METHOD & RESULTS: We conducted a genome-wide methylation analysis on 8 hypertensive cases and 8 normotensive age-matched controls aged 14-23 years and performed validation of the most significant CpG sites in 2 genes in an independent sample of 36 hypertensive cases and 60 normotensive controls aged 14-30 years. Validation of the CpG sites in the SULF1 gene was further conducted in a second replication sample of 36 hypertensive cases and 34 controls aged 15.8-40 years. A CpG site in the SULF1 gene showed higher methylation levels in cases than in healthy controls in the genome-wide step (p = 6.2×10(-5)), which was confirmed in the validation step (p = 0.011) for subjects ≤30 years old but was not significant for subjects of all ages combined (p = 0.095).

CONCLUSION: The identification of a difference in a blood leukocyte DNA methylation site between hypertensive cases and normotensive controls suggests that changes in DNA methylation may play an important role in the pathogenesis of hypertension. The age dependency of the effect further suggests complexity of epigenetic regulation in this age-related disease.

INTRODUCTION/HYPOTHESIS

•Adverse cardiac remodeling and fibrosis provide an arrhythmic substrate for atrial fibrillation (AF), but the role of matrix metalloproteinases (MMPs) as a biomarker is not well understood. MMPs are zinc-dependent endopeptidases known to degrade substrates such as elastin, gelatin and collagen.

•In excised human atrial tissue, MMP 2 and 9 levels rise as the AF burden increases from sinus rhythm (“No AF”) to non-permanent AF (“Non-Prm AF”) to permanent AF (“PrmAF”). Higher plasma levels of MMPs are also associated with recurrent AF after cardioversion.

•This study sought to elucidate 1) the relationship of these biomarker levels with AF burden and 2) the predictive value of biomarkers for future AF episode in patients with severely reduced left ventricular ejection fraction (LVEF) and implantable cardioverter-defibrillators (ICDs)

METHODS: We performed a retrospective cohort study including all patients admitted to the Christiana Care Health System 2-hospital, 1100-bed community-based academic health system in 2009 with normal white blood cells (3800-10,800 per mm(3)) on admission who had manual differentials performed. We defined our band groups as normal (≤10% bands and other immature cells), moderate (11%-19%), or high (≥20%). Via chart review, we ascertained vital signs and culture results for all patients with elevated bands and 407 randomly sampled patients with normal bands. Cultures likely to be contaminants were excluded. We used multivariable logistic regression to determine whether bandemia was predictive of significant positive cultures or death.

RESULTS: Of 2342 patients, 167 (7.1%) had high bands and 205 (8.6%) had moderate bands. The mean white blood cell count was 7.5 cells/mm(3), with no difference among groups. Bandemia was associated with increased odds of having any significant positive culture (adjusted odds ratio [OR], 2.0, 95% confidence interval [CI], 1.3-3.1 for moderate bands; adjusted OR, 2.8, 95% CI, 1.7-4.3 for high bands) and having positive blood cultures (adjusted OR, 3.8, 95% CI, 2.0-7.2 for moderate bands; adjusted OR, 6.2, 95% CI, 3.2-11.8 for high bands). Patients with moderate or high bands also had increased odds of in-hospital death (adjusted OR, 3.2, 95% CI, 1.7-6.1; adjusted OR, 4.7, 95% CI, 2.4-9.0, respectively).

CONCLUSIONS: Even with normal total white blood cells, patients with moderate and high bandemia on admission had significantly increased odds of having positive cultures, including blood cultures, and of in-hospital mortality.

METHODS: We randomly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to standard balloon angioplasty. Coronary angiography was performed at base line, immediately after the procedure, and six months later.

RESULTS: The patients who underwent stenting had a higher rate of procedural success than those who underwent standard balloon angioplasty (96.1 percent vs. 89.6 percent, P = 0.011), a larger immediate increase in the diameter of the lumen (1.72 +/- 0.46 vs. 1.23 +/- 0.48 mm, P < 0.001), and a larger luminal diameter immediately after the procedure (2.49 +/- 0.43 vs. 1.99 +/- 0.47 mm, P < 0.001). At six months, the patients with stented lesions continued to have a larger luminal diameter (1.74 +/- 0.60 vs. 1.56 +/- 0.65 mm, P = 0.007) and a lower rate of restenosis (31.6 percent vs. 42.1 percent, P = 0.046) than those treated with balloon angioplasty. There were no coronary events (death; myocardial infarction; coronary-artery bypass surgery; vessel closure, including stent thrombosis; or repeated angioplasty) in 80.5 percent of the patients in the stent group and 76.2 percent of those in the angioplasty group (P = 0.16). Revascularization of the original target lesion because of recurrent myocardial ischemia was performed less frequently in the stent group than in the angioplasty group (10.2 percent vs. 15.4 percent, P = 0.06).

