text:
Recent studies have demonstrated that volatile anesthetic postconditioning confers myocardial protection against ischemia-reperfusion (IR) injury through activation of the reperfusion injury salvage kinase (RISK) pathway. As RISK has been shown to be impaired in hypercholesterolemia. Therefore, we investigate whether anesthetic-induced cardiac protection was maintained in hypercholesterolemic rats. In the present study, normocholesteolemic or hypercholesterolemic rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. Animals received 2.4% sevoflurane for 5 min or 3 cycles of 10-s ischemia/10-s reperfusion. The hemodynamic parameters, including left ventricular developed pressure, left ventricular end-diastolic pressure and heart rate, were continuously monitored. The infarct size, apoptosis, p-Akt, p-ERK1/2, p-GSK3β were determined. We found that both sevoflurane and ischemic postconditioning significantly improved heart pump function, reduced infarct size and increased the phosphorylation of Akt, ERK1/2 and their downstream target of GSK3β in the healthy rats. In the hypercholesterolemic rats, neither sevoflurane nor ischemic postconditioning improved left ventricular hemodynamics, reduced infarct size and increased the phosphorylated Akt, ERK1/2 and GSK3β. In contrast, GSK inhibitor SB216763 conferred cardioprotection against IR injury in healthy and hypercholesterolemic hearts. In conclusions, hyperchoesterolemia abrogated sevoflurane-induced cardioprotection against IR injury by alteration of upstream signaling of GSK3β and acute GSK inhibition may provide a novel therapeutic strategy to protect hypercholesterolemic hearts against IR injury.
Citation: Xu Y, Ma L-L, Zhou C, Zhang F-J, Kong F-J, Wang W-N, et al. (2013) Hypercholesterolemic Myocardium Is Vulnerable to Ischemia-Reperfusion Injury and Refractory to Sevoflurane-Induced Protection. PLoS ONE 8(10): e76652. doi:10.1371/journal.pone.0076652
Editor: Ramani Ramchandran, Medical College of Wisconsin, United States of America
Received: May 20, 2013; Accepted: August 27, 2013; Published: October 4, 2013
Copyright: © 2013 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Natural Science Foundation of China (numbers 81170118 and 81201496), the Natural Science Foundation of Zhejiang Province (number R2090259), Medicine Administration Bureau of Zhejiang Province (number 2011ZZ009), and the Foundation from Science and Technology Department of Zhejiang Province (numbers 2009C13G2010218 and 2012C33088). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Myocardial ischemia reperfusion injury can be reduced by multiple interventions, such as ischemic postconditioning [1] and volatile anesthetic postconditioning [2], in animal hearts and human hearts. Activation of reperfusion injury salvage kinase (RISK) pathway (mainly PI3K-Akt-GSK3β axis and ERK1/2) contributes to ischemic/anesthetic-induced myocardial protection [1,2]. Multiple prosurvival signaling pathways, including PI3K-Akt and ERK1/2, converge on glycogen synthase kinase 3β (GSK3β) [3]. In addition, the phosphorylation of GSK3β inhibits the opening of mitochondrial permeability transition pore (mPTP) and reduces mitochondria-dependent apoptosis and necrosis [4]. Recent studies have demonstrated that MG53, a newly identified tripartite motif-containing (TRIM) family protein, is indispensable for ischemic postconditioning-induced cardioprotection through the activation of PI3K-Akt-GSK3β axis and ERK1/2 pathway [5]. Although anesthetic and ischemic postconditioning can activate overlapping signal events, whether MG53 is related to the cardiac sevoflurane postconditioning remains elusive.
In recent years, anesthetic postconditioning has mainly been documented in healthy subjects, and the effect of sevoflurane postconditioning on hypercholesterolemic rat heart remains unclear. A number of prospective clinical studies have shown that both coronary artery disease (CAD) and the risk factor for cardiac death after acute myocardial infarct (AMI) are directly related to hypercholesterolemia [6,7]. Furthermore, hypercholesterolemia is associated with alterations of Akt and ERK1/2 phosphorylation and abrogates ischemic postconditioning-induced cardioprotection by interfering with nitric oxide synthase signaling [8,9]. These studies indicate that hypercholesterolemia may adversely affect sevoflurane-induced cardioprotection. Therefore, the aim of the current study was to investigate whether sevoflurane-induced cardioprotection was maintained in hypercholesterolemic rats.
Materials and Methods
1. Animals
All of the animals were treated according to the guidelines of the Guide for the Care and Use of Laboratory Animals (United States National Institutes of Health). The Laboratory Animal Care Committee of Zhejiang University approved all experimental procedures and protocols. All efforts were made to minimize the number of animals used and their suffering. The rats were housed in polypropylene cages, and the room temperature was maintained at 22 °C, with a 12-hour light-dark cycle. Six-week-old male Sprague-Dawley rats, weighing 130-180 g, were used for all experiments.
2. Study Groups and Experimental Protocol
To investigate whether sevoflurane-induced cardioprotection was maintained in hypercholesterolemic rats, the experiments were conducted as follows: 1) normocholesterolemic ischemia reperfusion group (IR): rats were fed standard pellet chow for 8 weeks and received no further treatment before myocardial ischemia; 2) normocholesterolemic sevoflurane postconditioning group (IR + SPO): rats were fed standard pellet chow for 8 weeks and then treated with 2.4% sevoflurane (Maruishi Pharmaceutical Co, Ltd, Osaka, Japan) via sevoflurane vaporizer (Sevotec 5; Datex-Ohmeda, Tewksbury, MA, USA) for 5-min immediately after reperfusion [10]; 3) normocholesterolemic ischemic postconditioning group (IR + IPO): rats were fed standard pellet chow for 8 weeks and then treated with three episode of 10-s of ischemia/10-s reperfusion immediately after reperfusion [11]; 4) hypercholesterolemic ischemia reperfusion group (HC + IR): rats were fed 2% cholesterol pellet chow for 8 weeks and received no further treatment before myocardial ischemia; 5) hypercholesterolemic sevoflurane postconditioning group (HC + IR + SPO): rats were fed 2% cholesterol pellet chow for 8 weeks and then treated with 2.4% sevoflurane for 5-min immediately after reperfusion. 6) hypercholesterolemic ischemic postconditioning group (HC + IR + IPO): rats were fed standard pellet chow for 8 weeks and then treated with three episode of 10-s of ischemia/10-s reperfusion immediately after reperfusion; To explore the cardioprotective role of GSK3β phosphorylation in hypercholesterolemic rat hearts, we conducted a second experiment. The selective GSK inhibitor SB216763 (0.6 mg/kg i.v., 5 min before reperfusion) [12] were administered to normocholesterolemic and hypercholesterolemic rats. All inhibitors were from Sigma-Aldrich Inc (St Louis, Mo, USA).
3. Serum Lipid Assay
Blood was harvested from the caudal vein and centrifuged (3000 rpm, 10 min, 4°C) to obtain serum. Serum lipid levels were measured by spectrophotometry using commercial assay kits for total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) (Beijing BHKT Clinical Reagent Co., Ltd., Beijing, China) according to the manuals and as described by Ballantyne et al [13].
4. Hematoxylin-eosin Staining
To determine that chronic treatment with a high-cholesterol diet for 8 weeks does not result in the development of coronary atherosclerosis in rats, hematoxylin-eosin staining for thoracic aorta and coronary artery was conducted. The small segments of thoracic aorta and the heart were harvested from rats fed with either high cholesterol or normal chow for 8 weeks for histologic examination. The samples were fixed in 4% paraformaldehyde and embedded in paraffin. Hematoxylin-eosin staining was conducted as Iliodromitis et al [14] have described elsewhere.
5. Surgical Preparation
The IR surgery was performed according to the methods of Zhang et al [15] with modifications. Briefly, rats were anesthetized with sodium pentobarbital (50 mg/kg i.p.), plus additional doses (25 mg/kg i.p.) every 60 min to maintain effective anesthesia [16] and were mechanically ventilated with room air to maintain arterial pH, PCO2 and PO2 within the normal physiological range. The pericardium was opened and a 6-0 silk suture was passed under the left atrial appendage for 2-3 mm through a small polytetrafluoroethylene tube. The tube was pulled to occlude the coronary artery for 30 min and the occlusion was confirmed by epicardial cyanosis in the area at risk, while successful reperfusion (for 120 min) was verified by epicardial hyperemia. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP) and heart rate (HR) were measured throughout the experimental period by a polyethylene catheter placed into the left ventricle connecting a pressure transducer connected to a data acquisition system (PowerLab; ADInstruments, Shanghai Trading Co, Ltd, Shanghai, China).
6. Determination of Infarct Size
At the end of reperfusion, the coronary artery was reoccluded and perfused with 1% Evans blue dye to identify the unstained area as the area at risk. The left ventricle was separated, frozen, cut into transverse slices, and incubated in 1% triphenyltetrazolium chloride solution at 37°C for 10 min. The area of infarct (pale) and risk (red) was measured by planimetry using ImageJ 1.37 from the National Institutes of Health (Bethesda, MD, USA). The infarct size was expressed as a percentage of the area at risk. Samples with an area at risk <15% or >45% of the left ventricle were excluded [17].
7. Detection of Myocardial Apoptosis
Apoptosis was assessed using the TUNEL method. At the end of reperfusion, the hearts were fixed in 4% paraformaldehyde and embedded in paraffin for TUNEL staining. The heart tissue sections were stained using an in situ cell death detection kit (POD; Roche Diagnostics Corp, Indianapolis, IN, USA), following the manufacturer's protocol. Ten microscopic fields (400×) from each section were assayed by counting brown nuclei. The percentage of TUNEL-positive nuclei (brown nuclei) was calculated.
