Prospective registry of symptomatic severe aortic stenosis in octogenarians: a need for intervention.

OBJECTIVE To study the factors associated with choice of therapy and prognosis in octogenarians with severe symptomatic aortic stenosis (AS). STUDY DESIGN Prospective, observational, multicenter registry. Centralized follow-up included survival status and, if possible, mode of death and Katz index. SETTING Transnational registry in Spain. SUBJECTS We included 928 patients aged ≥80 years with severe symptomatic AS. INTERVENTIONS Aortic-valve replacement (AVR), transcatheter aortic-valve implantation (TAVI) or conservative therapy. MAIN OUTCOME MEASURES All-cause death. RESULTS Mean age was 84.2 ± 3.5 years, and only 49.0% were independent (Katz index A). The most frequent planned management was conservative therapy in 423 (46%) patients, followed by TAVI in 261 (28%) and AVR in 244 (26%). The main reason against recommending AVR in 684 patients was high surgical risk [322 (47.1%)], other medical motives [193 (28.2%)], patient refusal [134 (19.6%)] and family refusal in the case of incompetent patients [35 (5.1%)]. The mean time from treatment decision to AVR was 4.8 ± 4.6 months and to TAVI 2.1 ± 3.2 months, P < 0.001. During follow-up (11.2-38.9 months), 357 patients (38.5%) died. Survival rates at 6, 12, 18 and 24 months were 81.8%, 72.6%, 64.1% and 57.3%, respectively. Planned intervention, adjusted for multiple propensity score, was associated with lower mortality when compared with planned conservative treatment: TAVI Hazard ratio (HR) 0.68 (95% confidence interval [CI] 0.49-0.93; P = 0.016) and AVR HR 0.56 (95% CI 0.39-0.8; P = 0.002). CONCLUSION Octogenarians with symptomatic severe AS are frequently managed conservatively. Planned conservative management is associated with a poor prognosis.

Intrauterine devices and endometrial cancer risk : a pooled analysis of the Epidemiology of Endometrial Cancer Consortium

Intrauterine devices (IUDs), long-acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual-level data from 4 cohort and 14 case-control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled-ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled-OR = 0.81, 95% CI = 0.74-0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled-OR = 0.69, 95% CI = 0.58-0.82), older age at first use (≥35 years pooled-OR = 0.53, 95% CI = 0.43-0.67), older age at last use (≥45 years pooled-OR = 0.60, 95% CI = 0.50-0.72), longer duration of use (≥10 years pooled-OR = 0.61, 95% CI = 0.52-0.71) and recent use (within 1 year of study entry pooled-OR = 0.39, 95% CI = 0.30-0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes.

Pacing redistributes glycogen within the developing myocardium.

Electrical pacing at physiological rate induces myocardial remodeling associated with regional changes in workload, blood flow and oxygen consumption. However, to what extent energy-producing pathways are also modified within the paced heart remains to be investigated. Pacing could particularly affect glycogen metabolism since hypertrophy stimulates glycolysis and increased workload favors glucose over fat oxidation. In order to test this hypothesis, we used the embryonic chick heart model in which ventricular pacing rapidly resulted in thinning of the ventricle wall and thickening of the atrial wall. Hearts of stage 22HH chick embryos were submitted in ovo to asynchronous and intermittent ventricular pacing delivered at physiological rate during 24 h. The resulting alterations of glycogen content were determined in atrium, ventricle and conotruncus of paced and sham-operated hearts. Hemodynamic parameters of the paced and spontaneously beating hearts were derived from computerized image analysis of video recordings. With respect to sham, paced hearts showed a significant decrease in glycogen content (nmoles glucose units/microg protein; mean+/-S.D.) only in atrium (1.48+/-0.40 v 0.84+/-0.34, n=8) and conotruncus (0.75+/-0.28 v 0.42+/-0.23, n=8). Pacing decreased the end diastolic and stroke volumes by 34 and 44%, respectively. Thus, the rapid glycogen depletion in regions remote from the stimulation site appears to be associated with regional changes in workload and remodeling. These findings underscore the importance of the coupling mechanisms between metabolic pathways and myocardial remodeling in the ectopically paced heart.

Direct visualization of the trimeric structure of the ASIC1a channel, using AFM imaging.

