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February 21, 2012
Prospects Will Break Your Heart
What Could Go Wrong in 2012: New York Yankees
Prospect #1: C Gary Sanchez
What Could Go Wrong in 2012: Sanchez is a hitter who seems to see the ball very well; he tracks and diagnoses pitches like a much more experienced player. In High-A, the young right-hander will no doubt face a more advanced secondary sequence, and despite the good pitch-recognition skills, the characteristics of his swing could limit his ability to make contact against such offerings. Like most power hitters, Sanchez has a leveraged swing with length and loft, making him susceptible to inner-half velocity and off-speed stuff that will require barrel manipulation to stay on. Sanchez has a good feel for hitting, but I don't think the hit tool can stand shoulder-to-shoulder with the power, which should end up as an easy 70 on the 20/80 scale, and possibly a legit 80 at the top of his developmental arc. The explosion that occurs on contact is loud and violent and sexy and people will pay money to see it and the skies will turn red with the blood of his enemies, but the hitchy trigger and the lengthy path to the ball make exploitation possible. However, it should be noted that Sanchez's offensive game doesn't have the glaring weaknesses that scar the faces of most prospects his age. This is a minor nitpick. Sanchez could be very special at the plate. I want to have a son and name him Gary.
Prospect #2: LHP Manny Banuelos
What Could Go Wrong in 2012: Banuelos is unlikely to win a rotation spot out of camp, so he will head back to Triple-A to wait in the wings for an opportunity to take the big stage. His command needs refinement; he's still very loose in the zone and hittable when he elevates and provides hitters with a flat-plane look at the ball. The southpaw's path will be determined by command refinement; it'll either keep him in the minors for another season, or propel him to Yankee Stadium. Another minor complaint about Banuelos—and one that might lead to exploitation at the highest level—is that the arsenal seems to play a little soft. That's not to say the stuff isn't good; it's very good. The offerings are just a little round, a little dull. The overall intensity of his pitches seems to be muted (e.g., a softer break on the curve, a fastball that shows intimidating velocity on the radar gun but doesn't seem to intimidate minor-league hitters, etc.).
As long as Banuelos can use the fastball to get ahead in the count, he can throw the changeup as an out pitch to both righties and lefties alike, mixing in the curve to keep hitters off-balance. That combo is going to work in Triple-A, and the young starter should continue to show solid on-field production. At the major-league level, the curve will need to play a larger role, the command will need to take a big step forward, and the overall intensity of the arsenal will need a few more volts. Banuelos has legit stuff and could develop into a number-two/-three starter, but his limited size shrinks his margin of error and puts more pressure on the development of his command for sustainable major-league success.
Prospect #3: RHP Dellin Betances
Built like an NBA power forward with the athleticism of a designated hitter, Betances is an imposing figure on the mound. He uses his 6-foot-8 frame to create a steep plane to the plate that few pitchers in the game can match. His fastball is lively and heavy, with low-90s velocity out of the rotation and easy plus-plus velocity in short bursts. The curveball can also look scary good; some in the industry suggest it could eventually be a 70-grade pitch. Like the fastball, the curve is thrown on a steep plane with a nasty vertical break, but Betances has a tendency to slip under the ball, losing the tight rotation and subsequent vertical depth. Betances struggles with his delivery because of his size and limited athleticism; he loses his release point and drops his slot, which negatively affects his changeup and his overall command.
What Could Go Wrong in 2012: I don't think Betances is ever going to be a consistent strike-thrower, and given the electricity of his short-burst arsenal, a move to the bullpen has to be in the cards at some point. For now, it seems Betances will continue to pitch out of the rotation, where he can attempt to refine his command and encourage secondary development. However, there is going to come a time when the Yankees have to use the weapon they have rather than fantasize about the weapon they don't. As long as Betances remains 6-foot-8 and can pump that fastball on a steep plane, he's going to miss bats at any professional level. But after multiple looks, the steep fastball will need a few accouterments to remain in fashion; add to the mix a command profile where below average is the reality and solid-average is the fantasy, and you have a pitcher that is going to struggle in a rotation. In 2012, what could go wrong is also what could go right, as failure out of the rotation could lead to success out of the 'pen, where Betances can play to his strengths and send that waterslide fastball into the zone at intense velocity and use his demon curve to force awkward swings.
Prospect #4: CF Mason Williams
What Could Go Wrong in 2012: Williams has a body that makes Dee Gordon look bulky. A coordinated, fast-twitch athlete, Williams gets the most out of his 6-foot-0, 150-pound (when wet) body, but he lacks strength, and given his narrow frame, it's unlikely that he'll add substantial strength to his game. In 2012, he will move up to full-season ball, and with his combination of speed and bat control, he's going to continue to hit for a high average. However, pitchers will eventually start to challenge Williams, daring the slender slugger to muscle up and drive velocity up in the zone. Without a physical presence to his offensive game, Williams becomes more of a one-dimensional hitter, capable of contact but lacking the type of punch that forces pitchers to adjust. Against arms bringing quality stuff and aggressive approaches, the biggest weakness in Williams' game will be put to the test. In the long run, I think Williams emerges as a solid-average regular at the major-league level, with defense as his calling card and enough stick to justify his spot in the lineup. Despite the crazy-impressive offensive performance in 2011, I just don't see anything special at the plate.
