La marche (un moyen standardisable de l'évaluation des capacités au cours des maladies cardiovasculaires ?)

Les maladies cardio et cérébro-vasculaires représentent la première cause de mortalité et de handicap dans le monde. Du fait des progrès thérapeutiques dans la prise en charge de ces pathologies à la phase aigüe, le nombre de patients porteurs de formes chroniques de ces affections limitant leurs capacités d effort est en augmentation constante. La problématique de ce travail de thèse s articule autour de l utilisation des tests de marche standardisés dans l évaluation des capacités d effort des patients porteurs de pathologies coronariennes. Nous avons dans un premier temps rappelé les notions de handicap et de qualité de vie appliqués aux maladies chroniques, et la nécessité d évaluations fonctionnelles spécifiques pour en apprécier le retentissement et l évolution. Puis nous avons fait le point sur les modalités actuelles de la réadaptation cardiaque, en développant plus particulièrement la place de l activité physique. Nous avons entrepris ensuite l étude des sollicitations physiologiques induites par un test de marche rapide de 200 mètres (TMR200) chez des sujets âgés sains, puis sur une population de patients coronariens. Ce test s est avéré bien toléré, et correspond à une intensité d exercice intermédiaire entre le premier seuil ventilatoire et les capacités maximales d exercice. Il apparaît ainsi particulièrement intéressant pour apprécier les capacités à effectuer des efforts fréquents de la vie quotidienne, plus intenses que ceux correspondant à la marche à vitesse spontanément adoptée au cours du classique tes de marche de 6 minutes (correspondant à un effort essentiellement aérobie). Par la suite nous avons cherché à définir la différence minimale cliniquement pertinente du test de marche (MCID) de 6 minutes (TM6) et du TMR200, afin de mieux interpréter les progrès fonctionnels des patients intégrés dans les programmes de réadaptation cardiaque après un syndrome coronarien aigu. Cette dernière a été estimée à 25 mètres pour le TM6. Enfin, nous avons étudié l intérêt de ces tests de marche dans l aide à l individualisation de la prescription de l intensité du réentraînement chez les patients coronariens. Ces modalités permettent aux patients d être plus souvent proches des intensités d entraînement conventionnellement préconisées, en aboutissant à des résultats comparables, sans la nécessité de pratiquer un test d effort maximal mobilisant des moyens significatifs en personnel et en matériel. Au total, ce travail apporte des arguments pour l utilisation en pratique clinique courante de ces tests de marche standardisés. Ils apparaissent complémentaires dans le cadre de l évaluation objective des capacités fonctionnelles et de la qualité de vie perçue des patients âgés et coronariens. Ces résultats ouvrent des perspectives pour poursuivre l étude de leurs propriétés métrologiques et de leurs applications cliniques au cours des affections chroniques incapacitantes.Cardiovascular and cerebrovascular diseases remain the first cause of mortality and handicap in the world. With the improvements in the management of the acute phase, the number of patients with limited exercise capacity due to chronic cardiovascular disease is increasing. The aim of this thesis was to conduct a thorough study of the use of standardized walk tests to assess exercise capacity in coronary artery disease patients. We first explain the concepts of handicap and quality of life in chronic diseases, and the need for functional evaluations in order to assess their impact and evolution. We then present the current modalities of cardiac rehabilitation, emphasizing the importance of physical activity. We studied the physiological demands of a 200-meter fast-walk test (200MFWT) in healthy elderly subjects, and in coronary artery disease patients. This test was well tolerated, and corresponds to an effort intensity lying between the ventilatory threshold and maximal exercise capacity. It therefore appears interesting to assess the capacities of an individual to perform activities encountered in daily life that are more intense than walking at a self-selected comfortable speed, as during the 6-minute walk test (6-MWT) (corresponding to a moderate submaximal intensity solicitation, mainly aerobic). We then investigated the minimal clinically important difference of the 6MWT and 200MFWT, in order to better appraise functional improvements in patients undergoing cardiac rehabilitation after an acute coronary syndrome. This difference has been estimated at 25 metres for the 6MWT. Finally, we studied the interest of using these walk tests to individualize training intensity prescription in these patients. These modalities bring patients closer to the recommended intensity, while leading to results comparable to those of more traditional training programs, without the need for repeated expensive tests. In conclusion, this work supports the use of these standardized walk tests in routine clinical setting. They bring complementary information in the assessment of functional capacity and perceived quality of life in elderly patients and those with coronary artery disease. These results are a basis for further investigations regarding their metrological properties and clinical applications in various chronic diseases that reduce exercise capacity.DIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

