Le déclin cognitif dans la maladie d'Alzheimer

Les travaux sur l'histoire naturelle de la maladie d'Alzheimer (MA) ont souligné que le mode et la vitesse du déclin cognitif au cours de la maladie étaient très variables selon les patients. L'étude des patients ayant un déclin cognitif rapide (DCR) mérite une attention particulière en raison de leur prévalence non négligeable et de leur pronostic plus péjoratif. En pratique clinique, c'est important de repérer les patients à risque de DCR le plus précocement possible afin d'anticiper une prise en charge plus adaptée pour ce groupe des patients. En l'absence de traitements curatifs, les enjeux de la recherche épidémiologique dans la MA sont essentiellement basés sur la prévention et le ralentissement de son évolution. Objectifs : Ce travail de thèse comporte deux objectifs généraux : 1) étudier le déclin cognitif rapide dans la MA: pronostic, définition, trajectoire et facteurs de risque ; 2) étudier des facteurs modifiables du déclin cognitif faciles à implémenter dans la pratique clinique: la perte de poids et le traitement par les inhibiteurs de l'enzyme de conversion de l'Angiotensine (IECs). Méthodes : Afin de répondre à ces objectifs, deux populations des patients atteints d'une MA à un stade léger à modéré ont été étudiées à l'issue de la cohorte Française REAL.FR et de la cohorte européenne ICTUS. Résultats : Les résultats majeurs de ce travail de thèse sont que les patients ayant un DCR, définit par une perte de = 4 points au MMSE durant 6 mois, présentent une augmentation significative du risque de mortalité (HR = 5,6, 95% CI 2,0-15,9), d'institutionnalisation (HR = 3,8, 95% CI 1,8-8,1) et de perte d'autonomie fonctionnelle (HR = 1,6, 95% CI 1,2-2,3) à 18 mois de suivi. Deux types de profils parmi les patients ayant un DCR ont été identifiés : 1) ceux avec un DCR " persistant " dans le temps (12%) et 2) ceux avec un déclin cognitif " réversibles " (21%). Le cluster " déclineurs rapides persistants " présente une perte annuelle de 5,5 points au MMSE. Les variables associées à un risque accru de DCR sont liées au mode de vie (seul à domicile), à un statut cognitif et fonctionnel plus altérés à l'inclusion et à l'absence d'hypertension. Dès le stade léger du déficit, tous les items de l'ADAS-cog explorant le langage (HR =2,8, 95%IC =1,7-4,5) sont des facteurs prédictifs indépendants d'un DCR de même que les items " Exécution d'ordres" (HR=1,9, 95%IC =1,9-4,3) et " Praxies constructives " (HR=2,8, 95%IC =1,9-4,3) à 2 ans de suivi. Ces résultats ont permis de distinguer un profil d'atteinte cognitive particulière prédictif d'un DCR. Ces résultats suggèrent que les patients atteints d'une MA avec DCR pourraient presenter une forme particulière et distincte de MA. Les résultats répondant au deuxième objectif général de ce travail de thèse démontrent que la perte de poids est un facteur prédictif de DCR (HR= 1,58, 95%IC = 1,14-2,21) et que la consommation des IECs est associée, indépendamment de la hypertension, à un moindre déclin cognitif à 4 ans de suivi par rapport aux ceux qui n'en ont jamais consommés (-7,5 points au MMSE ± 0,9 vs. -9,7 ± 0,4; p = 0,03).The rate of cognitive decline in Alzheimer's disease (AD) varies considerably between individuals. The assessment of how rapidly the disease is progressing has important implications in clinical practice and for care planification, since patients presenting with rapid cognitive decline (RCD) are frequent and have a poorer prognosis. Therefore, their early identification is essential. In the absence of a curative treatment for AD, the current challenge of the epidemiologic research is based on the prevention and on slowing down the progression of the disease. Objectives: This thesis has two general aims: 1) To study RCD in AD: prognostic, definition, trajectory and risk factors and a psychometric profile. 2) To study potential modifiable factors in affecting cognitive decline, and easy to be implemented in clinical practice: weight loss and the treatment by angiotensin-converting enzyme inhibitors (ACE-Is). Methods: In order to answer to our objectives, two populations of mild to moderate AD community-dwelling patients have been assessed from the multicenter French cohort REAL.FR and the multicenter European cohort ICTUS. Results: The main results of the this work are that patients with a RCD, defined as a loss of = 4 points in MMSE during 6 months, showed a significantly increased risk of mortality (HR = 5.6, 95% CI 2.0-15.9), risk of physical decline (HR = 1.6, 95% CI 1.2-2.3) and institutionalization (HR = 3.8, 95% CI 1.8-8.1) at the 2-year follow-up. Two types of profile of patients with RCD (~30%) have been identified: 1) those classified as either "temporary" (~21%) and 2) those as "continuous" (~12%). The cluster " continuous rapid decliners " presented a yearly loss of 5,5 points in MMSE. Living alone, lower cognitive level at entry into the study, greater loss of autonomy and the absence of hypertension were associated with a higher risk of RCD. Early language impairments assessed by ADAS-cog sub-scales are predictors of future RCD (HR =2,8, 95%IC =1,7-4,5), as well as for "Commands" (HR=1,9, 95%IC =1,9-4,3) and "Constructional praxis" (HR=2,8, 95%IC =1,9-4,3) at 2 years of follow-up. These results allowed identifying a particular psychometric profile of RCD. All these previous results could suggest that AD with RCD represent an AD sub-type with a distinct entity. The main results of the second part of this thesis show that weight loss is an independent predictor factor of RCD (HR= 1,58, 95%IC = 1,14-2,21) and that the use of ACE-s is associated, independently of hypertension at each visit, with a slower cognitive decline: participants who had continuously or intermittently used ACE-Is had a significant difference in 4-year MMSE decline from those who had never used ACE-Is (-7,5 points au MMSE ± 0,9 vs. -9,7 ± 0,4; p = 0,03)