8. Immunoblotting
Fifteen minutes following reperfusion, the samples were taken from ischemic zone. The expression of myocardial Akt, phosphorylated-Akt (Ser473) (p-Akt), ERK1/2 and phosphorylated-ERK1/2 (Thr202/Tyr204) (p-ERK1/2), GSK3β, phosphorylated-GSK-3β (Ser9) (p-GSK3β) (Cell Signaling Technology, Beverly, MA, USA) were determined by Western blotting as we described elsewhere [18]. At the end of reperfusion, the expression of MG53 (Gene Tex, San Antonio, TX, USA) and PI3K-p85 (Cell Signaling Technology, Beverly, MA, USA) was determined by Western blotting as we described elsewhere [18]. The quantitative protein band density was assayed by ImageJ 1.37.
9. Statistical Analysis
Data are shown as mean ± SD. Lipid levels were analyzed using the unpaired Student's t test. All other data were analyzed by one-way ANOVA following Newman-Keuls post hoc test. A value of P <0.05 was considered to be statistically significant. All statistical analyses were performed using GraphPad Prism Version 4.0 (GraphPad Prism Software, San Diego, CA, USA).
Seventy rats were used for myocardial infarction experiments (2 were excluded as a result of area at risk <15% and 4 died of refractory ventricular arrhythmias during the 30-min occlusion) and 79 animals were used for immunoblotting (7 died of refractory ventricular arrhythmias during the 30-min occlusion). An additional 53 rats were used for TUNEL staining (5 died of refractory ventricular arrhythmias during the 30-min occlusion). 10 rats were used for hematoxylin-eosin staining.
1. High-cholesterol Diet Induced a Moderate and Steady Increase in Serum Cholesterol without Substantial Development of Coronary Atherosclerosis in rats
Levels of TC (136.5 ± 12.8 mg/dl), LDL-C (57.9 ± 7.2 mg/dl), and TG (128.2 ± 7.1 mg/dl) were increased in rats fed high-cholesterol chow compared with those (68.3 ± 6.6 mg/dl, 26.1 ± 4.8 mg/dl, and 59.4 ± 8.9 mg/dl) fed normal chow (P < 0.01). The level of HDL-C (29.6 ± 3.9 vs. 28.3 ± 4.8) was not significantly different between normocholesterolemic and hypercholesterolemic rats.
Atherogenesis was detected in the form of subintimal accumulation of lipids and foamy macrophages. There was no deposition of lipids and foamy macrophages in the subintimal area in the cross-section of the aortic wall (Figure 1A) and the myocardial branch of coronary artery from rats fed with either high cholesterol or normal chow for 8 weeks (Figure 1B).
The arterial lumen is indicated by the arrow, n = 5 hearts/group.
2. Hypercholesterolemia Abrogates the Left Ventricular Hemodynamic Improvement Induced by Sevoflurane and Ischemic Postconditioning
As shown in Table 1, there was no significant difference in baseline left ventricular hemodynamic parameters among all groups (P > 0.05). After 60 min of reperfusion, LVDP and LVEDP were significantly increased in IR + SPO and IR + IPO compared with that in IR (P < 0.05). However, such improving effect was not observed in HC + SPO and HC + IPO compared with that in HC + IR (P > 0.05).
|30 min
|60 min
|90 min
|120 min
|LVDP, mmHg
|127 ± 8
|81 ± 5
|108 ± 11
|89 ± 9
|84 ± 6
|77 ± 10
|130 ± 9
|83 ± 5
|111 ± 11
|106 ± 5*
|101 ± 5*
|97± 6*
|123 ± 7
|80 ± 7
|115 ± 15
|107 ± 11*
|102 ± 5*
|96 ± 7*
|130 ± 12
|85 ± 11
|115 ±10
|98 ± 9
|88 ± 12
|80 ± 13
|134 ± 8
|80 ± 7
|110 ± 7
|94 ± 12
|87 ± 13
|83 ± 12
|127 ± 7
|84 ± 5
|107 ± 10
|92 ± 7
|86 ± 7
|84 ± 8
|LVEDP, mmHg
|4.1 ± 1.5
|10.1 ± 1.6
|5.3 ± 1.8
|7.6 ± 1.8
|7.9 ± 1.4
|8.2 ± 1.5
|3.9 ± 1.0
|9.4 ± 1.7
|4.5 ± 1.4
|5.1 ± 1.2*
|5.9 ± 1.1*
|5.7 ± 1.5*
|4.0 ± 1.4
|9.5 ± 2.1
|5.0 ± 1.1
|5.6 ± 1.2*
|5.5 ± 1.0*
|5.9 ± 1.1*
|4.1 ± 1.0
|9.9 ± 1.2
|5.4 ± 1.0
|6.9 ± 1.3
|7.8 ± 1.0
|8.4 ± 1.3
|4.5 ± 1.2
|10.4 ± 1.1
|6.3 ± 1.0
|7.2 ± 1.2
|7.4 ± 1.2
|7.8 ± 1.5
|3.9 ± 1.4
|10.0 ± 1.8
|6.4 ± 1.6
|7.0 ± 1.8
|7.3 ± 1.5
|7.7 ± 1.6
|HR, beats/min
|345 ± 35
|325 ± 41
|312 ± 48
|305 ± 39
|315 ± 42
|299 ± 41
|332 ± 32
|312 ± 41
|315 ± 39
|321 ± 35
|306 ± 40
|313 ± 39
|350 ± 34
|310 ± 34
|318 ± 40
|309 ± 37
|310 ± 39
|300 ± 41
|328 ± 31
|308 ± 43
|303 ± 39
|300 ± 34
|298 ± 41
|288 ± 39
|340 ± 39
|318 ± 39
|300 ± 39
|310 ± 30
|313 ± 44
|304 ± 41
|330 ± 38
|320 ± 38
|310 ± 32
|308 ± 36
|310 ± 33
|300 ± 37
3. Hypercholesterolemia Abrogates the Myocardial Infarct-sparing Effect of Sevoflurane and Ischemic Postconditioning
The area at risk was not significantly different among all groups (data not shown). As shown in Figure 2, the infarct size was larger by 18% in the HC + IR (52 ± 5%) compared with the IR group (44 ± 5%, P < 0.05). The infarct size was markedly decreased in the IR + SPO (27 ± 6%) and IR + IPO (26 ± 5%) over the IR group (44 ± 5%, P < 0.05). The reduced myocardial infarct conferred by sevoflurane and ischemic postconditioning was not found in hypercholesterolemic rats.
IR: ischemia reperfusion; SPO: sevoflurane posconditioning; IPO: ischemic posconditioning; HC: hypercholesterolemia. Data are mean ± SD, n = 8 hearts/group. *P < 0.05 vs. IR.
4. Hypercholesterolemia Inhibits the Myocardial Anti-apoptotic Effect of Sevoflurane and Ischemic Postconditioning
As shown in Figure 3, The number of TUNEL-positive nuclei expressed as a percentage of total nuclei was markedly decreased in the IR + SPO (13 ± 4%) and IR + IPO (12 ± 2%) over the IR group (23 ± 4%, P < 0.05), however, the reduced apoptotic nuclear conferred by sevoflurane and ischemic postconditioning was not found in hypercholesterolemic rats. Interestingly, the number of TUNEL-positive nuclei was increased by 30% in the HC + IR (30 ± 4%) compared to the IR group (23 ± 4%, P < 0.05).
TUNEL-positive nuclei (brown nuclei) was indicated by the arrow. a normocholesterolemic ischemia reperfusion group (IR), b normocholesterolemic sevoflurane postconditioning group (IR + SPO), c normocholesterolemic ischemic postconditioning group (IR + IPO), d hypercholesterolemic ischemia reperfusion group (HC + IR), e hypercholesterolemic sevoflurane postconditioning group (HC + IR + SPO), f hypercholesterolemic ischemic postconditioning group (HC + IR + IPO). IR: ischemia reperfusion; SPO: sevoflurane postconditioning; IPO: ischemic postconditioning; HC: hypercholesterolemia. Data are mean ± SD, n = 6 hearts/group. *P < 0.05 vs. IR.
5. Hypercholesterolemia Abrogates the Upregulation of MG53 Expression Induced by Sevoflurane and Ischemic Postconditioning
Neither sevoflurane nor hypercholesterolemia alters the expression of MG53 in the absence of IR, which indicates that sevoflurane doesn't have a direct effect on MG53 expression (Figure S1).
Sevoflurane and ischemic postconditioning upregulated the expression of MG53 in healthy rats (P < 0.05), but this was completely blocked by hypercholesterolemia (Figure 4A). The expression of MG53 was not significantly different between IR and HC + IR groups.
IR: ischemia reperfusion; SPO: sevoflurane postconditioning; IPO: ischemic postconditioning; HC: hypercholesterolemia. Data are mean ± SD, n = 6 hearts/group. *P < 0.05 vs. IR.
6. Hypercholesterolemia Abrogates the Upregulation of PI3K-p85 and p-Akt Expression Induced by Sevoflurane and Ischemic Postconditioning
The levels of total Akt were not significantly different among all groups. Therefore, the levels of p-Akt were expressed as the percentage of total protein. Sevoflurane and ischemic postconditioning significantly increased the expression of PI3K-p85 and p-Akt in healthy rats (P < 0.05), however, this didn't occur in hypercholesterolemic ones. The expression of PI3K-p85 and p-Akt didn't significantly differ between IR and HC + IR groups (Figure 4B and Figure 4C).
7. Hypercholesterolemia Abrogates the Upregulation of p-ERK1/2 Expression Induced by Sevoflurane and Ischemic Postconditioning
No significant differences were found in the expression of total ERK1/2 among any groups. Sevoflurane and ischemic postconditioning significantly increased the p-ERK1/2 in healthy rats (P < 0.05). Interestingly, this effect was inhibited in the hypercholesterolemic groups. No difference in the expression of p-ERK1/2 was observed between IR and HC + IR groups (Figure 4D).