094: Contribution of cardiac MRI to early evaluation and impact on the long term follow-up in myocarditis mimicking an acute coronary syndrome. A 43-cases prospective study

BackgroundAcute myocarditis (AM) diagnosis is a challenge to rule out an acute coronary syndrome (ACS). AM is thought to favour the evolution towards dilated cardiomyopathy (DCM) and the occurrence of severe arrhythmias. Three months after the acute episode, re-evaluation including cardiac MRI could help to identify patients at risk for unfavourable evolution. The use of MRI has rarely been investigated in AM prognosis stratification.Method and resultswe report a prospective series of 43 consecutive patients hospitalized for AM mimicking ACS: 36 men and 7 women, 32 years old on average, without sign of heart failure. All patients presented with troponine I elevation. Echocardiography showed moderate global left ventricular dysfunction in 6 cases and segmental wall motion abnormalities in 22. MRI performed early after admission never showed myocardial first-pass perfusion defect after gadolinium injection but subepicardial delayed-enhancement (DE) areas in 39 cases mainly located in lateral segments. Three months after the acute episode, no patient was symptomatic. Echocardiography, Holter monitoring and biological check-up were normal. MRI showed the persistence of DE in 23 cases without wall motion abnormality in the affected segments. The presence of these latter abnormalities led to effect an annually clinical examination with an ECG. One patient was lost at further follow-up. Among the other 22 patients, only one patient dysplayed heart failure revealing DCM with ventricular arrhythmias at 3 - year mean follow-up.Conclusionsat the time of admission, the absence of early perfusion defect at cardiac MRI after gadolinium injection and the subepicardial localization of the DE constitute reliable criteria in favour of AM diagnosis, allowing to rule out ACS. During the follow-up the persistence of a DE does not allow any prognosis stratification. In our series after a mean 3-year follow-up, it is not associated with any clinical and para-clinical disorder except in one case

Tetratricopeptide repeat domain 7A is a nuclear factor that modulates transcription and chromatin structure

A loss-of-function mutation in tetratricopeptide repeat domain 7A (TTC7A) is a recently identified cause of human intestinal and immune disorders. However, clues to related underlying molecular dysfunctions remain elusive. It is now shown based on the study of TTC7A-deficient and wild-type cells that TTC7A is an essential nuclear protein. It binds to chromatin, preferentially at actively transcribed regions. Its depletion results in broad range of epigenomic changes at proximal and distal transcriptional regulatory elements and in altered control of the transcriptional program. Loss of WT_TTC7A induces general decrease in chromatin compaction, unbalanced cellular distribution of histones, higher nucleosome accessibility to nuclease digestion along with genome instability, and reduced cell viability. Our observations characterize for the first time unreported functions for TTC7A in the nucleus that exert a critical role in chromatin organization and gene regulation to safeguard healthy immune and intestinal status.</p

Lipidomic approach in young adult triathletes: effect of supplementation with a polyphenols-rich juice on neuroprostane and F2-dihomo-isoprostane markers

