292 research outputs found

    Fibroblast growth factor 10 is a negative regulator of postnatal neurogenesis in the mouse hypothalamus

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    New neurons are generated in the postnatal rodent hypothalamus, with a subset of tanycytes in the third ventricular (3V) wall serving as neural stem/progenitor cells. However, the precise stem cell niche organization, the intermediate steps and the endogenous regulators of postnatal hypothalamic neurogenesis remain elusive. Quantitative lineage-tracing in vivo revealed that conditional deletion of fibroblast growth factor 10 (Fgf10) from Fgf10-expressing beta-tanycytes at postnatal days (P)4-5 results in the generation of significantly more parenchymal cells by P28, composed mostly of ventromedial and dorsomedial neurons and some glial cells, which persist into adulthood. A closer scrutiny in vivo and ex vivo revealed that the 3V wall is not static and is amenable to cell movements. Furthermore, normally beta-tanycytes give rise to parenchymal cells via an intermediate population of alpha-tanycytes with transient amplifying cell characteristics. Loss of Fgf10 temporarily attenuates the amplification of beta-tanycytes but also appears to delay the exit of their alpha-tanycyte descendants from the germinal 3V wall. Our findings suggest that transience of cells through the alpha-tanycyte domain is a key feature, and Fgf10 is a negative regulator of postnatal hypothalamic neurogenesis.Peer reviewe

    Does Simplicity Compromise Accuracy in ACS Risk Prediction? A Retrospective Analysis of the TIMI and GRACE Risk Scores

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    BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) risk scores for Unstable Angina/Non-ST-elevation myocardial infarction (UA/NSTEMI) and ST-elevation myocardial infarction (STEMI) and the Global Registry of Acute Coronary Events (GRACE) risk scores for in-hospital and 6-month mortality are established tools for assessing risk in Acute Coronary Syndrome (ACS) patients. The objective of our study was to compare the discriminative abilities of the TIMI and GRACE risk scores in a broad-spectrum, unselected ACS population and to assess the relative contributions of model simplicity and model composition to any observed differences between the two scoring systems. METHODOLOGY/PRINCIPAL FINDINGS: ACS patients admitted to the University of Michigan between 1999 and 2005 were divided into UA/NSTEMI (n = 2753) and STEMI (n = 698) subpopulations. The predictive abilities of the TIMI and GRACE scores for in-hospital and 6-month mortality were assessed by calibration and discrimination. There were 137 in-hospital deaths (4%), and among the survivors, 234 (7.4%) died by 6 months post-discharge. In the UA/NSTEMI population, the GRACE risk scores demonstrated better discrimination than the TIMI UA/NSTEMI score for in-hospital (C = 0.85, 95% CI: 0.81-0.89, versus 0.54, 95% CI: 0.48-0.60; p<0.01) and 6-month (C = 0.79, 95% CI: 0.76-0.83, versus 0.56, 95% CI: 0.52-0.60; p<0.01) mortality. Among STEMI patients, the GRACE and TIMI STEMI scores demonstrated comparably excellent discrimination for in-hospital (C = 0.84, 95% CI: 0.78-0.90 versus 0.83, 95% CI: 0.78-0.89; p = 0.83) and 6-month (C = 0.72, 95% CI: 0.63-0.81, versus 0.71, 95% CI: 0.64-0.79; p = 0.79) mortality. An analysis of refitted multivariate models demonstrated a marked improvement in the discriminative power of the TIMI UA/NSTEMI model with the incorporation of heart failure and hemodynamic variables. Study limitations included unaccounted for confounders inherent to observational, single institution studies with moderate sample sizes. CONCLUSIONS/SIGNIFICANCE: The GRACE scores provided superior discrimination as compared with the TIMI UA/NSTEMI score in predicting in-hospital and 6-month mortality in UA/NSTEMI patients, although the GRACE and TIMI STEMI scores performed equally well in STEMI patients. The observed discriminative deficit of the TIMI UA/NSTEMI score likely results from the omission of key risk factors rather than from the relative simplicity of the scoring system

    Association between gender and short-term outcome in patients with ST elevation myocardial infraction participating in the international, prospective, randomised administration of ticagrelor in the catheterisation laboratory or in the ambulance for new ST elevation myocardial infarction to open the coronary artery (ATLANTIC) trial: a prespecified analysis