8. Hypercholesterolemia Abrogates the Upregulation of p-GSK3β Expression Induced by Sevoflurane and Ischemic Postconditioning
Immunoblots of total GSK3β were not significantly different between groups. Sevoflurane and ischemic postconditioning significantly increased the p-GSK3β in healthy rats (P < 0.01), however, this effect was blocked by hypercholesterolemia. The expression of p-GSK3β didn't significantly differ between IR and HC + IR groups (Figure 4E).
9. GSK3β Inhibitor was Cardioprotective in Hypercholesterolemic Hearts
To investigate whether the significant inhibition of sevoflurane and ischemia-induced GSK3β phosphorylation in hypercholesterolemic rat hearts was due to the inactivation of Akt and ERK1/2, we treated healthy and hypercholesterolmic rats with GSK3β inhibitor SB216763.
While sevoflurane and ischemic postconditioning did not improve the hemodynamic parameters of hypercholesterolemic rat hearts, SB216763 significantly improved LVDP and LVEDP in the hypercholeslerolemic group as well as in the healthy group after 60 min of reperfusion (Table 2).
|30 min
|60 min
|90 min
|120 min
|LVDP, mmHg
|127 ± 8
|81 ± 5
|108 ± 11
|89 ± 9
|84 ± 6
|77 ± 10
|125 ± 9
|83 ± 9
|110 ± 12
|105 ± 8*
|102 ± 7*
|95 ± 7*
|130 ± 12
|85 ± 11
|115 ±10
|98 ± 9
|88 ± 12
|80 ± 13
|127 ± 7
|84 ± 8
|117 ± 10
|110 ± 7#
|100 ± 7#
|93 ± 8#
|LVEDP, mmHg
|4.1 ± 1.5
|10.1 ± 1.6
|5.3 ± 1.8
|7.6 ± 1.8
|7.9 ± 1.4
|8.2 ± 1.5
|3.8 ± 1.1
|9.8 ± 1.5
|5.0 ± 1.4
|5.3 ± 1.2*
|5.7 ± 1.3*
|5.9 ± 1.2*
|4.1 ± 1.0
|9.9 ± 1.2
|5.4 ± 1.0
|6.9 ± 1.3
|7.8 ± 1.0
|8.4 ± 1.3
|3.9 ± 1.4
|9.6 ± 1.4
|4.9 ± 1.2
|5.6 ± 1.1
|5.8 ± 1.3#
|6.0 ± 1.4#
|HR, beats/min
|345 ± 35
|325 ± 41
|312 ± 48
|305 ± 39
|315 ± 42
|299 ± 41
|322 ± 33
|310 ± 36
|320 ± 33
|311 ± 39
|315 ± 36
|310 ± 33
|328 ± 31
|308 ± 43
|303 ± 39
|300 ± 34
|298 ± 41
|288 ± 39
|320 ± 38
|310 ± 39
|312 ± 30
|318± 41
|310 ± 37
|302 ± 34
Interestingly, we found that SB216763 significantly reduced infarct size in both normal and hypercholesterolemic hearts (IR + SB, 29 ± 5% vs. IR, 44 ± 5%; HC+ IR + SB, 35 ± 8% vs. HC + IR, 52 ± 5%; P < 0.05) (Figure 5).
IR: ischemia reperfusion; SB: SB216763; HC: hypercholesterolemia. Data are mean ± SD, n = 8 hearts/group. *P < 0.05 vs. IR; # P < 0.05 vs. HC + IR.
Moreover, SB216763 significantly decreased the number of TUNEL-positive nuclei in both healthy and hypercholesterolemic hearts (IR + SB, 14 ± 4% vs. IR, 23 ± 4%; HC+ IR + SB, 18 ± 3% vs. HC + IR, 30 ± 4%; P < 0.05) (Figure 6).
a normocholesterolemic ischemia reperfusion group (IR), b normocholesterolemic SB216763-treated group (IR + SB), c hypercholesterolemic ischemia reperfusion group (HC + IR), d hypercholesterolemic SB216763-treated group (HC + IR + SB). IR: ischemia reperfusion; SB: SB216763; HC: hypercholesterolemia. Data are mean ± SD, n = 6 hearts/group. *P < 0.05 vs. IR; # P < 0.05 vs. HC + IR.
The current study suggested that sevoflurane and ischemic postconditioning-induced cardioprotection against IR was blunted in hypercholesterolemic rat hearts, with altered MG53/RISK signaling pathway that inhibit GSK3β. We found that inhibition of GSK3β may be a potential therapeutic intervention to reduce myocardial infarct and apoptosis in hypercholesterolemic subjects.
We used chronic treatment with a high-cholesterol diet for 8 weeks to induce hypercholesterolemia in rats [19,20]. We found that this diet induced a moderate and steady increase in serum cholesterol without substantial development of coronary atherosclerosis (Figure 1), which is consistent with previous studies and suggests that the factor influencing sevoflurane postconditioning in our study was hypercholesterolemia itself, and not subsequent atherosclerosis or other hypercholesterolemic complications [21,22]. Therefore, we used this hypercholesterolemic model to study the direct cardiac effects of hypercholesterolemia on sevoflurane postconditioning.
Effects of hypercholesterolemia on myocardial IR have yielded controversial results in rodents. A number of studies have shown that hypercholesterolemia increases myocardial infarct size in the setting of IR [8,19,20], but the underlying mechanism is poorly understood. In our study, the myocardial infarct size induced by 30-min occlusion and 120-min reperfusion was increased by 18% in hypercholesterolemic rat hearts than that in healthy ones and suggests that hypercholesterolemic rats are susceptible to IR injury. In contrast to our findings, Kupai et al [23] showed that the myocardial infarct size induced by 30-min left coronary artery occlusion and 120-min reperfusion was not significantly increased in hypercholesterolemic rats fed a 2% cholesterol-enriched diet for 12 weeks compared with that in normally fed rats, and Giricz et al [24] reported that the infarct size induced by 30-min global ischemia and 120-min reperfusion in hearts isolated from rats fed a 2% cholesterol diet for 12 weeks was not significantly increased than that from normally fed rats. The reasons for such diverse results are unknown but may be attributable to the different high-cholesterol diet treatment periods and the different IR models (in vivo or in vitro) [8,19,20,23,24].
Another principle finding of our current study was hypercholesterolemia alone increased myocardial apoptosis in the setting of IR. In the present study, the number of apoptotic nuclei was increased by 30% in hypercholesterolemic rat hearts than that in healthy ones. One reasonable explanation is increased free oxygen radicals and inflammation may prompt apoptotic signaling pathway [25]. Furthermore, hypercholesterolemia is associated with decreased expression of anti-apoptotic Bcl-2 [8], which plays a pivotal role in preventing apoptosis by inhibiting the activation of executioner caspases 3 [26] and the release of mitochondrial cytochrome c [27]. All of the above may contribute to the increased myocardial apoptosis in the setting of hypercholesterolemia during IR.
The present study has shown that hypercholesterolemia induced by high-cholesterol diet abrogated sevoflurane and ischemic postconditioning-induced cardioprotection and modified cardioprotective signaling pathways. Here, we demonstrated that the myocardial p-Akt and p-ERK1/2 expression was upregulated by sevoflurane and ischemic postconditioning. Interestingly, such cardioprotection and upregulation of myocardial p-Akt and p-ERK1/2 expression were both lost in hypercholesterolemic rats. Furthermore, previous studies have demonstrated that both PI3k-Akt and MEK-ERK1/2 signals play a pivotal role in the cardioprotection of sevoflurane or ischemic postconditioning [1,2]. These results at least indicate that the loss of upregulation of p-Akt and p-ERK1/2 expression is closely associated with the loss of cardioprotection of sevoflurane postconditioning in hypercholesterolemic rats. MG53, an upstream signaling cascade of Akt, forms a functional complex with the p85 subunit of PI3K and contributes to acute membrane repair in cardiomyocytes [5,28]. In addition, ischemic postconditioning-induced cardioprotection is lost in MG53-deficient mice and overexpression of MG53 attenuates hypoxia- and oxidative-induced cardiomyocytes death through the activation of PI3K-Akt-GSK3β and ERK1/2 signaling pathways [5,29]. In healthy rats, sevoflurane significantly increased the levels of MG53 and PI3k-p85, however, this didn't occur in hypercholesterolemic ones with sevoflurane postconditioning. Our results indicate that the dysfunction of the upstream protein kinases MG53 may in part contribute to the observed deficit in Akt and ERK1/2 phosphorylation in hypercholesterolemic rat hearts. Furthermore, the deficit in GSK3β phophorylation in hypercholesterolemic rat hearts may in part be attributed to the observed deficit in Akt and ERK1/2 phosphorylation. If, as mentioned above, upregulation of phosphorylated Akt, ERK1/2 and GSK3β plays a pivotal role in the infarct-sparing effect of sevoflurane postconditioning, we reasoned that the loss of cardioprotection in hypercholesterolemic myocardium, at least in part, be attributed to the dysfunction of Akt, ERK1/2 and GSK3β phosphorylation.
Our current study has shown that the cardioprotective effect of postconditioning was lost in hypercholesterolemic subjects, which suggests that hypercholesterolemic patients may not benefit from therapeutic application of sevoflurane in the clinical setting. Therefore, it is translationally important to explore novel cardioprotective strategies. We found that the GSK3β inhibitor SB216763 significantly improved heart pump function, reduced myocardial infarct size and apoptosis in hypercholesterolemic rats, which suggests that the downstream signal mechanisms of GSK3β in hypercholesterolemic myocardium is preserved. Together, these data indicate that inhibition of GSK3β would be a more promising therapeutic target to protect hypercholesterolemic hearts against IR injury.