CONCLUSIONS: In selected patients, placement of an intracoronary stent, as compared with balloon angioplasty, results in an improved rate of procedural success, a lower rate of angiographically detected restenosis, a similar rate of clinical events after six months, and a less frequent need for revascularization of the original coronary lesion.

Cdo is a multifunctional cell surface co-receptor that promotes Hedgehog signaling during rostroventral midline development and cadherin-mediated signaling during skeletal myogenesis. We report here novel roles for Cdo in patterning of the murine esophageal musculature and esophageal motility disorders such as achalasia.

METHODS: A total of 220 patients with new lesions in aortocoronary-venous bypass grafts were randomly assigned to placement of Palmaz-Schatz stents or standard balloon angioplasty. Coronary angiography was performed during the index procedure and six months later.

RESULTS: As compared with the patients assigned to angioplasty, those assigned to stenting had a higher rate of procedural efficacy, defined as a reduction in stenosis to less than 50 percent of the vessel diameter without a major cardiac complication (92 percent vs. 69 percent, P<0.001), but they had more frequent hemorrhagic complications (17 percent vs. 5 percent, P<0.01). Patients in the stent group had a larger mean (+/-SD) increase in luminal diameter immediately after the procedure (1.92+/-0.30 mm, as compared with 1.21+/-0.37 mm in the angioplasty group; P<0.001) and a greater mean net gain in luminal diameter at six months (0.85+/-0.96 vs. 0.54+/-0.91 mm, P=0.002). Restenosis occurred in 37 percent of the patients in the stent group and in 46 percent of the patients in the angioplasty group (P=0.24). The outcome in terms of freedom from death, myocardial infarction, repeated bypass surgery, or revascularization of the target lesion was significantly better in the stent group (73 percent vs. 58 percent, P = 0.03).

CONCLUSIONS: As compared with balloon angioplasty, stenting of selected venous bypass-graft lesions resulted in superior procedural outcomes, a larger gain in luminal diameter, and a reduction in major cardiac events. However, there was no significant benefit in the rate of angiographic restenosis, which was the primary end point of the study.

BACKGROUND: Histone methylation is regulated by a large number of histone methyltransferases and demethylases. The recently discovered SMCX/KMD5C demethylase has been shown to remove methyl residues from lysine 4 of histone H3 (H3K4), and constitutes an important component of the regulatory element-1-silencing transcription factor (REST) protein complex. However, little is known about the cellular mechanisms that control SMCX activity and intracellular trafficking.

RESULTS: In this study, we found that small interfering RNA-mediated knockdown of proliferating cell nuclear antigen (PCNA) resulted in the reduction of the chromatin-bound SMCX fraction. We identified a PCNA-interaction protein motif (PIP box) in the SMCX protein. Using site-directed mutagenesis, we found that the amino acids of the SMCX PIP box are involved in the association of SMCX with PCNA and its interaction with chromatin.

CONCLUSIONS: Our data indicate that the intracellular trafficking of SMCX is controlled by its association with PCNA.

METHODS AND FINDINGS: We found that expression of scavenger receptor CD36 coincided with proximal tubular epithelial cell (PTEC) apoptosis and TED specifically in human DNP. High glucose stimulated cell surface expression of CD36 in PTECs. CD36 expression was necessary and sufficient to mediate PTEC apoptosis induced by glycated albumins (AGE-BSA and CML-BSA) and free fatty acid palmitate through sequential activation of src kinase, and proapoptotic p38 MAPK and caspase 3. In contrast, paucity of expression of CD36 in PTECs in diabetic mice with diabetic glomerulopathy was associated with normal tubular epithelium and the absence of tubular apoptosis. Mouse PTECs lacked CD36 and were resistant to AGE-BSA-induced apoptosis. Recombinant expression of CD36 in mouse PTECs conferred susceptibility to AGE-BSA-induced apoptosis.

CONCLUSION: Our findings suggest a novel role for CD36 as an essential mediator of proximal tubular apoptosis in human DNP. Because CD36 expression was induced by glucose in PTECs, and because increased CD36 mediated AGE-BSA-, CML-BSA-, and palmitate-induced PTEC apoptosis, we propose a two-step metabolic hit model for TED, a hallmark of progression in DNP.