There has been confusion about the subunit stoichiometry of the degenerin family of ion channels. Recently, a crystal structure of acid-sensing ion channel (ASIC) 1a revealed that it assembles as a trimer. Here, we used atomic force microscopy (AFM) to image unprocessed ASIC1a bound to mica. We detected a mixture of subunit monomers, dimers and trimers. In some cases, triple-subunit clusters were clearly visible, confirming the trimeric structure of the channel, and indicating that the trimer sometimes disaggregated after adhesion to the mica surface. This AFM-based technique will now enable us to determine the subunit arrangement within heteromeric ASICs.

Péritonites infectieuses en dialyse péritonéale: Facteurs prédictifs et complications. Etude rétrospective au CHUV de 1995 à 2010

Contexte : La dialyse péritonéale (DP) est une méthode d'épuration extra-rénale qui utilise les propriétés physiologiques du péritoine comme membrane de dialyse. Cette technique requiert la présence d'un cathéter placé chirurgicalement dans le cul-de-sac de Douglas pour permettre l'instillation d'une solution de dialyse : le dialysat. Une des complications redoutée de cette technique est la survenue de péritonites infectieuses qui nécessitent l'administration rapide d'une antibiothérapie adéquate. Les péritonites peuvent parfois entrainer le retrait du cathéter de dialyse avec un échec définitif de la technique, ou plus rarement entrainer le décès du patient. Cette étude s'intéresse aux facteurs prédictifs de cette complication. Elle recense les germes impliqués et leur sensibilité aux différents antibiotiques. Cette étude analyse également les conséquences des péritonites, telles que la durée moyenne des hospitalisations, les échecs de la technique nécessitant un transfert définitif en hémodialyse et la survenue de décès. Méthode : Il s'agit d'une étude rétrospective monocentrique portant sur le dossier des patients inclus dans le programme de dialyse péritonéale du CHUV entre le 1er janvier 1995 et le 31 décembre 2010. Résultats : Cette étude inclus 108 patients, dont 65 hommes et 43 femmes. L'âge moyen est de 52.5 ans ± 17.84 (22-87). On répertorie 113 épisodes de péritonite pour une durée cumulative de 2932.24 mois x patients. L'incidence globale de péritonite s'él��ve à 1 épisode / 25.95 (mois x patient). La médiane de survie globale sans péritonite est de 23.56 mois. Une variabilité intergroupe statistiquement significative en matière de survie sans péritonite est démontrée entre les patients autonomes et non- autonomes [Log Rank (Mantel-Cox) :0.04], entre les patients diabétiques et non diabétiques [Log Rank (Mantel-Cox) : 0.002] et entre les patients cumulant un score de Charlson supérieur à 5 et ceux cumulant un score inférieur ou égal à 5 (Log Rank (Mantel-Cox) : 0.002). Une différence statistiquement significative en matière de survie de la technique a également pu être démontrée entre les patients autonomes et 2 non-autonome [Log Rank (Mantel-Cox) &lt; 0.001], et entre les patients cumulant un score de Charlson supérieur ou inférieur ou égal à 5 [Log Rank (Mantel-Cox) : 0.047]. Le staphylococcus epidermidis est le pathogène le plus fréquemment isol�� lors des péritonites (23.9%). Ce germe présente une sensibilité de 40.74% à l'oxacilline. Aucun cas de péritonite à MRSA n'a été enregistré dans ce collectif de patients. Une péritonite a causé la mort d'un patient (&lt;1%). Conclusion : L'incidence de péritonite calcul��e satisfait les recommandations de la Société Internationale de Dialyse Péritonéale (ISPD). Une variabilité intergroupe statistiquement significative en terme de survie sans péritonite est mis en évidence pour : l'autonomie, le statut métabolique et le score de comorbidité de Charlson. Une variabilité intergroupe statistiquement significative en terme de survie de la technique est également démontrée pour : l'autonomie et le score de comorbidité de Charlson. Les statistiques de sensibilité mettent en évidence une excellente couverture antibiotique sur les germes isol��s par le traitement empirique en vigueur (vancomycine + ceftazidime). La mortalité relative aux péritonites est extrêmement basse dans ce collectif de patients.