Our findings are translationally important in that they determined whether the myocardial protection induced by sevoflurane occurs in hypercholesterolemic animals. However, there are several limitations in our current study. First, the loss of cardioprotection of sevoflurane postconditioning in hypercholesterolemic rats might also be due to changes in cardiovascular oxidative/nitrosative stress [23,30], which were not explored in the current study. Second, patients with hypercholesterolemia are usually also have coronary atherosclerosis, and our hypercholesterolemic rats did not, which indicates that the hypercholesterolemic rat model we used may not fully simulate the complex clinical setting of hypercholesterolemic patients, so our results may only apply to effect of hypercholesterolemia on cardioprotection induced by sevoflurane in a limited clinical setting.
In summary, we report that sevoflurane-induced cardioprotection against IR injury was abrogated in hypercholesterolemic rats. Hypercholesterolemia blocked the ability of sevoflurane to phosphorylate components of RISK pathway and consequently, the phosphorylation of the downstream target GSK3β. These data indicate that direct inhibition of GSK3β before myocardial infarct may be a potential therapeutic approach to prevent IR injury in the presence of hypercholesterolemia.
Supporting Information
Figure S1.
Effects of sevoflurane on the expression of MG53 in sham-operated rat hearts. Normocholesterolemic and hypercholesterolemic sham-operated rats were treated with 2.4% sevoflurane via sevoflurane vaporizer for 5-min. Then hearts were harvested for immunoblotting. NC: normocholesterolemia; HC: hypercholesterolemia. Sev: sevoflurane. Data are mean ± SD, n = 6 hearts/group.
Author Contributions
Conceived and designed the experiments: CZ LLM FJZ MY. Performed the experiments: CZ YX LLM FJK WNW CCW. Analyzed the data: CZ LBQ XBL JAW. Contributed reagents/materials/analysis tools: MY JAW. Wrote the manuscript: CZ LLM YX.
- 1. Ferdinandy P, Schulz R, Baxter GF (2007) Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev 59: 418-458. doi:10.1124/pr.107.06002. PubMed: 18048761.
- 2. Pagel PS (2008) Postconditioning by volatile anesthetics: salvaging ischemic myocardium at reperfusion by activation of prosurvival signaling. J Cardiothorac Vasc Anesth 22: 753-765. doi:10.1053/j.jvca.2008.03.005. PubMed: 18922439.
- 3. Lecour S (2009) Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway? J Mol Cell Cardiol 47: 32-40. doi:10.1016/j.yjmcc.2009.03.019. PubMed: 19344728.
- 4. Juhaszova M, Zorov DB, Yaniv Y, Nuss HB, Wang S et al. (2009) Role of glycogen synthase kinase-3beta in cardioprotection. Circ Res 104: 1240-1252. doi:10.1161/CIRCRESAHA.109.197996. PubMed: 19498210.
- 5. Zhang Y, Lv F, Jin L, Peng W, Song R et al. (2011) MG53 participates in ischaemic postconditioning through the RISK signalling pathway. Cardiovasc Res 91: 108-115. doi:10.1093/cvr/cvr029. PubMed: 21285295.
- 6. Corti R, Fuster V, Badimon JJ, Hutter R, Fayad ZA (2001) New understanding of atherosclerosis (clinically and experimentally) with evolving MRI technology in vivo. Ann N Y Acad Sci 947: 181-195. PubMed: 11795266.
- 7. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR et al. (2001) Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 104: 3046-3051. doi:10.1161/hc5001.100624. PubMed: 11748098.
- 8. Osipov RM, Bianchi C, Feng J, Clements RT, Liu Y et al. (2009) Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion. Circulation 120: S22-S30. doi:10.1161/CIRCULATIONAHA.108.842724. PubMed: 19752371.
- 9. Sack MN, Murphy E (2011) The role of comorbidities in cardioprotection. J Cardiovasc Pharmacol Ther 16: 267-272. doi:10.1177/1074248411408313. PubMed: 21821527.
- 10. Drenger B, Ostrovsky IA, Barak M, Nechemia-Arbely Y, Ziv E et al. (2011) Diabetes blockade of sevoflurane postconditioning is not restored by insulin in the rat heart: phosphorylated signal transducer and activator of transcription 3- and phosphatidylinositol 3-kinase-mediated inhibition. Anesthesiology 114: 1364-1372. doi:10.1097/ALN.0b013e31820efafd. PubMed: 21368653.
- 11. Zhao HX, Wang XL, Wang YH, Wu Y, Li XY et al. (2010) Attenuation of myocardial injury by postconditioning: role of hypoxia inducible factor-1alpha. Basic Res Cardiol 105: 109-118. doi:10.1016/j.amjcard.2010.01.310. PubMed: 19597757.
- 12. Gross ER, Hsu AK, Gross GJ (2004) Opioid-induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts. Circ Res 94: 960-966. doi:10.1161/01.RES.0000122392.33172.09. PubMed: 14976126.
- 13. Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ et al. (2003) Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 107: 2409-2415. doi:10.1161/01.CIR.0000068312.21969.C8. PubMed: 12719279.
- 14. Iliodromitis EK, Zoga A, Vrettou A, Andreadou I, Paraskevaidis IA et al. (2006) The effectiveness of postconditioning and preconditioning on infarct size in hypercholesterolemic and normal anesthetized rabbits. Atherosclerosis 188: 356-362. doi:10.1016/j.atherosclerosis.2005.11.023. PubMed: 16376892.
- 15. Zhang SZ, Wang NF, Xu J, Gao Q, Lin GH et al. (2006) Kappa-opioid receptors mediate cardioprotection by remote preconditioning. Anesthesiology 105: 550-556. doi:10.1097/00000542-200609000-00019. PubMed: 16931988.
- 16. Yu CK, Li YH, Wong GT, Wong TM, Irwin MG (2007) Remifentanil preconditioning confers delayed cardioprotection in the rat. Br J Anaesth 99: 632-638. doi:10.1093/bja/aem261. PubMed: 17872933.
- 17. Mykytenko J, Kerendi F, Reeves JG, Kin H, Zatta AJ et al. (2007) Long-term inhibition of myocardial infarction by postconditioning during reperfusion. Basic Res Cardiol 102: 90-100. doi:10.1007/s00395-006-0625-0. PubMed: 17003965.
- 18. Zheng Z, Yang M, Zhang F, Yu J, Wang J et al. (2011) Gender-related difference of sevoflurane postconditioning in isolated rat hearts: focus on phosphatidylinositol-3-kinase/Akt signaling. J Surg Res 170: e3-e9. doi:10.1016/S0022-4804(11)00696-2. PubMed: 21704330.
- 19. Zhao H, Wang Y, Wu Y, Li X, Yang G et al. (2009) Hyperlipidemia does not prevent the cardioprotection by postconditioning against myocardial ischemia/reperfusion injury and the involvement of hypoxia inducible factor-1alpha upregulation. Acta Biochim Biophys Sin (Shanghai) 41: 745-753. doi:10.1093/abbs/gmp063.
- 20. Penumathsa SV, Thirunavukkarasu M, Koneru S, Juhasz B, Zhan L et al. (2007) Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J Mol Cell Cardiol 42: 508-516. doi:10.1016/j.yjmcc.2006.10.018. PubMed: 17188708.
- 21. Roach PD, Balasubramaniam S, Hirata F, Abbey M, Szanto A et al. (1993) The low-density lipoprotein receptor and cholesterol synthesis are affected differently by dietary cholesterol in the rat. Biochim Biophys Acta 1170: 165-172. doi:10.1016/0005-2760(93)90067-J. PubMed: 8399341.
- 22. Horton JD, Cuthbert JA, Spady DK (1995) Regulation of hepatic 7 alpha-hydroxylase expression and response to dietary cholesterol in the rat and hamster. J Biol Chem 270: 5381-5387. doi:10.1074/jbc.270.10.5381. PubMed: 7890651.
- 23. Kupai K, Csonka C, Fekete V, Odendaal L, van Rooyen J et al. (2009) Cholesterol diet-induced hyperlipidemia impairs the cardioprotective effect of postconditioning: role of peroxynitrite. Am J Physiol Heart Circ Physiol 297: H1729-H1735. doi:10.1152/ajpheart.00484.2009. PubMed: 19734363.
- 24. Görbe A, Varga ZV, Kupai K, Bencsik P, Kocsis GF et al. (2011) Cholesterol diet leads to attenuation of ischemic preconditioning-induced cardiac protection: the role of connexin 43. Am J Physiol Heart Circ Physiol 300: H1907-H1913. doi:10.1152/ajpheart.01242.2010. PubMed: 21398600.
- 25. Wang TD, Chen WJ, Su SS, Lo SC, Lin WW et al. (2002) Increased cardiomyocyte apoptosis following ischemia and reperfusion in diet-induced hypercholesterolemia: relation to Bcl-2 and Bax proteins and caspase-3 activity. Lipids 37: 385-394. doi:10.1007/s1145-002-0906-2. PubMed: 12030319.
- 26. Okamura T, Miura T, Takemura G, Fujiwara H, Iwamoto H et al. (2000) Effect of caspase inhibitors on myocardial infarct size and myocyte DNA fragmentation in the ischemia-reperfused rat heart. Cardiovasc Res 45: 642-650. doi:10.1016/S0008-6363(99)00271-0. PubMed: 10728385.
- 27. Gustafsson AB, Gottlieb RA (2007) Bcl-2 family members and apoptosis, taken to heart. Am J Physiol Cell Physiol 292: C45-C51. PubMed: 16943242.
- 28. Wang X, Xie W, Zhang Y, Lin P, Han L et al. (2010) Cardioprotection of ischemia/reperfusion injury by cholesterol-dependent MG53-mediated membrane repair. Circ Res 107: 76-83. doi:10.1161/CIRCRESAHA.109.215822. PubMed: 20466981.
- 29. Cao CM, Zhang Y, Weisleder N, Ferrante C, Wang X et al. (2010) MG53 constitutes a primary determinant of cardiac ischemic preconditioning. Circulation. 121: 2565-2574. doi:10.1161/CIRCULATIONAHA.110.954628. PubMed: 20516375.
