Background We evaluated whether cardiac troponin T (cTnT) measured with a new highly sensitive assay was associated with incident coronary heart disease (CHD), mortality, and hospitalization for heart failure (HF) in a general population of participants in the Atherosclerosis Risk in Communities (ARIC) Study. Methods and Results Associations between increasing cTnT levels and CHD, mortality, and HF hospitalization were evaluated using Cox proportional-hazards models adjusted for traditional CHD risk factors, kidney function, high-sensitivity C-reactive protein (hs-CRP), and N-terminal pro–B-type natriuretic peptide (NT-proBNP) in 9,698 participants aged 54–74 years who at baseline were free from CHD and stroke (and HF in the HF analysis). Measurable cTnT levels (≥0.003 μg/L) were detected in 66.5% of individuals. In fully adjusted models, compared with participants with undetectable levels, those with cTnT levels in the highest category (≥0.014 μg/L, 7.4% of the ARIC population) had significantly increased risk for CHD (hazard ratio [HR] 2.29, 95% confidence interval [CI] 1.81–2.89), fatal CHD (HR 7.59, 95% CI 3.78–15.25), total mortality (HR 3.96, 95% CI 3.21–4.88), and HF (HR 5.95, 95% CI 4.47–7.92). Even minimally elevated cTnT (≥0.003 μg/L) was associated with increased risk for mortality and HF (p<0.05). Adding cTnT to traditional risk factors improved risk prediction parameters; the improvements were similar to those with NT-proBNP and better than that with the addition of hs-CRP. Conclusions cTnT detectable with a highly sensitive assay was associated with incident CHD, mortality, and HF in individuals from a general population without known CHD/stroke.
GnRH neurons form the final common pathway for central control of reproduction, with regulation achieved by changing the pattern of GnRH pulses. To help elucidate the neurobiological mechanisms underlying pulsatile GnRH release, we generated transgenic mice in which the green fluorescent protein (GFP) reporter was genetically targeted to GnRH neurons. The expression of GFP allowed identification of 84-94% of immunofluorescently-detected GnRH neurons. Conversely, over 99.5% of GFP-expressing neurons contained immunologically detectable GnRH peptide. In hypothalamic slices, GnRH neurons could be visualized with fluorescence, allowing for identification of individual GnRH neurons for patch-clamp recording and subsequent morphological analysis. Whole-cell current-clamp recordings revealed that all GnRH neurons studied (n = 23) fire spontaneous action potentials. Both spontaneous firing (n = 9) and action potentials induced by injection of depolarizing current (n = 17) were eliminated by tetrodotoxin, indicating that voltage-dependent sodium channels are involved in generating action potentials in these cells. Direct intracellular morphological assessment of GnRH dendritic morphology revealed GnRH neurons have slightly more extensive dendrites than previously reported. GnRH-GFP transgenic mice represent a new model for the study of GnRH neuron structure and function, and their use should greatly increase our understanding of this important neuroendocrine system.
Despite quite modest effect sizes, findings suggest that students' abilities to effectively manage affective states may be subject to some minor fluctuation across the undergraduate educational continuum. However, whether these observed declines constitute meaningful, clinically relevant changes remains unclear.