Mobilidade de metais pesados em solo tratado com resíduo siderúrgico ácido

Amostras do horizonte Bt de um Podzólico Vermelho-Amarelo (PV), predominante no aterro-piloto de resíduos industriais (ARSI) da Companhia Siderúrgica Nacional (CSN), foram acondicionadas, em 1992, em colunas de vidro com 5,4 cm de diâmetro e 37 cm de altura. Sobre essas amostras de solo foram colocadas amostras de um resíduo ácido da CSN na proporção solo-resíduo de 4:1 (conforme a concepção básica do projeto do ARSI). Tal sistema resíduo-solo foi lixiviado com 50 volumes-poro de água deionizada, com pH 4,5, com o objetivo de avaliar a movimentação de Cr, Mn, Ni, Cu, Zn, Cd e Pb nas colunas. Depois da lixiviação, removeu-se o resíduo do topo das colunas, e seccionaram-se as amostras de solo em 4 partes iguais. Os metais pesados das amostras do resíduo e do solo foram extraídos seqüencialmente. 0 Pb, Cu e Cr mobilizados do resíduo ficaram retidos nos primeiros 5 cm da coluna de solo. 0 Zn, Mn, Ni e Cd tiveram aumento da concentração em profundidade. Nos efluentes das colunas com o resíduo, foram observadas concentrações de Mn e Ni bem superiores aos padrões permitidos pela Fundação Estadual de Engenharia do Meio Ambiente (FEEMA, 1985).

Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced by many cells and tissues including pancreatic beta-cells, liver, skeletal muscle, and adipocytes. This study investigates the potential role of MIF in carbohydrate homeostasis in a physiological setting outside of severe inflammation, utilizing Mif knockout (MIF-/-) mice. Compared with wild-type (WT) mice, MIF-/- mice had a lower body weight, from birth until 4 months of age, but subsequently gained weight faster, resulting in a higher body weight at 12 months of age. The lower weight in young mice was related to a higher energy expenditure, and the higher weight in older mice was related to an increased food intake and a higher fat mass. Fasting blood insulin level was higher in MIF-/- mice compared with WT mice at any age. After i.p. glucose injection, the elevation of blood insulin level was higher in MIF-/- mice compared with WT mice, at 2 months of age, but was lower in 12-month-old MIF-/- mice. As a result, the glucose clearance during intraperitoneal glucose tolerance tests was higher in MIF-/- mice compared with WT mice until 4 months of age, and was lower in 12-month-old MIF-/- mice. Insulin resistance was estimated (euglycemic-hyperinsulinemic clamp tests), and the phosphorylation activity of AKT was similar in MIF-/- mice and WT mice. In conclusion, this mouse model provides evidence for the role of MIF in the control of glucose homeostasis.

Diffusion Spectrum Imaging after stroke shows structural changes in the contra-lateral motor network correlating with functional recovery

There is growing interest in understanding the role of the non-injured contra-lateral hemisphere in stroke recovery. In the experimental field, histological evidence has been reported that structural changes occur in the contra-lateral connectivity and circuits during stroke recovery. In humans, some recent imaging studies indicated that contra-lateral sub-cortical pathways and functional and structural cortical networks are remodeling, after stroke. Structural changes in the contra-lateral networks, however, have never been correlated to clinical recovery in patients. To determine the importance of the contra-lateral structural changes in post-stroke recovery, we selected a population of patients with motor deficits after stroke affecting the motor cortex and/or sub-cortical motor white matter. We explored i) the presence of Generalized Fractional Anisotropy (GFA) changes indicating structural alterations in the motor network of patientsâeuro? contra-lateral hemisphere as well as their longitudinal evolution ii) the correlation of GFA changes with patientsâeuro? clinical scores, stroke size and demographics data iii) and a predictive model.

An integrated encyclopedia of DNA elements in the human genome.

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.

Genome-wide association study identifies eight loci associated with blood pressure.