The aim of the this study was to determine the effect of a polyphenols-rich juice (aronia-citrus juice, ACJ) on F4-neuroprostanes and F2-dihomo-isoprostanes—markers of oxidative stress associated with the central nervous system (CNS)—in 16 elite triathletes under a controlled diet for triathlon training (145 days). In the triathletes, a decrease of the lipid peroxidation markers after ACJ intake, associated with neuronal membrane degradation (10-epi-10-F4t-neuroprostane and 10-F4t-neuroprostane), was observed when compared with placebo stage values. Regarding the F2-dihomo-isoprostanes, a significant decrease of the neuromotor system damage biomarkers (17-F2t-dihomo-isoprostane) with an increase of training load during the study was observed, although the decrease of the load training at the last stage showed a significant increase of the values of ent-7-(RS)-7-F2t-dihomo-IsoP, suggesting a possible role in adaptation post-training. On the other hand, the changes in the excretion of 17-epi-17-F2t-dihomo-IsoP provided a positive connection between physical exercise and ACJ intake. Thus, the results showed in this clinical study in young triathletes will help to elucidate novel interactions and mechanisms between the excretion of lipid peroxidation metabolites from CNS, supplementation of polyphenols-rich juice in the diet and physical exercise during a training season.This study was supported by the project AGL2011-23690 (CICYT) (Spanish Ministry of Economy and Competitiveness). This work has been partially funded by the “Fundación Séneca de la Región de Murcia” Grupo de Excelencia 19900/GERM/15. LAGF was granted a pre-doctoral FPI fellowship (BES2012-060185) by the Spanish government

Orthoparamyxovirinae C Proteins Have a Common Origin and a Common Structural Organization

The protein C is a small viral protein encoded in an overlapping frame of the P gene in the subfamily Orthoparamyxovirinae. This protein, expressed by alternative translation initiation, is a virulence factor that regulates viral transcription, replication, and production of defective interfering RNA, interferes with the host-cell innate immunity systems and supports the assembly of viral particles and budding. We expressed and purified full-length and an N-terminally truncated C protein from Tupaia paramyxovirus (TupV) C protein (genus Narmovirus). We solved the crystal structure of the C-terminal part of TupV C protein at a resolution of 2.4 Å and found that it is structurally similar to Sendai virus C protein, suggesting that despite undetectable sequence conservation, these proteins are homologous. We characterized both truncated and full-length proteins by SEC-MALLS and SEC-SAXS and described their solution structures by ensemble models. We established a mini-replicon assay for the related Nipah virus (NiV) and showed that TupV C inhibited the expression of NiV minigenome in a concentration-dependent manner as efficiently as the NiV C protein. A previous study found that the Orthoparamyxovirinae C proteins form two clusters without detectable sequence similarity, raising the question of whether they were homologous or instead had originated independently. Since TupV C and SeV C are representatives of these two clusters, our discovery that they have a similar structure indicates that all Orthoparamyxovirine C proteins are homologous. Our results also imply that, strikingly, a STAT1-binding site is encoded by exactly the same RNA region of the P/C gene across Paramyxovirinae, but in different reading frames (P or C), depending on which cluster they belong to.French Agence Nationale de la RechercheFond de la Recherche Médicale (FRM)Grenoble Instruct-ERIC centerFRISBIUniversity Grenoble Alpes graduate school (Ecoles Universitaires de Recherche)Peer Reviewe

Assessment oxidative stress biomarkers –neuroprostanes and dihomo-isoprostanes- in elite triathletes urine after two weeks of moderate altitude training

This randomized and controlled trial investigated whether the increase in elite training at different altitudes altered the oxidative stress biomarkers of the nervous system. This is the first study to investigate four F4-neuroprostanes and four F2-dihomo-isoprostanes quantified in 24-hour urine. The quantification was carried out by Ultra High Pressure Liquid Chromatography-triple Quadrupole-Tandem Mass Spectrometry (UHPLC-QqQ-MS/MS). Sixteen elite triathletes agreed to participate in the project. They were randomized in two groups, a group submitted to Altitude Training (n=8) and a group submitted to Sea Level Training (n=8), with a Control group of non-athletes (n=8). After experimental period, the Altitude Training group triathletes gave significant data: 17-epi-17-F2t-dihomo-IsoP (from 5.2 ± 1.4 µg/mL 24 h-1 to 6.6 ± 0.6 µg/mL 24 h-1), ent-7(RS)-7-F2t-dihomo-IsoP (from 6.6 ± 1.7 µg/mL 24 h-1 to 8.6 ± 0.9 µg /mL 24 h-1), and ent-7-epi-7-F2t-dihomo-IsoP (from 8.4 ± 2.2 µg/mL 24 h-1 to 11.3 ± 1.8 µg/mL 24 h-1) increased, while, of the neuronal degeneration-related compounds, only 10-epi-10-F4t-NeuroP (8.4 ± 1.7 µg/mL 24 h-1) and 10-F4t-NeuroP (5.2 ± 2.9 µg/mL 24 h-1) were detected in this group. For the control group and sea level training groups, no significant changes had occurred at the end of the 2-weeks experimental period. Therefore, and as the main conclusion, the training at moderate altitude increased the F4-NeuroPs- and F2-dihomo-isoPs-related oxidative damage of the central nervous system (CNS) compared to similar training at sea level.This study was supported by the project AGL2011-23690 (CICYT) (Spanish Ministry of Economy and Competitiveness). LAGF was granted with a pre-doctoral FPI fellowship BES2012-060185 by the Spanish government. The authors are also grateful to the University of Alicante for its collaboration. Sonia Medina was appointed under a research contract from the project AGL2011-23690 (CICYT)