- 30. Iliodromitis EK, Andreadou I, Prokovas E, Zoga A, Farmakis D et al. (2010) Simvastatin in contrast to postconditioning reduces infarct size in hyperlipidemic rabbits: possible role of oxidative/nitrosative stress attenuation. Basic Res Cardiol 105: 193-203. doi:10.1007/s00395-009-0078-3. PubMed: 20066537.


text:
Description: Created from the immunology and rheumatology chapters of Harrison's Principles of Internal Medicine, 18th edition, Longo et al. (McGraw-Hill, 2011), this book begins with the basics of immunobiology, then moves into a series of disease-specific chapters encompassing both inflammatory rheumatic conditions and common, noninflammatory musculoskeletal conditions.
Purpose: The authors present the information practitioners need to care for patients with rheumatic disease, with the goal of improving patient care. They also want the information to reflect the importance of rheumatology to the practice of internal medicine.
Audience: This is directed at practitioners caring for adult patients with a rheumatological disorder seeking more information to improve patient care, regardless of the practitioner's level of training. The authors also hope that providing this information will generate increased interest in the field of rheumatology. Given its origin in Harrison's, this book will be of most interest to practitioners of internal medicine.
Features: The book is divided into three sections. The first reviews basic immunobiology and includes insights into how malfunction of normal immune processes can predispose to autoimmunity. Section two reviews the clinical features, epidemiology, pathogenesis, diagnosis, and treatment of rheumatic diseases. Section three addresses these topics for other musculoskeletal disorders including osteoarthritis, fibromyalgia, and overuse conditions. The treatment sections are nicely highlighted in yellow textboxes, but the chapters otherwise do not follow a standardized format. However, the book is not written in a quick reference format. Instead, its paragraphs tackle complex issues in immunology and pathophysiology and are more encompassing than concise. A self-assessment test ends the book. As this is an extract from a larger book published two years prior, it carries a 2013 copyright, but content is updated only to 2011.
Assessment: Given the rapid pace of advances in immunology and rheumatology, updates are always valuable. This is useful for those who want a comprehensive review of rheumatology in a readable physical package. It has not been crafted for quick reference, but for those with time to engage in the learning process. It should be used with the understanding that, in such a rapidly advancing field as rheumatology, no textbook can be as current as the primary literature.

subset: commoncrawl


text:
By Mr. Robert H Mcelroy (IMCOM)December 17, 2009
USAG HUMPHREYS, South Korea - Army Chief of Staff Gen. George Casey visited Humphreys Garrison Dec. 16, bringing with him messages of praise, pride and encouragement.
Addressing a crowd of nearly 150 Soldiers, Family Members and Civilians, Casey said that he was proud of their service and the sacrifice they make so far from home.
Casey touched on a number of subjects including the state of the Army, the Year of the Noncommissioned Officer and the Comprehensive Soldier Fitness program.
He said that he and the Army leadership recognize the toll the wars in Iraq and Afghanistan have taken on Soldiers and their Families.
"We continue to build dwell time but we're not quite there yet."
Casey said that the drawdown of Army forces in Iraq over the next year will help and should help ease the deployment rotation.
Iraq will be down to about 50,000 by next year and we can do Afghanistan without going to 15-month tours, he said.
Casey also discussed the Comprehensive Soldier Fitness Program which will help develop resiliency in Soldiers, Families and Civilians.
It will help them to be as resilient as they can be, Casey stressed. We want to bring mental fitness up to the same level as physical fitness.
The Comprehensive Soldier Fitness Program will be part of every Army training program from basic training up to the War College, Casey said.
"Every Army School will teach a course on resilience. We'll have master resilience trainers, just as we had master fitness trainers."
Casey next spoke of the Army's Year of the Noncommissioned Officer.
"The Year of the NCO recognized the contributions of our NCOs, he said. "The Secretary of the Army and I believe NCOs provide the glue that hold the force together and we wanted to let the American people know that."
Casey said that President Barack Obama spoke highly of the Year of the NCO when he presented the Medal of Honor to the family of Sgt. 1st Class Jared C. Monti in September.
According to Casey Obama praised Monti and all NCOs for their dedication, commitment and warrior ethos.
"I feel pretty good about what we've done to recognize all of our NCOs," Casey said. "Thank you very much for what you do to hold us together."
Casey then took questions from the audience and provided answers on subjects ranging from the lack of spouse employment opportunities at Humphreys to revising the Army's Physical Fitness manual to a potential drawdown of the Army when the wars in Iraq and Afghanistan are over.
Regarding spouse employment and other quality of life issues at Humphreys, Casey said that it's clear to him that "...we've created expectations that we need to realize faster than by 2013."
According to current plans, by 2013 many of the new facilities at Humphreys should be coming online as the post grows and transforms. This should provide more job opportunities for spouses.
On revising the PT manual, Casey said that he thought it was a good idea to review it with an eye toward revising it.
"I'll take that back with me, that's a good suggestion," he said.
Casey said that he does not expect the Army to drawdown any time soon given its commitments to Iraq, Afghanistan and the rest of the world.
"I think the size of the Army is getting about right to meet the demand, I think we're going to stay here for a while," he said. "I think ultimately the size of the Army will come down but you'll be retired by then."
Casey offered a last bit of praise for all telling them that they are "...part of an Army that is the greatest force for good the world has ever seen. You need to know that is recognized by your country and your president."
For more information on the Comprehensive Soldier Fitness Program visit www.army.mil/csf


text:
I've been looking for a conditional statement for this for some time today, no luck, not even mention in the Codex..
I am using a multi-level navigation on my page:
-- Subcategory 1
---- Subpage 1
---- Subpage 2
---- Subpage 3
-- Subcategory 2
-- Subcategory 3
"Subcategory 1" is blank.
Is it possible, if user clicks "Subcategory 1", WordPress jumps to first subpage ("Subpage 1")? There is no need to display an empty buffer page IMO..
smth like: if subcategory=empty, jump to it's subpage 1?


text:
Garbage Collection in C Programs
The first word that came to mind when I heard about introducing Garbage Collection techniques into a C or C++ program was "nonsense". As with any other decent C programmer who loves this language, the thought of leaving the management of my own memory to others seemed nearly offensive. I had a similar feeling 15 years ago, when I first heard about compilers that would generate assembly code on my behalf. I was used to writing my code directly in 6510 opcodes, but that was Commodore 64—and a totally different story.
Garbage Collection (GC) is a mechanism that provides automatic memory reclamation for unused memory blocks. Programmers dynamically allocate memory, but when a block is no longer needed, they do not have to return it to the system explicitly with a free() call. The GC engine takes care of recognizing that a particular block of allocated memory (heap) is not used anymore and puts it back into the free memory area. GC was introduced by John McCarthy in 1958, as the memory management mechanism of the LISP language. Since then, GC algorithms have evolved and now can compete with explicit memory management. Several languages are natively based on GC. Java probably is the most popular one, and others include LISP, Scheme, Smalltalk, Perl and Python. C and C++, in the tradition of a respectable, low-level approach to system resources management, are the most notable exceptions to this list.
Many different approaches to garbage collection exist, resulting in some families of algorithms that include reference counting, mark and sweep and copying GCs. Hybrid algorithms, as well as generational and conservative variants, complete the picture. Choosing a particular GC algorithm usually is not a programmer's task, as the memory management system is imposed by the adopted programming language. An exception to this rule is the Boehm-Demers-Weiser (BDW) GC library, a popular package that allows C and C++ programmers to include automatic memory management into their programs. The question is: Why would they want to do a thing like this?
The BDW library is a freely available library that provides C and C++ programs with garbage collection capabilities. The algorithm it employs belongs to the family of mark and sweep collectors, where GC is split into two phases. First, a scan of all the live memory is done in order to mark unused blocks. Then, a sweep phase takes care of putting the marked blocks in the free blocks list. The two phases can be, and usually are, performed separately to increase the general response time of the library. The BDW algorithm also is generational; it concentrates free space searches on newer blocks. This is based on the idea that older blocks statistically live longer. To put it another way, most allocated blocks have short lifetimes. Finally, the BDW algorithm is conservative in that it needs to make assumptions on which variables are actually pointers to dynamic data and which ones only look that way. This is a consequence of C and C++ being weakly typed languages.
The BDW collector comes as a static or dynamic library and is installed easily by downloading the corresponding package (see Resources) and running the traditional configure, make and make install commands. Some Linux distributions also come with an already-made package. For example, with Gentoo you need to type only emerge boehm-gc to install it. The installed files include both a shared object (libgc.o) and a static library (libgc.a).
Using the library is a fairly straightforward task; for newly developed programs, you simply call GC_alloc() to get memory and then forget about it when you do not need it anymore. "Forget about it" means setting all the pointers that reference it to NULL. For already existing sources, substitute all allocation calls (malloc, calloc, realloc) with the GC-endowed ones. All free() calls are replaced with nothing at all, but do set any relevant pointers to NULL.
GC_alloc() actually sets the allocated memory to zero to minimize the risk that preexisting values are misinterpreted as valid pointers by the GC engine. Hence, GC_alloc() behaves more like calloc() than malloc().
If you want to try GC in an existing application, manually editing the source code to change mallocs and frees is not necessary. In order to redirect those calls to the GC version, you basically have three options: using a macro, modifying the malloc hooks and overriding glibc's malloc() with libgc's malloc(). The first approach is the easiest one; you simply need to insert something like:
#define malloc(x) GC_malloc(x) #define calloc(n,x) GC_malloc((n)*(x)) #define realloc(p,x) GC_realloc((p),(x)) #define free(x) (x) = NULL
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One of the best things about the UNIX environment (aside from being stable and efficient) is the vast array of software tools available to help you do your job. Traditionally, a UNIX tool does only one thing, but does that one thing very well. For example, grep is very easy to use and can search vast amounts of data quickly. The find tool can find a particular file or files based on all kinds of criteria. It's pretty easy to string these tools together to build even more powerful tools, such as a tool that finds all of the .log files in the /home directory and searches each one for a particular entry. This erector-set mentality allows UNIX system administrators to seem to always have the right tool for the job.