Prospect #5: 2B Angelo Gumbs
On a short-season team that featured up-the-middle talent like Cito Culver and Mason Williams, second baseman Angelo Gumbs stood out as the athlete worth watching. I've been noisy about Gumbs' athleticism and the projections he holds both on defense and at the plate. He flashed a bit of this promise in 2011, but his production won't spark much prospect love. If you were lucky enough to see the former second-round pick in action, there is a good chance you witnessed Gumbs' competitive fire take him out of games. Call it immaturity or give it another label, but when faced with a setback on the field, Gumbs' own disappointment in the result was often visible, and on quiet nights, quite audible. Some industry sources I've spoken with question Gumbs' makeup, but I'm not ready to call his competitive fire a flaw. It goes without saying that he needs to mature on the field. But Gumbs played the entire season as an 18-year-old, and at that age, I like to see a player who demands the best from himself.
From a BP report filed after a Staten Island Yankees game:
Based on the snapshot, Gumbs' athleticism stands out, as I was able to see a few routine ground-ball executions, and one nice glove-side play where Gumbs was able to flash his first-step quickness and reactions. I couldn't help but feel disappointed that Gumbs wasn't able to show off the full range of his physical abilities, as I was at the mercy of the balls in play, and Gumbs only touched the ball a handful of times. I would have paid extra to see him take flies in the outfield. His skill set belongs in the vast wilderness of center field.
What Could Go Wrong in 2012: Gumbs will no doubt be advancing to the Sally League as a 19-year-old. The jump to full-season ball can often trip up the most polished teenagers, and Gumbs is far from polished. He has a very quick trigger at the plate and his bat speed is evident, but the swing itself has some miss in it, and his aggressive approach could lead to high strikeout totals against more advanced pitching. Gumbs has a very long way to go, and it could take several years before the athlete transitions into the baseball player, but I'm still higher on Gumbs (long-term) than I am on Mason Williams, and I have Williams graded out as a solid-average regular. Gumbs has 6-grade potential if it all comes together, but it could get a little ugly before the clouds part. His prospect status could take a dip in 2012, but given his age and his collection of tools, the finished product will be worth the extra patience.
*Yes, I ranked Angelo Gumbs fifth in the Yankees system, ahead of several prospects with bigger profiles and better résumé. I offer no apology for this. I was fascinated with Gumbs in my first viewing, and I was fascinated with Gumbs in my last. My eyes told me Gumbs had star potential, a future you don't often envision when watching short-season baseball. I'm probably a few years too early with this ranking, and I understand if people wish to question my sanity. The truth is I'd rather trust my own evaluation and be dead wrong than equivocate in order to say I was right.
Jason Parks is an author of Baseball Prospectus. Follow @ProfessorParks
18 comments have been left for this article.
BP Comment Quick Links
I agree on Gumbs and I saw some Rickie Weeks in him when I saw him play. He hit the fastest HR out of the park of anyone I seen including Jesus Montero. Mason, he looked like he can get some more pop in his swing, as he has some loft to it. I've also heard some rumors out there that he is 6'2 175 now which in terms is a possible increase in his power ceiling.
Feb 21, 2012 02:50 AM
Benjamin Harris
Can you talk little hit about Culver? I know you had that article earlier this year, but I'm sure you've gathered more information since your one game look.
Feb 21, 2012 06:48 AM
Culver has some defensive tools, but they aren't the type of defensive tools that can carry a player to the majors on their own merits. He's talented, but he's not a wizard. The bat will need to take big steps forward to project Culver as a major league regular. I don't see it right now, but development isn't an overnight sensation. That said, I've never spoken to anyone who absolutely loves Culver and believes in the dream of a first-division talent.
Feb 21, 2012 06:59 AM
Mtn Jam
Great recap, as usual.
Feb 21, 2012 06:59 AM
Tanana Republic
"I want to have a son and name him Gary."
Feb 21, 2012 07:07 AM
My firstborn son will be named #TheLegend Parks. He will be a free-swinger with massive raw power, a really strong arm, and a Colombian faux hawk.
Feb 21, 2012 07:16 AM
Poor child will be born into a deluge of #want. He better hope his father is prognosticating well that day, otherwise he'll have great difficulty explaining at school why his name is Jorge Gary Ronald Parks.
Feb 21, 2012 07:27 AM
Adam Hobson
Regarding Gary Sanchez, what is the future projection of his hit tool, 60? It's not as high as Montero's was/is, right?
Feb 21, 2012 07:40 AM
I'm not so sure Sanchez's hit tool projects to 60, but others seem confident with that future. I think he's more of a ~.275 hitter, with lots of power.
Feb 21, 2012 07:46 AM
Shaun P.
Would it be fair to say that, in your opinion, Mason Williams with no increase in power is a slightly smaller Brett Gardner? That sounds pretty good to me.
Feb 21, 2012 11:38 AM
I think Williams (without any additional power) could surpass Gardner as a player, based solely on his defensive skill-set. Williams will need to add strength to keep the bat in his hands against better pitching, but just because he doesn't project to have above-average power doesn't mean he's going to be a weakling at maturity. He's just not going to be a physical-type of player.
Feb 21, 2012 11:51 AM
Is it safe to assume that Sanchez's bat may move him off C in the same way Wil Myers' bat was too advanced to wait for the catching side of things to round into shape? Is that where the similarities end between those two? It actually sounds to be two of the same (or at least similar) stories.