Environmental phosphate differentially affects virulence phenotypes of uropathogenic Escherichia coli isolates causative of prostatitis

K-12 Escherichia coli cells grown in static media containing a critical phosphate (Pi) concentration 25 mM maintained a high polyphosphate (polyP) level in stationary phase, impairing biofilm formation, a phenomenon that is triggered by polyP degradation. Pi concentration in human urine fluctuates according to health state. Here, the influence of environmental Pi concentration on the occurrence of virulence traits in uropathogenic E. coli (UPEC) isolated from acute prostatitis patients was evaluated. After a first screening, 3 isolates were selected according to differential biofilm formation profiles depending on media Pi concentration. For each isolate, biofilm positive and negative conditions were established. Regardless of the isolate, biofilm formation capacity was accompanied with curli and cellulose production and expression of some key virulence factors associated with adhesion. When the selected isolates were grown in their non-biofilm-forming condition, low concentrations of nalidixic acid and ciprofloxacin induced biofilm formation. Interestingly, similar to laboratory strains, polyP degradation induced biofilm formation in the selected isolates. Data demonstrated the complexity of UPEC responses to environmental Pi and the importance of polyP metabolism in the virulence of clinical isolates.Fil: Grillo Puertas, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Martinez Zamora, Martin Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Rintoul, Maria Regina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Soto, Sara M.. Universidad de Barcelona; EspañaFil: Rapisarda, Viviana Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentin

Environmental phosphate differentially affects virulence phenotypes of uropathogenic Escherichia coli isolates causative of prostatitis

K-12 Escherichia coli cells grown in static media containing a critical phosphate (Pi) concentration 25 mM maintained a high polyphosphate (polyP) level in stationary phase, impairing biofilm formation, a phenomenon that is triggered by polyP degradation. Pi concentration in human urine fluctuates according to health state. Here, the influence of environmental Pi concentration on the occurrence of virulence traits in uropathogenic E. coli (UPEC) isolated from acute prostatitis patients was evaluated. After a first screening, 3 isolates were selected according to differential biofilm formation profiles depending on media Pi concentration. For each isolate, biofilm positive and negative conditions were established. Regardless of the isolate, biofilm formation capacity was accompanied with curli and cellulose production and expression of some key virulence factors associated with adhesion. When the selected isolates were grown in their non-biofilm-forming condition, low concentrations of nalidixic acid and ciprofloxacin induced biofilm formation. Interestingly, similar to laboratory strains, polyP degradation induced biofilm formation in the selected isolates. Data demonstrated the complexity of UPEC responses to environmental Pi and the importance of polyP metabolism in the virulence of clinical isolates.Fil: Grillo Puertas, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Martinez Zamora, Martin Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Rintoul, Maria Regina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; ArgentinaFil: Soto, Sara M.. Universidad de Barcelona; EspañaFil: Rapisarda, Viviana Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentina. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química Biológica; Argentin

