In this population-based cohort, systolic blood pressure, but not diastolic pressure, changes over time aligned with change in sodium excretion, but this association did not translate into a higher risk of hypertension or CVD complications. Lower sodium excretion was associated with higher CVD mortality.
Background-Because the process of myocardial remodelling starts before the onset of symptoms, recent heart failure (HF) guidelines place special emphasis on the detection of subclinical left ventricular (LV) systolic and diastolic dysfunction and the timely identification of risk factors for HF. Our goal was to describe the prevalence and determinants (risk factors) of LV diastolic dysfunction in a general population and to compare the amino terminal probrain natriuretic peptide level across groups with and without diastolic dysfunction. Methods and Results-In a randomly recruited population sample (nϭ539; 50.5% women; mean age, 52.5 years), we measured early and late diastolic peak velocities of mitral inflow (E and A), pulmonary vein flow by pulsed-wave Doppler, and the mitral annular velocities (Ea and Aa) at 4 sites by tissue Doppler imaging. A healthy subsample of 239 subjects (mean age, 43.7 years) provided age-specific cutoff limits for normal E/A and E/Ea ratios and the differences in duration between the mitral A and the reverse pulmonary vein flows during atrial systole (⌬AdϪARd). The number of subjects in diastolic dysfunction groups 1 (impaired relaxation), 2 (elevated LV end-diastolic filling pressure), and 3 (elevated E/Ea and abnormally low E/A) were 53 (9.8%), 76 (14.1%), and 18 (3.4%), respectively. We used ⌬(AdϽARdϩ10) to confirm possible elevation of LV filling pressures in group 2. Compared with subjects with normal diastolic function (nϭ392, 72.7%), group 1 (209 versus 251 pmol/L; Pϭ0.015) and group 2 (209 versus 275 pmol/L; Pϭ0.0003) but not group 3 (209 versus 224 pmol/L; Pϭ0.65) had a significantly higher adjusted NT-probrain natriuretic peptide. Higher age, body mass index, heart rate, systolic blood pressure, serum insulin, and creatinine were significantly associated with a higher risk of LV diastolic dysfunction. Conclusions-The overall prevalence of LV diastolic dysfunction in a random sample of a general population, as estimated from echocardiographic measurements, was as high as 27.3%. (Circ Heart Fail. 2009;2:105-112.)
U nlike most mature cells, smooth muscle cells (SMCs) are remarkably plastic and can dedifferentiate in response to environmental cues, 1,2 adding a layer of complexity to the regulation of gene expression. Although several transcription factors have been identified, a global mechanism that coordinately regulates SMC phenotype has yet to be uncovered. How SMC genes become silenced and then reactivated is unknown and is an area of intense investigation. Recent demonstration that the ten-eleven-translocation (TET) family of proteins is involved in DNA demethylation  prompted us to evaluate the role of the TET proteins in the modulation of SMC phenotype. Editorial see p 2002 Clinical Perspective on p 2057The TET proteins (TET1-TET3) are a recently discovered family of DNA demethylases. TET proteins oxidize 5-methylcytosine (5-mC) to generate 5-hydroxymethylcytosine (5-hmC), frequently called the sixth DNA base, in mammalian cells. 4,5 Through the base excision repair pathway, 5-hmC is then converted to unmethylated cytosine, leading to DNA demethylation and gene activation.  Therefore, the 5-hmC modification and the TET enzymes have emerged as key activators of gene expression. Studies of TET proteins and 5-hmC function in embryonic stem cells (ESCs) demonstrate that they play a major role in maintaining cellular pluripotency through the regulation of lineage-specific genes. 4, In contrast to this role in ESC pluripotency, the TET proteins (and their 5-hmC products) have an opposing role in adult stem cells and somatic tissues. TET2 mutations have been described in several types of hematopoietic disorders in which the loss of TET2 has been shown to promote hematopoietic stem cell self-renewal.12 TET2 and 5-hmC levels are increased during neurogenesis, 13 and more recently, loss of TET2 and 5-hmC was demonstrated to be a key epigenetic event associated with Background-Smooth muscle cells (SMCs) are remarkably plastic. Their reversible differentiation is required for growth and wound healing but also contributes to pathologies such as atherosclerosis and restenosis. Although key regulators of the SMC phenotype, including myocardin (MYOCD) and KLF4, have been identified, a unifying epigenetic mechanism that confers reversible SMC differentiation has not been reported. Methods and Results-Using human SMCs, human arterial tissue, and mouse models, we report that SMC plasticity is governed by the DNA-modifying enzyme ten-eleven translocation-2 (TET2). TET2 and its product, 5-hydroxymethylcytosine (5-hmC), are enriched in contractile SMCs but reduced in dedifferentiated SMCs. TET2 knockdown inhibits expression of key procontractile genes, including MYOCD and SRF, with concomitant transcriptional upregulation of KLF4. TET2 knockdown prevents rapamycin-induced SMC differentiation, whereas TET2 overexpression is sufficient to induce a contractile phenotype. TET2 overexpression also induces SMC gene expression in fibroblasts. Chromatin immunoprecipitation demonstrates that TET2 coordinately regul...