Feb 21, 2012 11:55 AM
Myers is a more calculated hitter; almost passive at times. Sanchez lacks the same hit tool (in my opinion) but has just as much if not more power projection. Myers could have developed into a decent catcher, but as you said, the bat was developing at a faster rate and the position takes a lot of focus. Sanchez's bat will set a similar developmental pace, and given some of the makeup concerns that surfaced in 2011, the focus and dedication required to develop into a quality catcher might not be there in the first place. That said, players mature at different times for different reasons, so anything can happen with his developmental plan. It seems unlikely that he sticks at the position, but it's not a miracle if he does.
Feb 21, 2012 12:08 PM
A suggestion: can the "background with player" section be removed? 95% of the time its the same thing. The fact that Jason has a BP byline probably indicates that he is qualified to opine on the prospects in question.
Feb 22, 2012 10:41 AM
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Kobe Bryant expects to play in the Lakers' season-opening game on Christmas Day against the Bulls.
After setting out his team's second preseason game against the Clippers, Bryant told reporters, per ESPNLosAngeles.com, that he "should be fine" for next week's opening game.
"It's always been in my nature to try to figure out a way to play," Bryant said. "The injuries that I've had, I've been fortunate enough to be able to play through them because I haven't had injuries where they could get worse the more I played on them."
Bryant has a torn ligament in his right wrist, and ESPN reported he did not practice Thursday, instead spending that time getting treatment.
The injury, Bryant said, isn't something that's going to fully heal, and he'll have to figure out a way to play with the pain.
"I mean … the ligament is gone. So there's nothing I can do about it," Bryant said.
Bryant is coming off a season in which he played with a right knee injury that he told reporters was like "bone on bone."
This isn't the first time Bryant has dealt with an injury to his right hand. The Los Angeles Times noted that Bryant fractured his right index finger in December 2009. The injury bothered him throughout the season, which ended with a Lakers championship.
Lakers coach Mike Brown told reporters he expects Bryant to play, but he had a contingency plan at Thursday's practice, just in case.
The Lakers-Bulls matchup is one of five games on Christmas, the beginning date of this year's 66-game shortened season.


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Journal of Diabetes Research
Volume 2013 (2013), Article ID 716219, 8 pages
Antioxidant N-Acetylcysteine Attenuates the Reduction of Brg1 Protein Expression in the Myocardium of Type 1 Diabetic Rats
1Department of Anaesthesiology, The University of Hong Kong, HKSAR, Hong Kong
2Department of Anaesthesiology, Renmin Hospital of Wuhan University, Wuhan 430060, China
3Department of Anesthesiology, 3rd Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
4Department of Anesthesiology and Critical Care, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, China
5Department of Anesthesiology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China
Received 24 December 2012; Accepted 1 June 2013
Academic Editor: Bernard Portha
Copyright © 2013 Jinjin Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Brahma-related gene 1 (Brg1) is a key gene in inducing the expression of important endogenous antioxidant enzymes, including heme oxygenase-1 (HO-1) which is central to cardioprotection, while cardiac HO-1 expression is reduced in diabetes. It is unknown whether or not cardiac Brg1 expression is reduced in diabetes. We hypothesize that cardiac Brg1 expression is reduced in diabetes which can be restored by antioxidant treatment with N-acetylcysteine (NAC). Control (C) and streptozotocin-induced diabetic (D) rats were treated with NAC in drinking water or placebo for 4 weeks. Plasma and cardiac free15-F2t-isoprostane in diabetic rats were increased, accompanied with increased plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), while cardiac Brg1, p-STAT3 and HO-1 protein expression levels were significantly decreased. Left ventricle weight/body weight ratio was higher, while the peak velocities of early (E) and late (A) flow ratio was lower in diabetic than in C rats. NAC normalized tissue and plasma levels of 15-F2t-isoprostane, significantly increased cardiac Brg1, HO-1 and p-STAT3 protein expression levels and reduced TNF-alpha and IL-6, resulting in improved cardiac function. In conclusion, myocardial Brg1 is reduced in diabetes and enhancement of cardiac Brg1 expression may represent a novel mechanism whereby NAC confers cardioprotection.
1. Introduction
Diabetes mellitus-induced cardiovascular complication is a growing life-threatening disease worldwide. Diabetic cardiomyopathy (DCM) is a diabetes-associated ventricular dysfunction, resulted from abnormal ventricular structural alteration that is independent of other etiological factors such as hypertension [1]. Studies have shown that hyperglycemia-induced oxidative stress and the subsequent inflammation play critical roles in the development and progression of diabetic cardiomyopathy [2, 3]. Hyperglycemia-induced oxidative stress mainly results from increased production of reactive oxygen species (ROS) with or without concomitantly damped antioxidant defense system [4, 5]. Our previous study found that the major endogenous antioxidant enzyme superoxide dismutase (SOD), which plays an important role in balancing ROS generation and the overall tissue antioxidant capacity, was increased in both the plasma and heart tissue of rats at a relatively early stage (4 weeks) of diabetes, but tissue and plasma levels of free 15--isoprostane, a specific marker of lipid peroxidation, were also increased [6]. This indicates that the upregulation of SOD is not sufficient to resist hyperglycemia-induced oxidative stress. Of note, another important enzyme, heme oxygenase-1 (HO-1), a stress-inducible cytoprotective defense enzyme, has been shown to exert cytoprotective effect against oxidative insults [7]. Also, studies showed that enhancing myocardial HO-1 expression could attenuate diabetes-induced cardiac dysfunction. However, in contrast to the compensatory increase of SOD during early diabetes mellitus, a number of studies showed that myocardial HO-1 expression was significantly decreased in the myocardium of diabetic rats [8, 9]. Thus, unveiling the underlying mechanisms governing the reduction of myocardial HO-1 in diabetes should lead to the development of novel therapies to upregulate HO-1 expression in diabetic heart.