INVESTIGACIÓN EN QUÍMICA, BIOLOGÍA Y AGRONOMÍA

Este libro es el segundo de una serie de dos dedicado a los avances lo relativo a las mezclas de diesel y biodiesel obtenido a partir del aceite de semillas de jatropha curcas, entre otros temas de ese ombustible verde; es decir algo que está al día en cuanto a las búsqueda de fuentes de energía limpias; otro tema ampliamente tratado es el del nitrógeno como elemento de fertilización -que junto con la densidad poblacional de las plantas- buscan prácticas agronómicas para obtener mayores rendimientos. El objetivo final de este libro es el mismo: incorporar cada vez más bibliografía que enriquezca las opciones de consulta por parte de interesados en aspectos particulares y, desde luego, divulgar nuevos conocimentos y ofrecer los resultados del quehacer universitario

Meta-DiSc 2.0:a web application for meta-analysis of diagnostic test accuracy data

BACKGROUND: Diagnostic evidence of the accuracy of a test for identifying a target condition of interest can be estimated using systematic approaches following standardized methodologies. Statistical methods for the meta-analysis of diagnostic test accuracy (DTA) studies are relatively complex, presenting a challenge for reviewers without extensive statistical expertise. In 2006, we developed Meta-DiSc, a free user-friendly software to perform test accuracy meta-analysis. This statistical program is now widely used for performing DTA meta-analyses. We aimed to build a new version of the Meta-DiSc software to include statistical methods based on hierarchical models and an enhanced web-based interface to improve user experience. RESULTS: In this article, we present the updated version, Meta-DiSc 2.0, a web-based application developed using the R Shiny package. This new version implements recommended state-of-the-art statistical models to overcome the limitations of the statistical approaches included in the previous version. Meta-DiSc 2.0 performs statistical analyses of DTA reviews using a bivariate random effects model. The application offers a thorough analysis of heterogeneity, calculating logit variance estimates of sensitivity and specificity, the bivariate I-squared, the area of the 95% prediction ellipse, and the median odds ratios for sensitivity and specificity, and facilitating subgroup and meta-regression analyses. Furthermore, univariate random effects models can be applied to meta-analyses with few studies or with non-convergent bivariate models. The application interface has an intuitive design set out in four main menus: file upload; graphical description (forest and ROC plane plots); meta-analysis (pooling of sensitivity and specificity, estimation of likelihood ratios and diagnostic odds ratio, sROC curve); and summary of findings (impact of test through downstream consequences in a hypothetical population with a given prevalence). All computational algorithms have been validated in several real datasets by comparing results obtained with STATA/SAS and MetaDTA packages. CONCLUSION: We have developed and validated an updated version of the Meta-DiSc software that is more accessible and statistically sound. The web application is freely available at www.metadisc.es

Exercise-based interventions to enhance long-term sustainability of physical activity in older adults: a systematic review and meta-analysis of randomized clinical trials

Older adults; Physical activity; AdherenceAdultos mayores; Actividad física; AdherenciaAdults majors; Activitat física; AdherènciaExercise is a form of physical activity (PA). PA is an important marker of health and quality of life in older adults. The purpose of this study was to conduct a systematic review of the literature to assess the effect of exercise-based interventions on an at least six-month follow up PA measure, and to describe the specific strategies implemented during the intervention to strengthen the sustainability of PA in community-dwelling 65+ year-old adults. We registered and conducted a systematic review and meta-analysis (PROSPERO: CRD42017070892) of randomized clinical trials (RCT). We searched three electronic databases during January 2018 to identify RCT assessing any type of exercise-based intervention. Studies had to report a pre-, post-, and at least 6-month post-intervention follow-up. To be included, at least one PA outcome had to be assessed. The effect of exercise-based interventions was assessed compared to active (e.g., a low-intensity type of exercise, such as stretching or toning activities) and non-active (e.g., usual care) control interventions at several time points. Secondary analyses were conducted, restricted to studies that reported specific strategies to enhance the sustainability of PA. The intervention effect was measured on self-reported and objective measures of time spent in PA, by means of standardized mean differences. Standardized mean differences of PA level were pooled. Pooled estimates of effect were computed with the DerSimonian–Laird method, applying a random effects model. The risk of bias was also assessed. We included 12 studies, comparing 18 exercise intervention groups to four active and nine non-active control groups. Nine studies reported specific strategies to enhance the long-term sustainability of PA. The strategies were mostly related to the self-efficacy, self-control, and behavior capability principles based on the social cognitive theory. Exercise interventions compared to active control showed inconclusive and heterogeneous results. When compared to non-active control, exercise interventions improved PA time at the six-months follow up (standardized mean difference (SMD) 0.30; 95%CI 0.15 to 0.44; four studies; 724 participants; I2 0%), but not at the one- or two-years follow-ups. No data were available on the mid- and long-term effect of adding strategies to enhance the sustainability of PA. Exercise interventions have small clinical benefits on PA levels in community-dwelling older adults, with a decline in the observed improvement after six months of the intervention cessation.The present study was funded by United States Department of Health & Human Services National Institutes of Health (NIH), USA, and NIH National Institute on Aging (NIA), USA, (K24 AG057728)

