas, l’espèce montre des besoins particuliers, probablement relatifs à la température. La population des cabanons représente plus du quart de la population reproductrice totale des communes inspectées. Il est donc primordial de mettre en œuvre les mesures nécessaires au maintien de ce réseau de gîtes.Within the context of a programme coordinated by the regional nature Park of Luberon, the expert evaluation presented here is focused on the inventory of the colony of Lesser Horseshoe Bats (Rhinolophus hipposideros) present in the little built patrimony. In total, over the 561 cabins and little houses itemized, only 120 are uninhabited and present a compatible state for the accomodation of this bat. The authors have put in evidence that only the “canal” tile roof is a favourable architectural characteristic for the installation of a reproductive colony, but that is not verified for the simple frequenting of the species. No significant relation has been discovered for the general state criterion of the frame or the number of levels. The authors deduct a relative ecological plasticity of the Lesser Horseshoe Bat concerning the choice of its shelter, but during birth, the species shows special needs, probably relative to temperature. The population of the cabins represents more than the quarter of the total reproductive population of the inspected district. Therefore it is essential to take the measures necessary to maintain this network of shelters

Diversité génétique, variation géographique et flux géniques chez quelques Lépidoptères Rhopalocères français

International audienceWe present here a comparative and synthetic study of the genetic structure of the populations of three French butterfly species, Proclossiana eunomia, Parnassius apollo and Euphydryas aurinia. Using allozyme electrophoresis, it is possible to estimate the level of genetic variation within and between populations of these species in various regions of France and neighbouring countries. These data also allow us to suggest an explanation of this variation: present functioning of populations and metapopulations, adaptation to foodplants and history of the European biomes during the last twenty millenia. Each of the presented cases presents a biogeographical specificity: very disjunct distribution of the “glacial relict” type (Proclossiana eunomia), widespread mountain species, presently in strong regression (Parnassius apollo), ecologically very diversified species (Euphydryas aurinia). Generally speaking, genetic variation is large at both local and regional scale in southern regions where the genetic structure follows a clear geographic structure. Northern populations show a lower genetic diversity and a confused genetic structure, with an isolation-by-distance effect lower or absent. This phenomenon is the most obvious in P. eunomia populations resulting from a deliberate introduction in northeastern Massif Central 25 years ago. In the case of E. aurinia, the adaptation to different foodplants plays a rôle in genetic differentiation and its geographic variation. These characteristics can be explained at least in part by the postglacial colonization of northern Europe from southern refugia where temperate and mediterranean biomes were concentrated during glacial times. This extension has been accompanied by a loss of genetic diversity and a variation without clearcut geographic organization. Otherwise, the very large ecological diversity of southern Europe has allowed and still allows a larger genetic differentiation within species. The northwards shift of species distribution associated with present climate change is therefore likely to cause a severe loss of genetic diversity within species.Nous présentons une étude synthétique et comparative de la structure génétique des populations de trois papillons diurnes français, Proclossiana eunomia, Parnassius apollo et Euphydryas aurinia. Grâce à l’électrophorèse des allozymes, il a été possible d’estimer comparativement le niveau de variation génétique à l’intérieur des divers peuplements des espèces étudiées. Ces données permettent également de proposer des éléments d’explication de cette variation: fonctionnement actuel des populations et métapopulations, histoire des biomes ouest-européens au cours des vingt derniers millénaires. Chacun des cas étudiés possède une spécificité biogéographique: distribution de type „ relique glaciaire ” très disjointe (P. eunomia), espèce de montagne largement répandue, mais en forte régression (P. apollo), espèce très diversifiée écologiquement (E. aurinia). D’une manière générale, les populations méridionales montrent des variations importantes au niveau local et régional et présentent une structuration géographique nette. Les populations septentrionales montrent une diversité génétique plus faible et une structuration spatiale confuse, avec un effet d’isolement par la distance faible ou absent. Ce phénomène est le plus accusé pour les populations du Nord-Est du Massif Central de P. eunomia, qui résultent d’une introduction délibérée datant de 25 ans. Dans le cas d’ E. aurinia, l’adaptation à des plantes nourricières différentes est aussi liée à la différenciation génétique et à sa variation géographique. Ces caractéristiques peuvent être au moins partiellement expliquées par la colonisation postglaciaire du nord de l’Europe à partir des refuges méridionaux où les biomes tempérés et méditerranéens étaient concentrés pendant les glaciations. Cette colonisation s’est accompagnée d’une perte de diversité génétique et d’une variation sans structuration géographique nette. Par ailleurs, la diversification écologique très élevée du sud de l’Europe permet et a permis une plus grande diversification génétique. Le glissement vers le nord des aires de nombreuses espèces risque donc de s’accompagner d’une perte de diversité génétique