It has been reported that, in response to oxidative stress, Brahma-related gene 1 (Brg1) is necessarily required in Nuclear factor-E2 related factor 2 (Nrf2)/ARE-mediated induction of HO-1 [10]. Brg1 is the core ATPases in the SWI/SNF complex, which plays a central role in the activation and transcription of genes in mammalian cells [11]. The deficiency of Brg1 results in the dissolution of discrete heterochromatin domains, aberrant mitotic progression, and genomic instability, which eventually induces cell death or cell apoptosis [12]. A recent study showed that Brg1 can bind to the promoters of antioxidant defense genes and protect cells from oxidative damage [13], which means that Brg1 can exert antioxidative effect. Furthermore, increasing evidence shows that Brg1 can regulate gene expression during cardiac growth, differentiation, and hypertrophy [14–16]. Brg1 null mice embryos die when cardiomyocytes expansion and maturation begin, while in adult cardiomyocytes, Brg1 is activated by cardiac stresses and assembles a chromatin complex to activate downstream signal transduction, including HO-1 and signal transducer and activator of transcription 3 (STAT3) [10, 16–18], which are protective against ROS-induced cardiomyopathy. Studies by us and others found that myocardial HO-1 expression is reduced in diabetic rats [8, 9] which is accompanied with reduced phosphorylation of STAT3 (p-STAT3, the activated status of STAT3) [19]. We postulated that reductions in myocardial HO-1 and STAT3 in diabetes may be a consequence of reduction in cardiac Brg1 expression subsequent to hyperglycemia-induced oxidative stress.
Accumulated evidence proves that therapies that can reduce oxidative stress are effective to attenuate the development of diabetic cardiomyopathy [20, 21]. Our previous study also found that treatment with the antioxidant N-acetylcysteine (NAC) could attenuate the increase in inflammation factors tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) [6] and ameliorate myocardial dysfunction [2] in diabetic rats. Moderate levels of TNF-alpha or IL-6 have been shown to initiate the activation of STAT3, a key protein in cardioprotective signaling pathway, whose activation is Brg1 dependent [22, 23]. Therefore, the current study was designed to test the hypothesis that myocardial Brg1 is reduced in diabetes and antioxidant NAC may enhance cardiac Brg1 expression and concomitantly increase cardiac STAT3 activation and confer cardioprotection in diabetes.
2. Materials and Methods
2.1. Animals and Introduction of Diabetes
Sprague-Dawley male rats ( g, 8 weeks of age) were obtained from the Laboratory Animal Service Center (University of Hong Kong). All rats were allowed to adapt in their houses and have free access to standard chow and water according to the principles of Animal Care of the University of Hong Kong. The experiment procedures were approved by the Committee on the Use of Live Animals in Teaching and Research (CULATR). Diabetes was induced by a single tail vein injection of streptozotocin (STZ) at the dose of 65 mg/kg body weight (Sigma-Aldrich, St. Louis, MO), freshly dissolved in 0.1 M citrate buffer (PH 4.5) under anesthesia with sodium pentobarbital (65 mg/kg body weight), while control rats were given equal volume of citrate buffer alone. After three days of injection, blood glucose was measured using a Glucose Analyzer (Bayer Healthcare, Bayer AG, Germany), and rats with blood glucose over 16.7 mM were considered diabetic.
2.2. Experimental Protocol
Rats were randomly divided into three groups ( per group): control (C); diabetes (D); diabetes treated with NAC (1.5 g/kg/day) (D + NAC). NAC was administered to the D + NAC group dissolved in drinking water for 4 weeks after induction of diabetes starting one week after the onset of diabetes. Upon completion of treatment, the rats were anticoagulated with heparin (1000 IU/kg) and then anaesthetized with pentobarbital sodium (65 mg/kg body weight). Blood samples were obtained from the inferior vena cava, and plasma was separated and stored at −80°C for further analysis. Rats were sacrificed after completion of echocardiographic assessment of cardiac function, and hearts were harvested and rinsed with ice-cold phosphate buffer saline, dried, and weighted.
2.3. Echocardiography
At the end of 4-week treatment, the rats were examined by echocardiography using a High Resolution Imaging System (Vevo 770, VisualSonics Inc., Canada) equipped with a 17.5-MHz liner array transducer. The following validated parameters were automatically calculated by the ultrasound machine: LV end-diastolic volumes (LVVd), LV end-systolic volume (LVVs), fractional shortening (FS), ejection fraction (EF), and stroke volume (SV). M-mode images were recorded to detect heart rate (HR), LV internal diameter in systole (LVIDs) and diastole (LVIDd), interventricular septal thickness in systole (IVSs) and in diastole (IVSd), and LV posterior wall thickness in systole (LVPWs) and diastole (LVPWd). LV mass was assessed by calculating the formula: LV mass = 1.053 [(LVIDd + LVPWd + IVSd)3 − LVIDd3] × 0.8. The peak velocities of early (E) and late (A) flows were obtained from the apical four-chamber view. The E/A ratio and the isovolumetric relaxation time (IVRT) were used as indices of LV diastolic function.
All recordings were performed in rats that underwent inhalation of 3% isopentane in air throughout the whole process, and echocardiography was conducted by investigators who were blinded to the experimental group as we reported [24].