Comparative genomic hybridization and amplotyping by arbitrarily primed PCR in stage A B-CLL

Cytogenetic analysis is useful in the diagnosis and to assess prognosis of B-cell chronic lymphocytic leukemia (B-CLL). However, successful cytogenetics by standard techniques has been hindered by the low in vitro mitotic activity of the malignant B-cell population. Fluorescence in situ hybridization (FISH) has become a useful tool, but it does not provide an overall view of the aberrations. To overcome this hurdle, two DNA-based techniques have been tested in the present study: comparative genomic hybridization (CGH) and amplotyping by arbitrarily primed PCR (AP-PCR). Comparative genomic hybridization resolution depends upon the 400-bands of the human standard karyotype. AP-PCR allows detection of allelic losses and gains in tumor cells by PCR fingerprinting, thus its resolution is at the molecular level. Both techniques were performed in 23 patients with stage A B-CLL at diagnosis. The results were compared with FISH. The sensitivity of AP-PCR was greater than CGH (62% vs. 43%). The use of CGH combined with AP-PCR allowed to detect genetic abnormalities in 79% (15/19) of patients in whom G-banding was not informative, providing a global view of the aberrations in a sole experiment. This study shows that combining these two methods with FISH, makes possible a more precise genetic characterization of patients with B-CLL

National survey: how do we approach the patient at risk of clinical deterioration outside the ICU in the spanish context?

Background: Anticipating and avoiding preventable intrahospital cardiac arrest and clinical deterioration are important priorities for international healthcare systems and institutions. One of the internationally followed strategies to improve this matter is the introduction of the Rapid Response Systems (RRS). Although there is vast evidence from the international community, the evidence reported in a Spanish context is scarce. Methods: A nationwide cross-sectional research consisting of a voluntary 31-question online survey was performed. The Spanish Society of Intensive, Critical and Coronary Care Medicine (SEMICYUC) supported the research. Results: We received 62 fully completed surveys distributed within 13 of the 17 regions and two autonomous cities of Spain. Thirty-two of the participants had an established Rapid Response Team (RRT). Common frequency on measuring vital signs was at least once per shift but other frequencies were contemplated (48.4%), usually based on professional criteria (69.4%), as only 12 (19.4%) centers used Early Warning Scores (EWS) or automated alarms on abnormal parameters. In the sample, doctors, nurses (55%), and other healthcare professionals (39%) could activate the RRT via telephone, but only 11.3% of the sample enacted this at early signs of deterioration. The responders on the RRT are the Intensive Care Unit (ICU), doctors, and nurses, who are available 24/7 most of the time. Concerning the education and training of general ward staff and RRT members, this varies from basic to advanced and specific-specialized level, simulating a growing educational methodology among participants. A great number of participants have emergency resuscitation equipment (drugs, airway adjuncts, and defibrillators) in their general wards. In terms of quality improvement, only half of the sample registered RRT activity indicators. In terms of the use of communication and teamwork techniques, the most used is clinical debriefing in 29 centers. Conclusions: In terms of the concept of RRS, we found in our context that we are in the early stages of the establishment process, as it is not yet a generalized concept in most of our hospitals. The centers that have it are in still in the process of maturing the system and adapting themselves to our context