Cron traditionally has been considered another such a tool for job scheduling, but is it enough? This webinar considers that very question. The first part builds on a previous Geek Guide, Beyond Cron, and briefly describes how to know when it might be time to consider upgrading your job scheduling infrastructure. The second part presents an actual planning and implementation framework.
Join Linux Journal's Mike Diehl and Pat Cameron of Help Systems.
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- The Firebird Project's Firebird Relational Database
- Murat Yener and Onur Dundar's Expert Android Studio (Wrox)
- SUSE LLC's SUSE Manager
- Managing Linux Using Puppet
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With all the industry talk about the benefits of Linux on Power and all the performance advantages offered by its open architecture, you may be considering a move in that direction. If you are thinking about analytics, big data and cloud computing, you would be right to evaluate Power. The idea of using commodity x86 hardware and replacing it every three years is an outdated cost model. It doesn't consider the total cost of ownership, and it doesn't consider the advantage of real processing power, high-availability and multithreading like a demon.
This ebook takes a look at some of the practical applications of the Linux on Power platform and ways you might bring all the performance power of this open architecture to bear for your organization. There are no smoke and mirrors here—just hard, cold, empirical evidence provided by independent sources. I also consider some innovative ways Linux on Power will be used in the future.Get the Guide


text:
User/Comment Login
St. Augustine Beach
Many scholars have revealed the rich history of St. Augustine's diverse ethnic groups. The contributions of African Americans have been documented by Dr. Jane Landers, Dr. Kathy Deegan, David Nolan, Glennette Tilley and others.
A recent TV presentation entitled "America's Untold Story" further demonstrated the monumental impact of African-Americans on the development of the New World.
Seeing is believing
Editor: America has the finest police departments. Officers save lives when tragedies occur, help give birth to babies, track down and expose illegal activities and bring criminals successfully to justice. Several years ago when I was involved in a serious automobile accident on U.S 1, it was an officer who tenderly held my hand, while reassuring me an ambulance was on the way and that I would be all right.
Thank you for the informative articles titled "Rabbis Recall", and "Why We Went," published June 19 about the rabbis who risked their lives to march 50 years ago with Dr. Martin Luther King Jr.
Throughout history, women have played an important role in the development of America. Today, communities are faced with many challenges such as high unemployment rates, and justice and education systems that need to be reformed. The 20th century brought forth many women who showed compassion for the poor, the disenfranchised and minorities. One outstanding person during that era was first lady Eleanor Roosevelt. She was compassionate about people throughout the world, and she had an impact on my life.
Editor: I realize that some readers will agree with Rick Mansfield's statements in his letter to the editor of April 4 on deriding marches on behalf on Trayvon Martin, "Let's presume Zimmerman innocent until proven guilty." However, the constant nightmare for every African-American mother is their son might face the same fate as Trayvon. Killings like Trayvon's have occurred too many times throughout history — even before the brutal 1955 murder of 14-year-old Chicago native Emmett Till.
Editor: I was appalled to read in your newspaper that Fort Mose State Park is on the list for closing due to budgeting cuts proposed by the Department of Environmental Protection. I hope the members know that Fort Mose is the oldest African-American settlement in America. A new state-of-the-art exhibit is in the process of completion for residents and tourists to learn first hand of this significant period in American history.
St. Augustine Record ©2016. All Rights Reserved.


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Shrine Cabinet1 comment
This cabinet is 63" long and 32" high. It was designed for a client using a design line from a major shrine cabinet in a meditation center. The line was of the major shrine was designed by the...view details
Nara Desk1 comment
The Nara desk is made from figured walnut and cherry with maple drawers. Breadboard ends on the table top are draw bored and keep the piece stable. Through tenons add accents to the face of the...view details
Communion Table
This table was done as a donation to my church. The design is my own and it was constructed from Cherry with a curly maple top panel and walnut inlay. The lettering was done by a friend with a...view details
A Maloof inspired walnut rocker with some little variations.4 comments
I perform this Maloof inspired walnut rocker with some luck, and some personal detail add on. It take 200H.. Finish with Danish oil and oil-wax. www.my-rocker.com Dr Richard Zimmermann-Belgiumview details
Jewellery cabinet (10th anniversary)
I have made this for my wife on 10th anniversary 2015. Maple burl and curly was used in front doors with wenge frame. Walnut wooden hinges were utilized to install the front doors. Greene & Greene...view details
Merlin - Teak and Beech credenza3 comments
Nesting Cabinet in stand. cabinet is fassened to stand with through wedged tenons. integral drawer and door pulls. stand, drawer fronts, carcasse interrior; European Beech. Carcasse is shopcut...view details
TV Lift Cabinet - Large Radius2 comments
Large Radius TV Cabinet for 65" TV. Designed and built to fit in the specific spot shown in pictures. Constructed of Walnut and Wormy Maple. Walnut Frame is a bent lamination. The doors and...view details
Tree cabinet1 comment
Made from figured maple and black walnut. Handles for drawers and doors on the front are cut out of the tree figure.view details
Woodworking Business - What To Build To Make Profits2 comments
Woodworking is a great art and hobby that you can quickly turn into business. You need to know that different woodwork projects will have different markets. For instance, if you are making toys, then...view details
Standing Cabinet
Cabinet Legs: Black Cherry Cabinet Body: Spalted Maple Cabinet Top: Live Edge Black Cherry Cabinet Door: Live Edge Jatoba, Black Cherry, White Birch Cabinet Shelves: Spalted Mapleview details
Corner Cabinet
The left side of this cabinet pivots out and is basically one big box to hold all the bedding and sheets. Drawers are dovetailed, the maple and wenge inlay breakes up the large front on the left...view details
Fireplace furniture
From old to new: This was my first time to recover a old fireplace.I hope this well help you in changing a old bad fireplace into built-in piece of fireplace furniture for your home.I made all the...view details
Custom living room built-ins
Walnut and maple living room built-ins. Ply boxes with walnut face frames, raised solid maple panels in walnut doors, and walnut and maple panel walnut drawer fronts. Had a granite top...view details
Wine rack with glass storage1 comment
My own design of a wine rack with glass storage. Joinery includes hand-cut dovetails, machine-cut sliding dovetails and my own modification of bridle joints.view details
Three Surprises
I hadn't intended on creating an Art Deco-inspired piece when I came up with the design of the liquor cabinet "Three Surprises", but it ended up that way. It is intended to house one's most precious...view details
Home Office Bookcase Wall
This project took nearly 2-1/2 years of Sundays to complete. Luckily it was commissioned by my (still) very close friends, so their patience and collaboration was unlimited. This is my first builtin...view details
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Sculptural 4 Drawer Cabinet on Cantilevered Frame Functional and Sculptural… …The frames are my refined interpretation of a barn structure …Showing the beauty and strength of wood in dynamic...view details
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I built these adjustable speaker stands for the control room of my son's recording studio business. Precision height adjustment is crucial as is strength - each speaker weighs 41...view details
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I designed and built in these libary bookshelves in my home office in our new home. The shelves are 3/4 " cherry veneer MDF. The trim is walnut, with occasional maple inset and routed column grooves...view details
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This curio display cabinet was vaguely inspired by the form of arched railroad bridges (imagine a train cruising along the top of it). The top is made from walnut, both solid and veneered bent...view details
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IMDb > Gilbert Radburn (Character)
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Gilbert Radburn (Character)
from "Warehouse 13" (2009)
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- "Warehouse 13"
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marriage and divorce
- Romantic Couples Through the Ages
- 6 Tips to Help Your Marriage Survive a New Baby
- Romantic Couples in Literature
- TV Couples Quiz
- 6 Tips to Avoid Hurt Feelings on Valentine's Day
healthy marriage
- Are You and Your Spouse a Match Made in Heaven?
- Part-Time Job: A Good Idea for a High School Student?
- 10 Simple Ways to Spice Up Your Marriage
- The 14 Rules of Long-Lasting Relationships
- Are You Married to Your Work or to Your Spouse?


text:
, Volume 138, Issue 3, pp 433-451
First online:
The intOA Experiment: A Study of Ocean-Atmosphere Interactions Under Moderate to Strong Offshore Winds and Opposing Swell Conditions in the Gulf of Tehuantepec, Mexico
- F. J. Ocampo-TorresAffiliated withDepartamento de Oceanografía Física, CICESE Email author
- , H. García-NavaAffiliated withDepartamento de Oceanografía Física, CICESE
- , R. DurazoAffiliated withFacultad de Ciencias Marinas, Universidad Autónoma de Baja California
- , P. OsunaAffiliated withDepartamento de Oceanografía Física, CICESE
- , G. M. Díaz MéndezAffiliated withFacultad de Ciencias Marinas, Universidad Autónoma de Baja California
- , H. C. GraberAffiliated withRosenstiel School of Marine and Atmospheric Science, University of Miami
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The Gulf of Tehuantepec air–sea interaction experiment (intOA) took place from February to April 2005, under the Programme for the Study of the Gulf of Tehuantepec (PEGoT, Spanish acronym for Programa para el Estudio del Golfo de Tehuantepec). PEGoT is underway aiming for better knowledge of the effect of strong and persistent offshore winds on coastal waters and their natural resources, as well as performing advanced numerical modelling of the wave and surface current fields. One of the goals of the intOA experiment is to improve our knowledge on air–sea interaction processes with particular emphasis on the effect of surface waves on the momentum flux for the characteristic and unique conditions that occur when strong Tehuano winds blow offshore against the Pacific Ocean long period swell. For the field campaign, an air–sea interaction spar (ASIS) buoy was deployed in the Gulf of Tehuantepec to measure surface waves and the momentum flux between the ocean and the atmosphere. High frequency radar systems (phase array type) were in operation from two coastal sites and three acoustic Doppler current profilers were deployed near-shore. Synthetic aperture radar images were also acquired as part of the remote sensing component of the experiment. The present paper provides the main results on the wave and wind fields, addressing the direct calculation of the momentum flux and the drag coefficient, and gives an overview of the intOA experiment. Although the effect of swell has been described in recent studies, this is the first time for the very specific conditions encountered, such as swell persistently opposing offshore winds and locally generated waves, to show a clear evidence of the influence on the wind stress of the significant steepness of swell waves.