2.4. Measurement of Free 15--Isoprostane, TNF-Alpha, and IL-6
Free 15--isoprostane (15--IsoP), a specific marker of oxidative stress, was measured by using an enzyme-linked immunoassay kit (Cayman chemical, Ann Arbor, MI) as described [20]. Plasma samples and homogenized heart tissue (in PBS) were purified using Affinity Sorbent and Affinity Column (Cayman chemical, Ann Arbor, MI), then processed for analysis, according to the protocol provided by the manufacturer. The values of plasma or cardiac free 15--IsoP were expressed as pg/mL in plasma or pg/mg protein in cardiac homogenates, respectively.
Plasma levels of TNF-alpha and IL-6 were determined by using the commercially available rat ELISA kit (Bender Med, Vienna, Austria).
2.5. Western Blot Assay for HO-1, STAT3, and p-STAT3
Frozen heart tissue was homogenized using lysis buffer (20 mmol/L Tris-HCl PH = 7.5, 50 mmol/L 2-mercaptoethanol, 5 mmol/L EGTA, 2 mmol/L EDTA, 1% NP40, 0.1% sodium dodecyl sulfonate (SDS), 0.5% deoxycholic acid, 10 mmol/L NaF, 1 mmol/L PMSF, 25 mg/mL leupeptin, and 2 mg/mL aprotinin) for 30 min and then sonicated and centrifuged at 12000 g for 20 min at 4°C. Protein concentrations were determined using the Bradford assay (Bio-Rad, USA). Samples containing equal amounts were separated on a 10% SDS-polyacrylamide gel, and then proteins were transferred to PVDF membrane overnight at 4°C. Membranes were blocked with 5% nonfat milk in Tris-Buffered Saline (TBS)-Tween for 1 hour and were incubated with anti-Brg1 (Abcam, USA) or anti-STAT3, anti-phospho-STAT3 (T705), anti-HO-1 antibodies (Cell Signaling Technology, Beverly, MA, USA), and GAPDH (Cell Signaling Technology, Beverly, MA, USA) at 1 : 1000 dilution for overnight at 4°C. After washing with phosphate buffered saline-tween (PBST) three times for 30 min, membranes were then incubated with horseradish-peroxidase- (HRP-) conjugated anti-rabbit IgG at 1 : 2000 dilution for 1 hour. Protein bands were developed with enzymatic chemiluminescence, and images were measured by a densitometer with analysis software.
2.6. Statistical Analysis
Data are presented as means ± standard error of the mean (S.E.M.). Data were analysed by the ANOVA within the same group and between groups. Multiple comparisons of group means were analyzed by Tukey's test. The analysis was performed using statistical software package (GraphPad Prism, San Diego, CA, USA). Significant difference was defined as .
3. Results
3.1. General Characteristics and Effects of NAC Treatment
Administration of STZ resulted in increased plasma glucose and food and fluid intake and reduced body weight gain as compared with age-matched control rats (all , Table 1). Treatment with NAC for 4 weeks significantly reduced food consumption and water intake in diabetic rats (, D + NAC versus D) but did not have significant effect on glucose levels and body weight gain.
3.2. Oxidative Stress Marker Free 15--IsoP Levels
Compared with the control group, the levels of free 15--IsoP were significantly increased in both the plasma and cardiac tissues of diabetic rats ( or versus C, Table 2). NAC treatment reduced plasma and cardiac tissue 15--IsoP to a level comparable to that in the control ( versus D, D + NAC versus C, Table 2).
3.3. Effect of NAC on Left Ventricular Dimension and Function
As shown in Table 3, LVM was much lower in diabetic rats ( versus C), despite the fact that there were no significant differences in IVSd, IVSs, LVIDs, LVPWd, and LVPWs between the control and the diabetic rats. However, LVM to body weight ratio, an indicator of myocardial hypertrophy, was remarkably increased in diabetic rats ( versus C). NAC reduced LVM to body weight ratio to a level comparable to that in the control (, D + NAC versus D; D + NAC versus C, Table 3). The HRs of diabetic rats were significantly decreased as compared to those of the controls ( versus C Table 3). NAC had no effect on HR. LVVd and the E/A ratio in diabetic rats were significantly decreased, while IVRT increased (all versus C Table 3). This is indicative of compromised LV relaxation, which may contribute to the significantly reduced SV ( D versus C, Table 3). NAC treatment did not have significant effects on LVVd and IVRT nor did it improve SV ( D + NAC versus D, Table 3) but remarkably increased E/A ratio which primarily resulted from a reduction in MVA ( D + NAC versus D, Table 3). There was no difference in values of FS and EF between the control and diabetic rats.
3.4. Plasma Il-6 and TNF-α
As shown in Figures 1(a) and 1(b), the plasma levels of TNF-α and IL-6 in diabetic rats were significantly increased as compared with the control group (). NAC treatment reduced plasma TNF-α and IL-6 to a level comparable to that in the control ( versus D; versus C) although they were slightly higher than that in the control rats.
3.5. Effect of NAC on Protein Expression of Brg1
To investigate whether the cardiac protein expression of Brg1 is altered in diabetic rats at an early stage of the disease and whether or not it can be affected by antioxidants, we explored the effects of NAC on cardiac levels of Brg1 in STZ-induced diabetic rats 4 weeks after the establishment of diabetes. As shown in Figure 2(a), the protein expression of Brg1 was significantly decreased in diabetic rats as compared to that of control group (). NAC treatment partially but significantly restored the protein expression of Brg1.