Background The enhanced sensitivity of cardiac troponin T (cTnT) assays calls for its use as a prognostic marker in chronic heart failure, as an accurate and early marker of myocyte damage, and as a sensitive indicator of acute episodes in chronic disease. To facilitate these applications and inform required benchmarks, we estimated the variability in cTnT measurements, the sources of this variability, and the stability of cTnT using samples stored at −70 °C. Methods and Results Stored samples from the Atherosclerosis Risk in Communities Study (ARIC) study (1996–1998) and ARIC Carotid MRI study participants (2005–06) were assayed in 2009–10 to examine variability in cTnT attributable to laboratory (replicates after freeze thaw, n=29), processing (blind replicates from same blood draw, n = 87), short- (n = 40) and long-term biological variation (repeat visit, n = 38), and degradation in frozen storage (n = 10,870). The Elecsys Troponin T (Roche Diagnostics, Indianapolis, IN) was used to assay cTnT on an automated Cobas e411 analyzer. The lower limit of detection was 3 ng/L. Approximately 1/4th to 1/3rd of the participants had values below the detection limit. The paired correlation for all other comparisons exceeded 0.93 (except for samples drawn 8 years apart = 0.36). The coefficients of variation for individual sources of variation in cTnT were as follows: laboratory 2.1% in those with heart failure (HF) and 11.2% in those without HF; processing 18.3%; biological at six weeks 16.6%, and at eight years 48.4%. The reference change value at 6 weeks was 68.5% and would require 4 samples to determine homeostatic set point within ± 25%. Only modest degradation was detected in stored frozen samples for an average of 8 years. Conclusions cTnT is detectable in approximately 70% of community-dwelling men and women aged 53 to 75 years. The laboratory reliability was high: the reliability coefficient (r) was 0.99 in those with heart failure and 0.94 in those without heart failure. The intra-individual (biologic) variability was low on repeat testing after 6 weeks (r=0.94), and increased for measurements taken 8 years apart (R=0.36). Troponin T is stable in storage at −70° C and the variability in cTnT values attributable to one freeze-thaw cycle is of small magnitude.
Purpose Identify a reproducible measure of axial globe position (AGP) for multicenter studies of patients with thyroid eye disease (TED). Methods This is a prospective, international, multicenter, observational study in which 3 types of AGP evaluation were examined: radiologic, clinical, and photographic. In this study, computed tomography (CT) was the modality to which all other methods were compared. CT AGP was measured from an orthogonal line between the anterior lateral orbital rims to the cornea. All CT measurements were made at a single institution by 3 individual clinicians. Clinical evaluation was performed with exophthalmometry. Three clinicians from each clinical site assessed AGP with 3 different exophthalmometers and horizontal palpebral width using a ruler. Each physician made 3 separate measurements with each type of exophthalmometer, not in succession. All photographic measurements were made at a single institution. AGP was measured from lateral photographs in which a standard marker was placed at the anterior lateral orbital rim. Horizontal and vertical palpebral fissure were measured from frontal photographs. Three trained readers measured 3 separate times, not in succession. Exophthalmometry and photography method validity was assessed by agreement with CT (mean differences calculation, ICC’s, Bland-Altman figures). Correlation between palpebral fissure and CT AGP was assessed with Pearson correlation. Intraclinician and interclinician reliability was evaluated using intraclass correlation coefficients (ICC). Results Sixty-eight patients from 7 centers participated. CT mean AGP was 21.37mm (15.96 – 28.90mm) right, 21.22mm (15.87 – 28.70mm) left (ICC 0.996 and 0.995). Exophthalmometry AGP fell between 18mm and 25mm. Intraclinician agreement across exophthalmometers was ideal (ICC 0.948 – 0.983). Agreement between clinicians was greater than 0.85 for all upright exophthalmometry measurements. Photographic mean AGP was 20.47mm (10.92 – 30.88mm) right, 20.30mm (8.61 – 28.72mm) left. Intrareader and interreader agreement was ideal (ICC 0.991 – 0.989). All exophthalmometers’ mean differences from CT ranged between −0.06mm (+/− 1.36mm) and 0.54mm (+/− 1.61mm); 95% CI fell within 1mm. Magnitude of AGP did not affect exophthalmometry validity. Oculus best estimated CT AGP but differences form other exophthalmometers were not clinically meaningful in upright measurements. Photographic AGP (right ICC=0.575, left ICC=0.355) and palpebral fissure do not agree with CT. Conclusions Upright clinical exophthalmometry accurately estimates CT AGP in TED. AGP measurement was reliably reproduced by the same clinician and between clinicians at multiple institutions using the protocol in this study. These findings allow reliable measurement of AGP that will be of considerable value in future outcome studies.