KeywordsAir–sea interaction Field measurements intOA Momentum flux Sea state
Reference tools
- Title
- The intOA Experiment: A Study of Ocean-Atmosphere Interactions Under Moderate to Strong Offshore Winds and Opposing Swell Conditions in the Gulf of Tehuantepec, Mexico
- Journal
Boundary-Layer Meteorology
Volume 138, Issue 3 , pp 433-451
- Cover Date
- 2011-03
- 10.1007/s10546-010-9561-5
- Print ISSN
- 0006-8314
- Online ISSN
- 1573-1472
- Publisher
- Springer Netherlands
- Additional Links
- Topics
- Keywords
- Air–sea interaction
- Field measurements
- intOA
- Momentum flux
- Sea state
- Industry Sectors
- Authors
- F. J. Ocampo-Torres (1)
- H. García-Nava (1)
- R. Durazo (2)
- P. Osuna (1)
- G. M. Díaz Méndez (2)
- H. C. Graber (3)
- Author Affiliations
- 1. Departamento de Oceanografía Física, CICESE, Ensenada, BC, México
- 2. Facultad de Ciencias Marinas, Universidad Autónoma de Baja California, Ensenada, BC, México
- 3. Rosenstiel School of Marine and Atmospheric Science, University of Miami, Miami, FL, USA


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Wednesday Was a 'Very Good Night' in Ferguson
No Molotov cocktails, no tear gas, and no shootings.
After 11 days of violent clashes between police and protesters, Ferguson, Missouri, finally saw a night of relative calm on Wednesday. Only about 150 people came out to march down West Florissant Avenue, and Missouri Highway Patrol Captain Ron Johnson said there were "less agitators" in the crowd. The dramatic shift is being attributed to several factors, including heavy rain around 8 p.m., efforts by both sides to deescalate the situation, and the arrival of Attorney General Eric Holder earlier in the day. Johnson said people feel that "their voices are being heard by the chief law enforcement officer in the land."
OMG LOOK AT THIS CLOUD #Ferguson with @ryanjreilly pic.twitter.com/2eYTQgIVWc— Amanda Terkel (@aterkel) August 21, 2014
After Holder's visit with community leaders and an evening downpour, media now outnumbers protesters. #Ferguson pic.twitter.com/7coLQdsV7h— Alex Bolton (@alexanderbolton) August 21, 2014
The night wasn't entirely conflict-free. Johnson said that around 8 p.m., an officer was hit by a bottle, but he wasn't injured. Later a white woman showed up holding a sign supporting Officer Darren Wilson, the cop who shot 18-year-old Michael Brown. Some taunted her and one man was led away by police, but a few minutes later protesters linked arms and formed a circle around her to prevent a more serious incident. The woman was taken away in a police vehicle and later released.
In an early-morning press conference, Captain Ron Johnson said there were no shootings, fires, tear gas, mace, or Molotov cocktails. Only six people were arrested, compared to 47 on Tuesday night. "It was a very good night in Ferguson," said Johnson. "I am going to enjoy the peace we had today and not focus on what ifs."


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BOC District 1 - Republican
Nancy Schulz has been reelected to the Newton County Board of Commissioners in District 3, and will be joined on the board by Republican Stan ...
Visitors to the Covington Square unable to find a parking spare directly in front of their dining or shopping destination, will not have to worry ...
Page 8 of 8
More than 500 local youth and young adults will participate in the Newton County Special Olympics.
In Newton County, the athletes train and compete in sports such as basketball, volleyball, softball, tennis, soccer, bowling, roller skating, horseback riding, power lifting, golf, field and track, developmental sports and wheelchair activities.
Covington police arrested three men for loitering and prowling in front on an empty house for sale.
When the officer approached the car, he noticed that the inside of the Nissan Maxima was smoky and smelled of marijuana.
A man was hit in the head with a pipe after confronting a mechanic who was cussing at his girlfriend.
Dozens of migrant workers on their way to work in the tobacco fields of North Carolina were detained Thursday morning, after a passerby on Interstate 20 saw what they thought was someone being forced into the undercarriage of one of the workers' charter buses and called 911.
Volunteers with Kohl's in Conyers, led by local resident Donna Sneed, are hoping to beautify the Garden of Gethsemane Homeless Shelter on Turner Lake Circle on April 26.
Sneed hopes to erect a sign at the street entrance to the shelter and landscape and plant flowers around the sign, in addition to putting potted flowers at the entrance to each of the shelter's buildings and planters along the side of some of the buildings. She also hopes to get the shelter's playground equipment repaired.
The 11th annual Covington Cheerios Challenge will be held Saturday, April 21, at the YMCA on Newton Drive.
Property tax revenues for the county continue to decline, yet for the first time in four years the county's budget is actually projected to increase.
A woman was arrested after tailgating a family of four down Floyd Street while blowing her horn and flipping the bird.
Pittman Construction expects to restart resurfacing work Tuesday on Interstate 20 between mile marker 102 and 105 in Morgan County, while weekend work in Newton County between mile marker 98 and 93 will run from 9 a.m. April 20 through 6 a.m. April 23.
Motorist can expect daily lane closures and short delays, according to the Georgia Department of Transportation, Pittman Construction Company and E. R. Snell Contractor were awarded this $27 million project, which consists of 19.5 miles of milling and resurfacing, beginning east of Ga. Highway 142 in Newton County and extending east of Ga ...
Newton County Reads, Executive Director Paryn Wallace recently received an award during the Certified Literate Community Program (CLCP) Conference at Amicalola Falls, Ga. Gov. Nathan Deal and First Lady Mary Deal were guest speakers during the event.
A Newton County deputy arrested a man for simple battery after he tried to choke his girlfriend and threw her to the ground.
The girlfriend was upstairs with her eight-month-old daughter texting when the boyfriend entered the room. The boyfriend told the talking baby to shut up and the girlfriend told the boyfriend not to talk to her daughter that way. The girlfriend then went to pick the baby up and the boyfriend grabbed her wrist instructing her not to.
A woman was woken up in the wee hours of the morning to someone trying to get into the front door of her home on Conyers Street.
She then heard noises in the house and a male with a Southern voice opened her bedroom door.
This Thursday, April 12, from 6 to 8 p.m., the city of Covington will be challenged to explore their artistic side during Southern Heartland Arts' first Spring Community Paint Out & Party at the Gallery.
Last year, for Spring Fling, Southern Heartland Arts put on a fashion show that had a satisfying turn-out of 200-300 people, but this year they opted to do something different. Wendy Harrington came up with the idea of the Paint Out.
On Saturday, April 14, The Church at Covington will host a fundraiser for Jason Joyner. Family and friends have put together BBQ plates that consist of pulled-pork BBQ, buns, stew, slaw, chips and a cookie.
Tickets are being pre-sold for $10 and can be purchased by calling Sheri Joyner at (678) 270-0905. Extra plates will be sold at the event after all pre-ordered plates have been filled.
Local black officials held the seventh annual commemoration of Black Easter Sunday on the square.
Elected officials and other community leaders spoke about events past and present as all remembered the civil rights march of 1970 in Covington.
Page 365 of 641


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ODT Online
ODT /directory
Flavours from around the world drew hundreds of people to the
Otago Museum lawn on Saturday.
Studholme College first-year resident Hadley Van Schaik
(18) talks to reporter Vaughan Elder about what he enjoyed
most about O-Week.
Now in its 83rd year, the Student Christian Movement book
exchange has become an institution of O-Week, with students
coming back each year to save money on textbooks.
A cooking competition held as part of O-Week yesterday went
some way to disproving the reputation of scarfies as being
lousy in the kitchen.
10am-4pm: Tent city, museum lawn - featuring shopping and
information marquees.
10am-5pm: Student Christian Movement textbook exchange -
All Saints' Hall, 786 Cumberland St Nth.
A wave of success swept through the stadium and riding on top
of it, with an arm waving in the air, was Macklemore singing:
''I wear your granddad's clothes, I look incredible, I'm in
this big ass coat, From that thrift shop down the road''.
Jake Hanrahan (21), from the United States, talks to
reporter Vaughan Elder about coming to Dunedin to study.
10am-4pm: Tent city, museum lawn - featuring shopping and
information marquees.
10am-5pm: Student Christian Movement textbook exchange -
All Saints' Hall, 786 Cumberland St Nth.
Caped Christchurch crusader Flat Man thought he had seen the
most devastated homes imaginable in the wake of the
Canterbury earthquakes. But nothing could prepare him for the
student flats of Dunedin.
Whether you were into meditation or hunting large animals,
there was something for everyone at the Otago University
Students' Association's (OUSA) Clubs Day yesterday.
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Clearwire, Dendreon, Gap, McDermott, PMI: U.S. Equity Movers
Shares of the following companies had unusual moves in U.S. trading. Stock symbols are in parentheses and prices are as of 4 p.m. in New York.
Air Transport Services Group Inc. (ATSG US) increased 16 percent, the most since April 2011, to $5.65. The aircraft leasing and cargo transportation provider said its second quarter earnings were 19 cents a share, beating the average analyst estimate by 16 percent.
Alpha Natural Resources Inc. (ANR US) fell 17 percent, the most since December 2008, to $33.24. The coal company, which bought Massey Energy Co. for $7.1 billion in June, reported a second-quarter loss of $56.4 million on takeover-related costs.