3.6. Effect of NAC on Protein Expression of STAT3 and HO-1
Recent study demonstrated that Brg1 is required to establish chromatin accessibility at STAT3 binding targets [18], which is essential to enable these sites to respond to downstream signaling. Therefore, in addition to exploring the changes of myocardial Brg1 protein in diabetes, we also investigated the myocardial protein levels and phosphorylation/activation status of STAT3 in diabetic heart. As shown in Figures 2(c) and 2(d), the protein expression of p-STAT3 (Tyr705 and Ser727) but not total STAT3 was significantly reduced in the myocardium of diabetic rats, accompanied with concomitant reduction of cardiac protein expression of HO-1 (all versus C, Figure 2(b)), an important signaling protein downstream of Brg1. NAC completely restored myocardial p-STAT3 at site Tyr705 and HO-1 protein expression and partially but significantly enhanced p-STAT3 at site Ser-727 in diabetic rats ( versus D; , versus C).
4. Discussion
Consistent with our previous studies, we have shown in the current study that oxidative stress increased in the early stage (at 4 weeks) rats with STZ-induced type 1 diabetes as indicated by a significant increase in both plasma and heart tissue levels of free 15--isoprostane, a specific index of oxidative stress [25]. Enhanced levels of oxidative stress were accompanied by increased TNF-alpha and IL-6. In the current study, we further discovered that diabetic rat hearts exhibited decreased expression of Brg1, which was coincident with decreased cardiac expressions of p-STAT3 and HO-1 and compromised cardiac diastolic function as assessed by echocardiography. Effective antioxidant treatment with NAC evidenced as complete prevention of hyperglycemia-induced increases in plasma and heart tissue free 15--isoprostane significantly attenuated the reduction of myocardial Brg1 protein expression, subsequently significantly enhanced myocardial p-STAT3 and HO-1, and improved cardiac relaxation in diabetic rats. To our knowledge, this is the first study to explore the changes of cardiac Brg1 in diabetic rats and the effectiveness of antioxidant treatment on Brg-1 cardiac expression in diabetes.
Oxidative stress occurs in diabetes as a consequence of hyperglycemia-induced abnormalities, including glucose autooxidation, the formation of advanced glycation end products, and impairment of antioxidant defense system [4]. We previously reported that the heart tissue SOD activity was compensatorily increased, but both the plasma and heart tissue levels of free 15--isoprostanes were still increased in diabetic rats at the early stage of 4-week diabetes [6], which indicates that, during early stage of diabetes, compensatory increase in myocardial SOD was not sufficient to combat hyperglycemia-induced oxidative stress. While in our current study conducted in the same model of early stage of 4-week diabetes [6], we showed that the protein expression of HO-1, another important antioxidative enzyme, was decreased significantly in the myocardium of diabetic rats, which suggests that a decrease in HO-1 expression may be a major contributor to hyperglycemia-induced oxidative stress in early diabetes. Many studies confirmed that HO-1 plays a central role in cardiovascular protection [26]. It has been shown that, in response to oxidative stress, HO-1 expression can be induced through the Nrf2/ARE signaling pathway, while, effective Nrf2/ARE signaling needs the participation of Brg1 [10]. However, as we showed in the current study, cardiac Brg1 expression in rats at the 4th week after STZ-induced type 1 diabetes was significantly reduced, which might be the major reason why cardiac protein expression of HO-1 was significantly decreased. Antioxidant NAC normalized cardiac free 15--isoprostanes in diabetic rats and enhanced myocardium Brg1 expression, leading to full restoration of cardiac HO-1 expression. This finding suggests that enhancing Brg1 may represent a novel mechanism whereby NAC confers its antioxidant protection at least in early diabetes.
Consistent with our recent study findings [24], we showed in the current study that ventricular dysfunction occurs during early stage of diabetes manifested as abnormal relaxation function that was coincident with significant reduction in myocardial Brg1 protein expression. This finding is similar in nature to a previous study which showed that mice with cardiac-specific deletion of Brg1 developed impaired cardiac relaxation evidenced as reduction in E/A ratio as determined by ultrasound [15]. The findings by us and others [15] point out the importance of Brg1 in the maintenance of normal cardiac function. In our study, NAC treatment mediated improvement in cardiac diastolic function manifested as significant elevation of E/A ratio in diabetes which may be contributable to enhancement of cardiac Brg1 protein expression.
The risk of progression to heart failure after myocardial ischemia and reperfusion was significantly higher in diabetes compared with nondiabetes [27]. Myocardial STAT3 is an important transcription factor in the SAFE pathway (i.e., JAK2/STAT3 signaling cascade), especially during myocardium ischemia reperfusion injury [28], but cardiac p-STAT3 is reduced in diabetes [19]. Further, STAT3-deficient mice spontaneously develop a form of dilated cardiomyopathy similar to that which occurred in diabetic mice [29], indicating that reduced STAT3 activation may lead to myocardial remodeling. Brg1 is necessarily required to establish chromatin restructure for the activation of STAT3, especially STAT3 phosphorylation at site Try705 in various cells such as cancer cell and macrophagocyte [30], and for STAT3 signaling transduction. In the current study, we also found that STAT3 phosphorylation at both Ser727 and Try705 was dramatically reduced in the hearts of diabetic rats, which was concomitant with decreased Brg1 expression. NAC treatment increased the expression of Brg1 and consequently enhanced p-STAT3 at both Try705 and Ser727 in the myocardium of diabetic rats. Based on the fact that Brg1 is a needed component for STAT3 activation [30], our findings suggest that Brg1 may play a key role in the transcriptional induction of cardiac STAT3, especially at Try705 in diabetic rats. NAC may have increased STAT3 phosphorylation in diabetes through enhancing Brg1 expression, although further study is needed to confirm this hypothesis.