Association between hypothyroidism and metabolic profile in gestational diabetes mellitus

IntroductionThyroid hormones exert many effects on glucose metabolism. Gestational diabetes mellitus (GDM) and hypothyroidism during gestation (HG) are the most common gestational endocrinopathies and seem to be associated. We therefore explored in women with GDM whether the presence of HG is associated with a different metabolic profile.Materials and methodsWe included 1,290 pregnant women with GDM [International Association of the Diabetes and Pregnancy Study Group (IADPSG)/World Health Organization (WHO) criteria] and no history of hypothyroidism prior to pregnancy who had a measure of thyroid-stimulating hormone (TSH) and anti-thyroperoxidase antibodies during their hospital stay after GDM diagnosis. Patients with thyrotoxicosis and previous bariatric surgery were excluded. We evaluated concomitant blood pressure, fasting glycemia, insulinemia [with calculation of homeostatic model assessment for insulin resistance (HOMA-IR) index], glycated hemoglobin (HbA1c), and lipid profile according to the presence of HG (American Thyroid Association 2017 definition: TSH ≥ 4 mUI/L).ResultsThe mean (± standard deviation) age was 33 ± 5 years, the mean body mass index was 27 ± 5 kg/m2, and 117 women (9%) displayed HG. HG was associated with higher HbA1c (5.35 ± 0.56% vs. 5.22 ± 0.52%, p = 0.009), even after adjustment for gestational age, age, and body mass index. TSH was also positively associated with HbA1c (p = 0.006) and HOMA-IR (p = 0.002). Patients with HG displayed less often an early GDM, with their fasting glycemia before 24 weeks of amenorrhea being lower than that of patients with a TSH &lt; 4 mU/L.ConclusionIn our cohort of patients with GDM, women with HG showed higher HbA1c than those without and HOMA-IR was positively associated with the level of TSH

Insights into Myodes glareolus / Puumala hantavirus interactions from rodent immunogenetics

Nephropathia epidemica (NE) is a mild form of hemorrhagic fever with renal syndrome (HFRS) caused by the hantavirus Puumala (PUUV). In Europe, its distribution is fragmented, whereas the bank vole Myodes glareolus, which is the reservoir of PUUV, is common all over the continent. Determining the causes underlying this heterogeneity is of main importance to better understand and prevent the risks of NE emergence. Besides climatic and ecological hypotheses, we have proposed that the geographic variability of bank vole immune responses to PUUV infection could shape differences in PUUV prevalence, and consequently NE incidence. We have tested this hypothesis by studying polymorphisms and / or expression levels of six candidate genes involved in the immune response to PUUV (DRB-MHC, TNF-alpha promoter, TLR4, TLR7, Mx2, Integrin bêta3) on ten populations of bank voles sampled in the French Ardennes, along a North-South transect including PUUV endemic and non-endemic areas. Signatures of selection have been evidenced for TNF-alpha and Mx2 genes using population genetics (FST scan) and genotype - phenotype association approaches. These genes have antiviral properties but also induce immunological damages, what make them central for driving a balance of resistance / tolerance to PUUV. Bank voles vary in their basal ability to tolerate/resist to PUUV. In high PUUV prevalence areas, TNF-alpha and Mx2 expression seemed down-regulated what suggest selection or phenotypic plasticity for higher tolerance to PUUV, at the benefit of lower immunopathological costs. Some of these results have been confirmed at the European scale.Le campagnol roussâtre Myodes glareolus est le réservoir de l’hantavirus Puumala (PUUV), responsable chez l’Homme d’une forme atténuée de Fièvre Hémorragique à Syndrome Rénal (FHSR), la Néphropathie Épidémique (NE). En Europe, l’incidence de la NE présente, malgré la distribution continue du réservoir, une forte variabilité géographique dont les causes ne sont à ce jour pas identifiées. Aux hypothèses climatiques et paysagères, nous proposons que des facteurs intrinsèques aux campagnols puissent également être impliqués. Une plus forte tolérance à l’infection par le virus PUUV, chez certains campagnols roussâtres, favoriserait la persistance et la transmission de ce virus, ce qui devrait accroître le risque de NE chez l’Homme. Nous avons testé cette hypothèse en étudiant les polymorphismes et/ou les niveaux d'expression de six gènes candidats impliqués dans la réponse immunitaire à PUUV (DRB-CMH, promoteur du TNF-alpha, TLR4, TLR7, Mx2, intégrine bêta3) chez dix populations de campagnols échantillonnées le long d’un axe nord/sud dans les Ardennes françaises, couvrant des zones endémiques et non endémiques à PUUV. Des signatures de sélection ont été détectées pour TNF-alpha et Mx2 grâce à des approches de génétique des populations (scan FST) et d’associations génotypes / phénotypes. Ces gènes codent des protéines dont les propriétés antivirales sont connues, mais qui induisent des coûts immunopathologiques importants. Ils pourraient donc jouer un rôle central dans une balance de tolérance / résistance à PUUV. De plus, dans les zones d’endémie, les gènes TNF-alpha et Mx2 sont sous-exprimés, ce qui suggère l’évolution d’une plus forte tolérance à PUUV, potentiellement au bénéfice d’un moindre coût immunopathologique. Certains de ces résultats ont été confirmés à l’échelle européenn