An atypical cyclin-dependent kinase controls Plasmodium falciparum proliferation rate

Malaria parasites multiply in human erythrocytes through schizogony, a process characterised by nuclear divisions in the absence of cytokinesis, leading to the formation of a multinucleated schizont from which individual daughter cells are subsequently generated. Here, we provide evidence that parasites lines lacking Pfcrk-5, an atypical cyclin-dependent kinase, display a reduced parasitemia growth rate linked to a decrease in the number of daughter nuclei produced by each schizont. We show that in vitro activity of recombinant Pfcrk-5 is indeed cyclin-dependent and that the enzyme localises to the nuclear periphery. Thus, Pfcrk-5 is part of a regulatory pathway that mediates the proliferation rate of Plasmodium falciparum through the control of nuclear divisions during schizogony

Dietary antioxidant intake is inversely associated with 2,3-dinor oxylipin metabolites, the major excreted oxylipins in overweight and obese subjects

Cardiometabolic disease risk factors, including obesity, insulin resistance, high blood pressure, and dyslipidemia, are associated with elevated oxidative stress biomarkers like oxylipins. Increased adiposity by itself induces various isomers of this oxidized lipid family, while dietary polyphenols show benefits in its regulation. Previously, we showed that specific co-abundant microorganisms characterized the gut microbiota of Colombians and associated differentially with diet, lifestyle, obesity, and cardiometabolic health status, which led us to hypothesize that urinary oxylipins would reflect the intensity of oxidative metabolism linked to gut microbiota dysbiosis. Thus, we selected a convenience sample of 105 participants (age: 40.2 ± 11.9 years, 47.6% women), grouped according to microbiota, cardiometabolic health status, and body mass index (BMI); and evaluated 33 urinary oxylipins by HPLC-QqQ-MS/MS (e.g., isoprostanes, prostaglandins, and metabolites), paired with anthropometry and blood chemistry information and dietary antioxidants estimated from a 24-h food recall. In general, oxylipins did not show differences among individuals who differed in gut microbiota. While the unmetabolized oxylipin levels were not associated with BMI, the total content of oxylipin metabolites was highest in obese and cardiometabolically abnormal subjects (e.g., insulin resistant), mainly by prostaglandin-D (2,3-dinor-11β-PGF) and 15-F-IsoPs (2,3-dinor-15-F-IsoP and 2,3-dinor-15-epi-15-F-IsoP) metabolites. The total polyphenol intake in this cohort was 1070 ± 627 mg/day. After adjusting for body weight, the polyphenol intake was significantly higher in lean than overweight and showed an inverse association with dinor-oxylipin levels in principal component analysis. These results suggest that the 2,3-dinor-oxylipins could be more specific biomarkers associated with BMI than their parent oxylipins and that are sensitive to be regulated by dietary antioxidants.The authors thank the volunteers who agreed to participate in this study, the Colombian Ministry of science, technology, and innovation (Minciencias; grant number 832-2018), and Grupo Empresarial Nutresa. They also thank the Ibero-American Programme for Science, Technology and Development (CYTED) – Action 112RT0460 CORNUCOPIA networ