Inflammation has been considered as an important process in the progression of diabetes [31, 32]. Elevation of TNF-alpha and IL-6 was detected in diabetes, which was related to the progression of diabetic complications [33]. In the current study, we showed that plasma levels of TNF-alpha and IL-6 were remarkably elevated in diabetic rats at 4 weeks after the establishment of diabetes, and NAC treatment decreased them, indicating that NAC can inhibit the inflammation reaction in diabetes. Studies found that moderate levels of TNF-alpha or IL-6 can increase the phosphorylation of STAT3 at Try705, and this is Brg1 dependent [22, 23]. In our study, we found that the levels of TNF-alpha and IL-6 in NAC-treated diabetic rats were significantly lower than that in the untreated diabetes, but still slightly higher than that in nondiabetic rats. These remaining slight elevations in TNF-alpha and IL-6 after NAC treatment should have contributed to the enhancement of cardiac p-STAT3 as seems to be in the NAC treated group, which added to the effect of Brg1 in enhancing cardiac Brg1-mediated STAT3 activation as previously mentioned. This explains why NAC treatment did not completely restore cardiac Brg1 protein expression in diabetic rats but completely restored cardiac p-STAT3 at site Try705.
In summary, we first report that the expression of Brg1 was decreased significantly in the myocardium of diabetic rats, which may be responsible at least in part for the reduced expressions of HO-1 and p-STAT3 and impairment of cardiac diastolic function as summarized in the schematic diagram (Figure 3). Enhancement of cardiac Brg1 expression may thus represent a novel mechanism whereby NAC enhanced cardiac HO-1 and p-STAT3 expressions and attenuated cardiac diastolic dysfunction in diabetes.
Conflict of Interests
The authors have no potential conflict of interests to declare.
This study was supported by the Hong Kong Research Grant Council (RGC), GRF Grant (782910), and NSFC Grants (81200609, 81270899).
- I. Falcão-Pires and A. F. Leite-Moreira, "Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment," Heart Failure Reviews, vol. 17, no. 3, pp. 325–344, 2012. View at Publisher · View at Google Scholar · View at Scopus
- Y. Liu, S. Lei, X. Gao et al., "PKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfuntion in rats with streptozotocin-induced diabetes," Clinical Science, vol. 122, no. 4, pp. 161–173, 2012. View at Publisher · View at Google Scholar · View at Scopus
- M. Rajesh, P. Mukhopadhyay, S. Btkai et al., "Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy," Journal of the American College of Cardiology, vol. 56, no. 25, pp. 2115–2125, 2010. View at Publisher · View at Google Scholar · View at Scopus
- L. E. Wold, A. F. Ceylan-Isik, and J. Ren, "Oxidative stress and stress signaling: menace of diabetic cardiomyopathy," Acta Pharmacologica Sinica, vol. 26, no. 8, pp. 908–917, 2005. View at Publisher · View at Google Scholar · View at Scopus
- D. Du, Y.-H. Shi, and G.-W. Le, "Oxidative stress induced by high-glucose diet in liver of C57BL/6J mice and its underlying mechanism," Molecular Biology Reports, vol. 37, no. 8, pp. 3833–3839, 2010. View at Publisher · View at Google Scholar · View at Scopus
- S. Lei, Y. Liu, H. Liu, H. Yu, H. Wang, and Z. Xia, "Effects of N-acetylcysteine on nicotinamide dinucleotide phosphate oxidase activation and antioxidant status in heart, lung, liver and kidney in streptozotocin-induced diabetic rats," Yonsei Medical Journal, vol. 53, no. 2, pp. 294–303, 2012. View at Publisher · View at Google Scholar · View at Scopus
- J. A. Araujo, M. Zhang, and F. Yin, "Heme oxygenase-1, oxidation, inflammation, and atherosclerosis," Frontiers in Pharmacology, vol. 3, article 119, 2012. View at Publisher · View at Google Scholar
- C. Kusmic, A. L'Abbate, G. Sambuceti et al., "Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signaling," Journal of Cellular Biochemistry, vol. 109, no. 5, pp. 1033–1044, 2010. View at Publisher · View at Google Scholar · View at Scopus
- V. Selvaraju, M. Joshi, S. Suresh, J. A. Sanchez, N. Maulik, and G. Maulik, "Diabetes, oxidative stress, molecular mechanism, and cardiovascular disease-an overview," Toxicology Mechanisms and Methods, vol. 22, pp. 330–335, 2012. View at Google Scholar
- J. Zhang, T. Ohta, A. Maruyama et al., "BRG1 interacts with Nrf2 to selectively mediate HO-1 induction in response to oxidative stress," Molecular and Cellular Biology, vol. 26, no. 21, pp. 7942–7952, 2006. View at Publisher · View at Google Scholar · View at Scopus
- L. Mohrmann and C. P. Verrijzer, "Composition and functional specificity of SWI2/SNF2 class chromatin remodeling complexes," Biochimica et Biophysica Acta, vol. 1681, no. 2-3, pp. 59–73, 2005. View at Publisher · View at Google Scholar · View at Scopus