Clearwire Corp. (CLWR US) lost 29 percent to $1.76, the lowest price since its initial public offering in March 2007. The money-losing wireless broadband provider reported its net loss widened to $168.7 million, or $1.01 per share, from $125.9 million, or 61 cents.
Dendreon Corp. (DNDN US) plunged 67 percent to $11.69 for the biggest retreat in the Russell 1000 Index. The drugmaker withdrew its sales estimates for 2011 and announced job cuts because of lower-than-expected growth in the use of prostate-cancer treatment Provenge.
DirecTV (DTV US) slid 5.7 percent, the most since February 2009, to $46.63. The largest satellite-TV provider added a net 26,000 subscribers in the U.S. during the second quarter, missing analysts' estimates, while growth in the average revenue per user slowed to 3 percent, a sign that the cost of competition "materializes," according to Nomura Holdings Inc.
Emdeon Inc. (EM US) rose 13 percent, the most in the Russell 1000 Index, to $18.35. The provider of health-care revenue and payment cycle management solutions agreed to be bought by Blackstone Group LP (BX US) for $19 a share, or $3 billion. Blackstone fell 11 percent to $13.72.
Entropic Communications Inc. (ENTR US) tumbled 38 percent, the most since its initial public offering in December 2007, to $4.14. The designer of digital home networking semiconductors posted second-quarter earnings that missed its April forecast. Revenue fell short of analyst projections, according to data compiled by Bloomberg.
Gap Inc. (GPS US) decreased 12 percent to $16.98, the lowest price since August 2010. The retailer said July same-store sales fell 5 percent, compared with analysts' estimates for a decline of 0.6 percent.
Huntsman Corp. (HUN US) fell 31 percent, the most since December 2008, to $12.50. The chemical maker reported second-quarter net income of 47 cents a share, missing analysts' estimates.
Leap Wireless International Inc. (LEAP US) declined 34 percent to $6.65, the lowest price since at least August 2004. The pay-as-you-go mobile-phone carrier reported a net loss of 85 cents a share in the second quarter, wider than analysts estimated.
Rival MetroPCS Communications Inc. (PCS US) fell 9.4 percent to $9.31, the lowest price since September.
McDermott International Inc. (MDR US) dropped 27 percent, the most since November 2008, to $13.95. The offshore oil and gas contractor posted second-quarter profit excluding some items of 27 cents a share, missing the average analyst estimate by 14 percent, according to Bloomberg data.
MEMC Electronic Materials Inc. (WFR US) slid 14 percent to $6.02, the lowest price since October 2002. The second-largest U.S. manufacturer of polysilicon posted second-quarter earnings of 29 cents a share, six times the average analyst projection, Bloomberg data show.
PMI Group Inc. (PMI US) dropped 53 percent, the most since its IPO in April 1995, to 41 cents. The third-largest mortgage insurer posted its 16th straight unprofitable quarter and failed to meet regulators' capital requirements.
Transocean Ltd. (RIG US) fell 8.6 percent, the most since June 1, to $53.98. The world's largest offshore driller posted an 11th straight quarterly profit decline. Daily rental rates for the company's vessels dropped as much as 26 percent during the second quarter because of competition from rival operators and an influx of newer rigs onto global drilling markets.
Walter Energy Inc. (WLT US) declined 30 percent, the most since at least 1995, to $77.89. The southern Appalachia producer of steelmaking coal reported second-quarter revenue of $766.7 million, missing the $931 million average estimate by analysts in a Bloomberg survey.
Web.com Group Inc. (WWWW US) soared 20 percent, the most in the Russell 2000 Index, to $10.37. The company that builds Web sites for small businesses said it is buying Network Solutions and expects the deal to add at least 20 percent to the consensus estimate of its 2012 earnings.
Zumiez Inc. (ZUMZ US) fell 20 percent, the most since July 2008, to $21.77. The retailer based in Everett, Washington, reported comparable sales for July that missed analysts' estimates for first month since December.


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I'm upgrading from 3.0.4 to 3.0.5.
Oddly, the automatic update - which had worked without incident previously - is prompting FTP login as if permissions are incorrect. I've verified that the owner of all WP folders is the www user.
Now, I've had issues with automatic update before, so I've tried going to a manual update, working with each of the files listed here:
Those files all show updated, but WP is still asking me to update to 3.0.4. Did I somehow miss changing the version number somewhere in addition to the manual file copying?


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6 reviews | 4.5 out of 5
The top fit perfectly. The legs on the bottoms were large, it almost seems like the bottoms are a different size from the top. Overall I am pleased with the purchase, my granddaughter will grow into the bottoms, hopefully before she outgrows the top.
My 2YO is in swim lessons and since she isn't potty trained, she has to wear a reusable swim diaper over a disposable one. So I really just needed the top to go with the swim diaper we already had. The top is super cute, fits well and is comfortable. Hopefully it lasts as long as the last one. My daughter is only about 28lbs and is still in 12-18M sizes, but I bought the 24M size hoping she'd have room to grow and she does. It's not ridiculously big, but it will probably last into next swim season. My only complaint about this set is that the bottom is a bikini bottom, which is pretty ridiculous. It doesn't even cover her diaper! Why on earth they don't make a bigger bottom for little kids is beyond me. But regardless, $10 is a good price even just for the shirt.
I love the color and design of this suit. Purchased 18-24 size for my 22 month old for the upcoming summer. She's about 26 lbs, fits her very well. I agree with the other reviewer about the bottoms, would be nice if the bottoms had more coverage for a swim diaper, but am pleased otherwise. Good suit for the price!
I bought the 24 month sized suit for my (now) 18 month old. It fits her great (a little big), but I'm hoping it will last all Summer. She's worn it once and it fits great and looks cute (very bright colors).
LOVE this bathing suit it fits my girls well and I would DEFINITELY recommend it GREATEST swimsuit ever and its easy when I have to change them out of their swimpers
Great coverage on bottoms, although they do run a bit big


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Goodstein Law Associates is a firm focusing on estate planning, probate, trust administration and elder law issues. Based in King of Prussia, PA, our mission is to provide residents of King of Prussia and surrounding areas with quality estate planning resources, such as assistance with Living Trusts, Wills (simple & complex), Probate, Trust Administration, Powers of Attorney, Living Wills, Irrevocable Trusts, Family Limited Partnerships, and Charitable Giving. When you visit or call our office, we want you to feel comfortable discussing such an important issue concerning both you and your family. We want to arm you with the information you need to make an informed decision about your family's future. Visit our online Estate Planning Information Center to obtain timely, quality information on estate planning and related issues, including complimentary issues of our Special Reports and Estate Planning News articles. Residents of King of Prussia and surrounding areas can register to attend our Estate Planning Seminars.
We represent clients throughout eastern Pennsylvania, including the Philadelphia Main Line (Merion, Narberth, Gladwyne, Wynnewood, Ardmore, Haverford, Bryn Mawr, Rosemont, Villanova, St. David's, Radnor, Wayne, Strafford, Devon, Berwyn, and Paoli) and the communities of Newtown Square, Malvern, Valley Forge, Phoenixville, Reading, Doylestown, West Chester, Media, Lancaster, Allentown, Stroudsburg, Norristown, and Easton.
About Ricki Goodstein
As the Founder and Principal of the Montgomery County law firm of Goodstein Law Associates, with offices in both King of Prussia of Montgomery County and Chester County, Ricki has developed a practice committed to providing clients with the best in Estate Planning.
Ricki is a member of the American Academy of Estate Planning Attorneys. The Academy is an exclusive membership organization for estate planning attorneys. Goodstein Law Associates is proud to be the sole member firm in Chester County, one of only two member firms serving Montgomery County and one of three members in all of Pennsylvania.
Ricki Goodstein was recently named by Main Line Today magazine as among the Best Lawyers . Ricki is one of the few attorneys to have been recognized in two separate categories: Trusts & Estates and the area of Elder Law.
Ricki is also a regular guest on The Tax Reduction Network with David Warrick, C.F.P. - Saturday Mornings 8 to 9 on NewsTalk Radio 1180 WFYL.
As a widely noted speaker and seminar leader on topics ranging from Estate Planning to Asset Protection for families, couples, business owners and individuals Ricki enjoys delivering educational opportunities to the community. As both Associate and Assistant Professor, she has taught at Temple University, Cabrini College and The Philadelphia Institute for Paralegal Training. Ricki has published several articles and is currently co-authoring a new book on Estate Planning.
Ricki is a member of the American Bar Association, Pennsylvania Bar Association, Montgomery County Bar Association, and Philadelphia Bar Associations. She has been practicing law since 1992.
Having attended Sarah Lawrence College and Boston University Ricki graduated with a Bachelor of Science degree in 1980.
She obtained her law degree from Widener University School of Law in 1992. She was active in the Widener Tax Clinic practicing before the Supreme Court of Pennsylvania. She was also an editor for the Widener Law Forum.
Ricki Goodstein graduated with her Juris Doctor degree and was admitted to the Pennsylvania Bar in 1992.
Community Involvement
Ricki serves on the Board of Directors of the Charles F. Sawyer, Jr. and Mary Esther Sawyer Foundation. The Foundation works to fund worthy organizations providing charitable and religious services to the local community. Educational scholarships are awarded to qualifying students unable to fund their own education. The Foundation also raises and contributes funds for medical and scientific purposes.
As an Alumni of Widener University School of Law, Ricki serves as Moot Court Judge for the Law School Moot Court competitions.
Ricki Goodstein approaches each challenge with not just solid expertise, but also remarkable caring and enthusiasm. She continually makes a real difference in the lives of families and organizations. Because Estate Planning is often a delicate process, Ricki's goal is to ensure that each one of her clients finds security in the knowledge that their Estate Planning needs are addressed competently, thoroughly and with sensitivity.
Ricki is the proud parent of Maya Eve, an avid student and lover of musical theater. Together, they regularly attend concerts, shows and dance performances.
Free consultation (60 minutes)
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