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Oculopalatal Tremor : Variations on a theme by Guillain and Mollaret

Le trémor oculo-palatin (TOP) est une complication tardive et rare faisant suite à une l��sion au niveau du tronc cérébral. Il est caractérisé par des contractions involontaires du voile du palais (pratiquement toujours asymptomatique), synchronisées avec un nystagmus pendulaire à environ 2 Hz (toujours symptomatique, se manifestant par des oscillopsies). Un hypersignal du noyau de l'olive inférieure (HNOI) est visible en IRM ; l'HNOI persiste au fil des ans. Notre objectif était de mieux définir le profil clinique des patients avec un TOP. Pour ceci nous avons effectué une étude rétrospective de 8 patients présentant un TOP et avons compil�� ces résultats avec les 82 cas que nous avons retrouvé dans la littérature mondiale (revue PubMed). L'âge moyen était de 54 ans, avec une prédominance masculine. L'étiologie la plus fréquente était une l��sion vasculaire du tronc cérébral (80%). Un nystagmus pendulaire principalement vertical a été retrouvé dans 90% des cas. Un nystagmus dissocié était principalement associé à une HNOI controlatérale et unilatérale sur l'IRM. Un nystagmus bilatéral et symétrique résultait d'une HNOI bilatérale dans la majorité des cas. Trois singularités ont été retrouvées parmi nos 8 patients : 1) une HNOI ipsilatérale à un nystagmus dissocié ; 2) la persistance du nystagmus en cas de disparition de l'HNOI ; 3) la découverte d'un micronystagmus asymptomatique. Le profil clinique du TOP reste assez stéréotypé, malgré quelques variations possibles (cf nos trois singularités). Les oscillopsies sont parfois handicapantes et il n'existe pas à ce jour de traitement spécifique du TOP.

Metabolic adaptation to cancer growth: from the cell to the organism.

Tumour cells proliferate much faster than normal cells; nearly all anticancer treatments are toxic to both cell types, limiting their efficacy. The altered metabolism resulting from cellular transformation and cancer progression supports cellular proliferation and survival, but leaves cancer cells dependent on a continuous supply of energy and nutrients. Hence, many metabolic enzymes have become targets for new cancer therapies. In addition to its well-described roles in cell-cycle progression and cancer, the cyclin/CDK-pRB-E2F1 pathway contributes to lipid synthesis, glucose production, insulin secretion, and glycolytic metabolism, with strong effects on overall metabolism. Notably, these cell-cycle regulators trigger the adaptive "metabolic switch" that underlies proliferation.

Symmetric periodic orbits near a heteroclinic loop in R3 formed by two singular points, a semistable periodic orbit and their invariant manifolds

In this paper we consider C1 vector fields X in R3 having a “generalized heteroclinic loop” L which is topologically homeomorphic to the union of a 2–dimensional sphere S2 and a diameter connecting the north with the south pole. The north pole is an attractor on S2 and a repeller on . The equator of the sphere is a periodic orbit unstable in the north hemisphere and stable in the south one. The full space is topologically homeomorphic to the closed ball having as boundary the sphere S2. We also assume that the flow of X is invariant under a topological straight line symmetry on the equator plane of the ball. For each n ∈ N, by means of a convenient Poincar´e map, we prove the existence of infinitely many symmetric periodic orbits of X near L that gives n turns around L in a period. We also exhibit a class of polynomial vector fields of degree 4 in R3 satisfying this dynamics.

The protective effect of the obesity-associated rs9939609 A variant in fat mass- and obesity-associated gene on depression.

Candidate gene and genome-wide association studies have not identified common variants, which are reliably associated with depression. The recent identification of obesity predisposing genes that are highly expressed in the brain raises the possibility of their genetic contribution to depression. As variation in the intron 1 of the fat mass- and obesity-associated (FTO) gene contributes to polygenic obesity, we assessed the possibility that FTO gene may contribute to depression in a cross-sectional multi-ethnic sample of 6561 depression cases and 21 932 controls selected from the EpiDREAM, INTERHEART, DeCC (depression case-control study) and Cohorte Lausannoise (CoLaus) studies. Major depression was defined according to DSM IV diagnostic criteria. Association analyses were performed under the additive genetic model. A meta-analysis of the four studies showed a significant inverse association between the obesity risk FTO rs9939609 A variant and depression (odds ratio=0.92 (0.89, 0.97), P=3 × 10(-4)) adjusted for age, sex, ethnicity/population structure and body-mass index (BMI) with no significant between-study heterogeneity (I(2)=0%, P=0.63). The FTO rs9939609 A variant was also associated with increased BMI in the four studies (β 0.30 (0.08, 0.51), P=0.0064) adjusted for age, sex and ethnicity/population structure. In conclusion, we provide the first evidence that the FTO rs9939609 A variant may be associated with a lower risk of depression independently of its effect on BMI. This study highlights the potential importance of obesity predisposing genes on depression.