Rationale Matrix metalloproteinase (MMP)-28 regulates the inflammatory and extracellular matrix (ECM) responses in cardiac aging, but the roles of MMP-28 after myocardial infarction (MI) have not been explored. Objective To determine the impact of MMP-28 deletion on post-MI remodeling of the left ventricle (LV) Methods and Results Adult C57BL/6J wild type (WT, n=76) and MMP null (MMP-28−/−, n=86) mice of both sexes were subjected to permanent coronary artery ligation to create MI. MMP-28 expression decreased post-MI, and its cell source shifted from myocytes to macrophages. MMP-28 deletion increased day 7 mortality as a result of increased cardiac rupture post-MI. MMP-28−/− mice exhibited larger LV volumes, worse LV dysfunction, a worse LV remodeling index, and increased lung edema. Plasma MMP-9 levels were unchanged in the MMP-28−/− mice but increased in WT mice at day 7 post-MI. The mRNA levels of inflammatory and ECM proteins were attenuated in the infarct regions of MMP-28−/− mice, indicating reduced inflammatory and ECM responses. M2 macrophage activation was impaired when MMP-28 was absent. MMP-28 deletion also led to decreased collagen deposition and fewer myofibroblasts. Collagen cross-linking was impaired, due to decreased expression and activation of lysyl oxidase in the infarcts of MMP-28−/− mice. The LV tensile strength at day 3 post-MI, however, was similar between the two genotypes Conclusions MMP-28 deletion aggravated MI induced LV dysfunction and rupture, due to defective inflammatory response and scar formation by suppressing M2 macrophage activation.
Twenty-eight human isolates of Escherichia coli from Argentina and Spain and eight veterinary isolates received from the Ministry of Agriculture Fisheries and Foods in the United Kingdom required 2 to > 128 micrograms of ciprofloxacin per ml for inhibition. Fragments of gyrA and parC encompassing the quinolone resistance-determining region were amplified by PCR, and the DNA sequences of the fragments were determined. All isolates contained a mutation in gyrA of a serine at position 83 (Ser83) to an Leu, and 26 isolates also contained a mutation of Asp87 to one of four amino acids: Asn (n = 14), Tyr (n = 6), Gly (n = 5), or His (n = 1). Twenty-four isolates contained a single mutation in parC, either a Ser80 to Ile (n = 17) or Arg (n = 2) or a Glu84 to Lys (n = 3). The role of a mutation in gyrB was investigated by introducing wild-type gyrB (pBP548) into all isolates; for three transformants MICs of ciprofloxacin were reduced; however, sequencing of PCR-derived fragments containing the gyrB quinolone resistance-determining region revealed no changes. The analogous region of parE was analyzed in 34 of 36 isolates by single-strand conformational polymorphism analysis and sequencing; however, no amino acid substitutions were discovered. The outer membrane protein and lipopolysaccharide profiles of all isolates were compared with those of reference strains, and the concentration of ciprofloxacin accumulated (with or without 100 microM carbony cyanide m-chlorophenylhydrazone [CCCP] was determined. Twenty-two isolates accumulated significantly lower concentrations of ciprofloxacin than the wild-type E. coli isolate; nine isolates accumulated less then half the concentration. The addition of CCCP increased the concentration of ciprofloxacin accumulated, and in all but one isolate the percent increase was greater than that in the control strains. The data indicate that high-level fluoroquinolone resistance in E. coli involves the acquisition of mutations at multiple loci.
Resveratrol is a naturally occurring polyphenol that exhibits pleiotropic health beneficial effects, including anti-inflammatory, cardio-protective, and cancer-protective activities. It is recognized as one of the more promising natural molecules in the prevention and treatment of chronic inflammatory and autoimmune disorders. Ulcerative colitis is an idiopathic, chronic inflammatory disease of the colon associated with a high colon cancer risk. Here, we used a dextran sulfate sodium (DSS) mouse model of colitis, which resembles human ulcerative colitis pathology. Resveratrol mixed in food ameliorates DSS-induced colitis in mice in a dose-dependent manner. Resveratrol significantly improves inflammation score, downregulates the percentage of neutrophils in the mesenteric lymph nodes and lamina propria, and modulates CD3 + T cells that express tumor necrosis factor-α and IFN-γ. Markers of inflammation and inflammatory stress (p53 and p53-phospho-Ser 15) are also downregulated by resveratrol. Because chronic colitis drives colon cancer risk, we carried out experiments to determine the chemopreventive properties of resveratrol. Tumor incidence is reduced from 80% in mice treated with azoxymethane (AOM) + DSS to 20% in mice treated with AOM + DSS + resveratrol (300 ppm). Tumor multiplicity also decreased with resveratrol treatment. AOM + DSS-treated mice had 2.4 ± 0.7 tumors per animal compared with AOM + DSS + 300 ppm resveratrol, which had 0.2 ± 0.13 tumors per animal. The current study indicates that resveratrol is a useful, nontoxic complementary and alternative strategy to abate colitis and potentially colon cancer associated with colitis. Cancer Prev Res; 3(4); 549-59. ©2010 AACR.
The fabrication of tubular structures, with multiple cell types forming different layers of the tube walls, is described using a stress-induced rolling membrane (SIRM). Cell orientation inside the tubes can also be controlled by topographical contact guidance. These layered tubes precisely mimic blood vessels and many other tubular structures, suggesting that they may be of great use in tissue engineering.
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