GnRH neurons form the final common pathway for central control of reproduction, with regulation achieved by changing the pattern of GnRH pulses. To help elucidate the neurobiological mechanisms underlying pulsatile GnRH release, we generated transgenic mice in which the green fluorescent protein (GFP) reporter was genetically targeted to GnRH neurons. The expression of GFP allowed identification of 84-94% of immunofluorescently-detected GnRH neurons. Conversely, over 99.5% of GFP-expressing neurons contained immunologically detectable GnRH peptide. In hypothalamic slices, GnRH neurons could be visualized with fluorescence, allowing for identification of individual GnRH neurons for patch-clamp recording and subsequent morphological analysis. Whole-cell current-clamp recordings revealed that all GnRH neurons studied (n = 23) fire spontaneous action potentials. Both spontaneous firing (n = 9) and action potentials induced by injection of depolarizing current (n = 17) were eliminated by tetrodotoxin, indicating that voltage-dependent sodium channels are involved in generating action potentials in these cells. Direct intracellular morphological assessment of GnRH dendritic morphology revealed GnRH neurons have slightly more extensive dendrites than previously reported. GnRH-GFP transgenic mice represent a new model for the study of GnRH neuron structure and function, and their use should greatly increase our understanding of this important neuroendocrine system.
Objective To determine the prevalence of poor response to aspirin (ASA) therapy over 12-month follow-up in patients with lower extremity peripheral arterial disease (PAD), and to compare the classification agreement among different ASA response assays. Subjects Patients with PAD on ASA therapy at baseline were included from the ongoing Effect of Lipid Modification on Peripheral Arterial Disease after Endovascular Intervention Trial (ELIMIT), which is a randomized trial testing whether combination treatment with ezetimibe, niacin, and a statin will halt/regress atherosclerosis compared to statin monotherapy. Main Outcome Measures Patients who had baseline platelet testing and repeat testing at 6-month or 12-month follow-up were included. ASA responsiveness was tested using three different assays: Optical aggregation with 0.5-mg/mL of arachidonic acid (AA), optical aggregation with 10-μM of adenosine diphosphate (ADP), and platelet function analyzer-100 (PFA-100) testing with collagen/Epinephrine (Epi) loaded cartridges. ASA response was defined as AA aggregation <30%, ADP aggregation <70%, or PFA-100 Epi> 164 sec. Patients who showed response to ASA at baseline were classified as Responders. Poor response to ASA was defined as AA aggregation ≥30%, ADP aggregation ≥70%, or PFA-100 Epi ≤164 sec. Patients who showed poor response (PR) to an assay at baseline, but then were responsive at follow-up visits were classified as Initial PRs. Patients who showed poor response at baseline and all follow-up visits were classified as Persistent PRs. The classification agreement between assays was tested using the kappa statistic. Results Of 102 patients randomized in ELIMIT, 80 patients satisfied inclusion criteria. There were no significant baseline demographic differences between Responders, Initial PRs, and Persistent PRs. The prevalence of persistent poor response varied by the assay used; 5% of subjects (4/80) were Persistent PRs by AA aggregation, compared to 27.5% (22/80) of subjects by ADP aggregation, and 9.9% (7/71) of patients by PFA-100 Epi. Regarding the agreement of the assays, only AA aggregation and PFA-100 Epi agreed significantly (K=0.3223; 95% CI 0.15–0.493, P=0.0001), and though statistically significant, the magnitude of this agreement is small. AA aggregation and ADP aggregation did not agree (K=0.1161; 95% CI −0.004–0.236, P=0.029), nor did ADP aggregation and PFA-100 Epi (K=0.0044; 95% CI −.151–0.160, P=0.48). Conclusions Between 5–27.5% of PAD patients were Persistent PRs to ASA over 6–12-month follow-up using different platelet assays. Further, these commonly used platelet assays show weak agreement in determining poor response to aspirin.
Type 2 diabetes mellitus (DM) is associated with increased risk for developing heart failure (HF) and worse outcomes once HF is present. While the exact mechanisms underpinning these observations remain poorly understood, several metabolic perturbations associated with DM have been implicated as contributors to the HF risk, including alterations of cardiomyocyte metabolic substrate switching between free fatty acid (FFA) and glucose metabolism; increased FFA exposure and cellular accumulation; and alterations in peroxisome proliferator-activated receptor-(PPAR-)alpha activity, among others. The commonly coincident conditions of left ventricular hypertrophy and ischemic heart disease likely confound the metabolic derangements further increasing HF risk. Continued investigation into these mechanistic connections is necessary to better understand the pathophysiology and ideally inform the pursuit of novel therapeutic targets and strategies to intervene on the HF associated with DM.
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