Sex inequalities in cardiovascular risk factors and their management in primary prevention in adults living with type 1 diabetes in Germany and France : findings from DPV and SFDT1

Introduction & objectives: To evaluate whether cardiovascular risk factors and their management differ in primary prevention between adult males and females with type 1 diabetes (T1D) in two European countries in 2020–2022 and sex inequalities in achievement of standards of care in diabetes. Methods: We used 2020–2022 data of patients without a cardiovascular history in the Prospective Diabetes Follow-up registry (DPV) centres, in Germany, and the Société Francophone du Diabète– Cohorte Diabète de Type 1 cohort (SFDT1), in France. Results: We included 2,657 participants from the DPV registry and 1,172 from the SFDT1 study. Body mass indexes were similar in females and males with similar proportions of HbA1c  3.4 mmol/L (DPV: 19.9 (females) vs 23.9% (males), p = 0.01; SFDT1 17.0 vs 19.2%, p = 0.43), statin therapy was less often prescribed in females than males in DPV (7.9 vs 17.0%, p < 0.01), SFDT1 (18.2 vs 21.0%, p = 0.42). Conclusion: In both studies, females in primary prevention have a better cardiovascular risk profile than males. We observed a high rate of therapeutic inertia, which might be higher in females for statin treatment and nephroprotection with ACEi-ARB, especially in Germany. Diabetologists should be aware of sex-specific differences in the management of cardiorenal risk factors to develop more personalized prevention strategies

Antagonistic effects of smoking and maternal glycemia on fetal growth: a retrospective study among 13,958 pregnant French women

IntroductionSmoking and hyperglycemia first diagnosed during pregnancy (H1inP) have opposing effects on fetal growth. The aim of this study was to explore adverse pregnancy outcomes, particularly fetal growth, according to the smoking and H1inP status.MethodsWe included 13,958 women from a large French dataset (2012–2018). Using multivariable regression analyses, we retrospectively evaluated the risk of large-for-gestational-age (LGA) babies and other adverse outcomes according to the H1inP and smoking status in four groups: no H1inP/non-smoker (group A: n = 10,454, 88.2%), no H1inP/smoker (group B: n = 819, 5.9%), H1inP/non-smoker (group C: n = 2,570, 18.4%), and H1inP/smoker (group D: n = 115, 0.8%).ResultsThe rates of LGA were 8.9%, 4.0%, 14.6%, and 8.7% in groups A, B, C, and D, respectively (global ANOVA p &lt; 0.0001, factor H1inP p = 0.0003, factor smoking p = 0.0002, and interaction p = 0.48). After adjustment for potential confounders including age, body mass index, employment, ethnicity, parity, hypertension before pregnancy, gestational weight gain, and alcohol and drug consumption, H1inP was associated with a higher risk [odds ratio (OR) = 1.50, 95% confidence interval (95%CI) = 1.30–1.74] and smoking with a lower risk (OR = 0.35, 95%CI = 0.25–0.50) of LGA. In addition, H1inP was associated with a lower total gestational weight gain and a lower rate of small-for-gestational-age (SGA) babies, but higher rates of hypertensive disorders and more frequent caesarean sections and admissions in the neonatal intensive care unit. Smoking was associated with higher rates of SGA, including severe SGA (&lt;3rd centile), and this despite a higher total gestational weight gain. Smoking increased the risk of hypertensive disorders only in women with H1inP.DiscussionSmoking among women with H1inP could mask the risk of maternal hyperglycemia for LGA babies. This could provide a false sense of security for women with H1inP who smoke, particularly when assessing for LGA alone, but these women still face other risks to their health, such as hypertensive disorders and the health of the fetus

Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia

WSTĘP. Celem badania było ustalenie wartości predykcyjnej niemego niedokrwienia mięśnia sercowego (SMI, silent myocardial ischemia) i neuropatii układu autonomicznego serca (CAN, cardiac autonomic neuropathy) u chorych na cukrzycę bez objawów choroby niedokrwiennej serca. MATERIAŁ I METODY. Do badania włączono 120 chorych na cukrzycę, którzy nie przebyli zawału serca i u których wcześniej nie rozpoznano dławicy piersiowej, z prawidłowym zapisem elektrokardiograficznym (EKG) z 12 odprowadzeń oraz z co najmniej dwoma dodatkowymi czynnikami ryzyka. Nieme niedokrwienie mięśnia sercowego rozpoznawano na podstawie elektrokardiograficznej próby wysiłkowej, scyntygrafii mięśnia sercowego z zastosowaniem talu201 po obciążeniu dipirydamolem i 48-godzinnego monitorowania EKG. Neuropatię układu autonomicznego serca wykrywano za pomocą standaryzowanych badań oceniających zmienność rytmu serca. Dokładne dane z trwającej 3-7 lat (średnio 4,5 roku) obserwacji uzyskano od 107 osób. WYNIKI. U 33 chorych (30,7%) stwierdzono SMI. U 33 spośród 75 zbadanych osób (38,9%) wykryto CAN, a u 11 z nich doszło do poważnych incydentów sercowych. Spośród tych 75 chorych poważne incydenty sercowe występowały podobnie często w grupach SMI+ i SMI- (odpowiednio 6 incydentów u 25 osób vs. 5 u 50 osób), natomiast były znacznie częstsze w grupie CAN+ niż CAN- (odpowiednio 8 u 33 vs. 3 u 42 osób, p = 0,04), z ryzykiem względnym wynoszącym 4,16 (95% CI 1,01-17,19). Największą częstość analizowanych incydentów obserwowano u chorych z SMI i CAN (u 5 z 10 osób). Po skorygowaniu względem SMI stwierdzono istotną zależność między CAN a poważnymi incydentami sercowymi (p = 0,04). WNIOSKI. W przypadku chorych na cukrzycę bez objawów choroby niedokrwiennej serca, CAN wydaje się lepszym parametrem zwiastującym możliwość wystąpienia poważnych incydentów wieńcowych niż SMI. Ryzyko związane z wystąpieniem CAN jest niezależne od występowania SMI i jest najwyższe, gdy CAN i SMI obserwuje się u tego samego pacjenta.INTRODUCTION. The aim of this study was to determine the predictive value of silent myocardial ischemia (SMI) and cardiac autonomic neuropathy (CAN) in asymptomatic diabetic patients. MATERIAL AND METHODS. We recruited 120 diabetic patients with no history of myocardial infarction or angina, a normal 12-lead electrocardiogram (ECG), and two or more additional risk factors. SMI assessment was carried out by means of an ECG stress test, a thallium-201 myocardial scintigraphy with dipyridamole, and 48-h ECG monitoring. CAN was searched for by standardized tests evaluating heart rate variations. Accurate follow-up information for 3&#8211;7 years (mean 4.5) was obtained in 107 patients. RESULTS. There was evidence of SMI in 33 patients (30.7%). CAN was detected in 33 of the 75 patients (38.9%) who were tested, and a major cardiac event occurred in 11 of them. Among these 75 patients, the proportion of major cardiac events in the SMI+ patients was not significantly higher than that in the SMI&#8211; patients (6 of 25 vs. 5 of 50 patients), whereas it was significantly higher in the CAN+ patients than in the CAN&#8211; patients (8 of 33 vs. 3 of 42 patients; P = 0.04), with a relative risk of 4.16 (95% CI 1.01&#8211;17.19) and was the highest in the patients with both SMI and CAN (5 of 10 patients). After adjusting for SMI, there was a significant association between CAN and major cardiac events (P = 0.04). CONCLUSIONS. In asymptomatic diabetic patients, CAN appears to be a better predictor of major cardiac events than SMI. The risk linked to CAN appears to be independent of SMI and is the highest when CAN is associated with SMI