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    Objectives: to evaluate gender differences in outcomes in patents with ST-segment elevation myocardial infarction (STEMI) planned for primary percutaneous coronary intervention (PPCI). Settings: a prespecified gender analysis of the multicentre, randomised, double-blind Administration of Ticagrelor in the catheterisation Laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery. Participants: between September 2011 and October 2013, 1862 patients with STEMI and symptom duration <6 hours were included. Interventions: patients were assigned to prehospital versus in-hospital administration of 180 mg ticagrelor. Outcomes: the main objective was to study the association between gender and primary and secondary outcomes of the main study with a focus on the clinical efficacy and safety outcomes. Primary outcome: the proportion of patients who did not have 70% resolution of ST-segment elevation and did not meet the criteria for Thrombolysis In Myocardial Infarction (TIMI) flow 3 at initial angiography. Secondary outcome: the composite of death, MI, stent thrombosis, stroke or urgent revascularisation and major or minor bleeding at 30 days. Results: women were older, had higher TIMI risk score, longer prehospital delays and better TIMI flow in the infarct-related artery. Women had a threefold higher risk for all-cause mortality compared with men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 to 5.51). After adjustment, the difference was attenuated but remained statistically significant (HR 2.08, 95% CI 1.03 to 4.20). The incidence of major bleeding events was twofold to threefold higher in women compared with men. In the multivariable model, female gender was not an independent predictor of bleeding (Platelet Inhibition and Patient Outcomes major HR 1.45, 95% CI 0.73 to 2.86, TIMI major HR 1.28, 95% CI 0.47 to 3.48, Bleeding Academic Research Consortium type 3-5 HR 1.45, 95% CI 0.72 to 2.91). There was no interaction between gender and efficacy or safety of randomised treatment. Conclusions: in patients with STEMI planned for PPCI and treated with modern antiplatelet therapy, female gender was an independent predictor of short-term mortality. In contrast, the higher incidence of bleeding complications in women could mainly be explained by older age and clustering of comorbidities

    Longer-term oral antiplatelet use in stable post-myocardial infarction patients: Insights from the long Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease (TIGRIS) observational study.

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    OBJECTIVE: To describe contemporary patient characteristics and treatment patterns, including antithrombotic management, of post-myocardial infarction (MI) stable coronary artery disease (CAD) patients at high atherothrombotic risk from different geographical regions. METHODS: Patients ≥50years with prior MI 1-3years ago and ≥1 risk factor (age ≥65years, diabetes, 2nd prior MI >1yr ago, multivessel CAD, creatinine clearance 15-1year was highest (39%) in Asia-Pacific and lowest (12%) in Europe. CONCLUSIONS: Despite guideline recommendations, 1 in 4 post-MI patients did not receive DAPT for ~1year. In contrast to guideline recommendations supporting newer ADPris, clopidogrel was mainly prescribed. Prior to recent RCT data supporting DAPT >1year post-MI/PCI, >1 in 4 patients have continued on DAPT, though with substantial international variability

    Predicting risk of cardiovascular events 1 to 3 years post-myocardial infarction using a global registry.

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    BACKGROUND: Risk prediction tools are lacking for patients with stable disease some years after myocardial infarction (MI). HYPOTHESIS: A practical long-term cardiovascular risk index can be developed. METHODS: The long-Term rIsk, Clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients prospective global registry enrolled patients 1 to 3 years post-MI (369 centers; 25 countries), all with ≥1 risk factor (age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, or chronic non-end-stage kidney disease [CKD]). Self-reported health was assessed with EuroQoL-5 dimensions. Multivariable Poisson regression models were used to determine key predictors of the primary composite outcome (MI, unstable angina with urgent revascularization [UA], stroke, or all-cause death) over 2 years. RESULTS: The primary outcome occurred in 621 (6.9%) of 9027 eligible patients: death 295 (3.3%), MI 195 (2.2%), UA 103 (1.1%), and stroke 58 (0.6%). All events accrued linearly. In a multivariable model, 11 significant predictors of primary outcome (age ≥65 years, diabetes, second prior MI, CKD, history of major bleed, peripheral arterial disease, heart failure, cardiovascular hospitalization (prior 6 months), medical management (index MI), on diuretic, and poor self-reported health) were identified and combined into a user-friendly risk index. Compared with lowest-risk patients, those in the top 16% had a rate ratio of 6.9 for the primary composite, and 18.7 for all-cause death (overall c-statistic; 0.686, and 0.768, respectively). External validation was performed using the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events registry (c-statistic; 0.748, and 0.849, respectively). CONCLUSIONS: In patients >1-year post-MI, recurrent cardiovascular events and deaths accrue linearly. A simple risk index can stratify patients, potentially helping to guide management
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