- R. J. Bourgo, H. Siddiqui, S. Fox et al., "SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity," Molecular Biology of the Cell, vol. 20, no. 14, pp. 3192–3199, 2009. View at Publisher · View at Google Scholar · View at Scopus
- W. Du, R. Rani, J. Sipple et al., "The FA pathway counteracts oxidative stress through selective protection of antioxidant defense gene promoters," Blood, vol. 119, no. 18, pp. 4142–4151, 2012. View at Publisher · View at Google Scholar
- M. Vallaster, C. D. Vallaster, and S. M. Wu, "Epigenetic mechanisms in cardiac development and disease," Acta Biochimica et Biophysica Sinica, vol. 44, no. 1, pp. 92–102, 2012. View at Publisher · View at Google Scholar · View at Scopus
- J. K. Takeuchi, X. Lou, J. M. Alexander et al., "Chromatin remodelling complex dosage modulates transcription factor function in heart development," Nature Communications, vol. 2, article 187, 2011. View at Publisher · View at Google Scholar · View at Scopus
- C. T. Hang, J. Yang, P. Han et al., "Chromatin regulation by Brg1 underlies heart muscle development and disease," Nature, vol. 475, no. 7357, p. 532, 2011. View at Publisher · View at Google Scholar · View at Scopus
- M. S. Willis, J. W. Homeister, G. B. Rosson et al., "Functional redundancy of SWI/SNF catalytic subunits in maintaining vascular endothelial cells in the adult heart," Circulation Research, vol. 111, no. 5, pp. e111–e122, 2012. View at Publisher · View at Google Scholar
- L. Ho, E. L. Miller, J. L. Ronan, W. Q. Ho, R. Jothi, and G. R. Crabtree, "EsBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function," Nature Cell Biology, vol. 13, no. 8, pp. 903–913, 2011. View at Publisher · View at Google Scholar · View at Scopus
- T. Wang, S. Qiao, S. Lei et al., "N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats," PLoS ONE, vol. 6, no. 8, Article ID e23967, 2011. View at Publisher · View at Google Scholar · View at Scopus
- Z. Xia, K.-H. Kuo, P. R. Nagareddy et al., "N-acetylcysteine attenuates PKCβ2 overexpression and myocardial hypertrophy in streptozotocin-induced diabetic rats," Cardiovascular Research, vol. 73, no. 4, pp. 770–782, 2007. View at Publisher · View at Google Scholar · View at Scopus
- V. Ramakrishna and R. Jailkhani, "Oxidative stress in non-insulin-dependent diabetes mellitus (NIDDM) patients," Acta Diabetologica, vol. 45, no. 1, pp. 41–46, 2008. View at Publisher · View at Google Scholar · View at Scopus
- M. N. Ndlovu, C. Van Lint, K. Van Wesemael et al., "Hyperactivated NF-κB and AP-1 transcription factors promote highly accessible chromatin and constitutive transcription across the interleukin-6 gene promoter in metastatic breast cancer cells," Molecular and Cellular Biology, vol. 29, no. 20, pp. 5488–5504, 2009. View at Publisher · View at Google Scholar · View at Scopus
- Z. Ni and R. Bremner, "Brahma-related gene 1-dependent STAT3 recruitment at IL-6-inducible genes," Journal of Immunology, vol. 178, no. 1, pp. 345–351, 2007. View at Google Scholar · View at Scopus
- X. Gao, Y. Xu, B. Xu et al., "Allopurinol attenuates left ventricular dysfunction in rats with early stages of streptozotocin-induced diabetes," Diabetes/Metabolism Research and Reviews, vol. 28, no. 5, pp. 409–417, 2012. View at Publisher · View at Google Scholar
- P. Faure, C. Polge, D. Monneret, A. Favier, and S. Halimi, "Plasma 15-F2t isoprostane concentrations are increased during acute fructose loading in type 2 diabetes," Diabetes and Metabolism, vol. 34, no. 2, pp. 148–154, 2008. View at Publisher · View at Google Scholar · View at Scopus
- M.-L. Wu, Y.-C. Ho, and S.-F. Yet, "A central role of heme oxygenase-1 in cardiovascular protection," Antioxidants and Redox Signaling, vol. 15, no. 7, pp. 1835–1846, 2011. View at Publisher · View at Google Scholar · View at Scopus
- M. J. Garcia, P. M. McNamara, T. Gordon, and W. B. Kannell, "Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow up study," Diabetes, vol. 23, no. 2, pp. 105–111, 1974. View at Google Scholar · View at Scopus
- B. Drenger, I. A. Ostrovsky, M. Barak, Y. Nechemia-Arbely, E. Ziv, and J. H. Axelrod, "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, vol. 114, no. 6, pp. 1364–1372, 2011. View at Publisher · View at Google Scholar · View at Scopus
- D. Hilfiker-Kleiner, A. Hilfiker, M. Fuchs et al., "Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury," Circulation Research, vol. 95, no. 2, pp. 187–195, 2004. View at Publisher · View at Google Scholar · View at Scopus
- S. Giraud, A. Hurlstone, S. Avril, and O. Coqueret, "Implication of BRG1 and cdk9 in the STAT3-mediated activation of the p21waf1 gene," Oncogene, vol. 23, no. 44, pp. 7391–7398, 2004. View at Publisher · View at Google Scholar · View at Scopus
- G. S. Hotamisligil, "Endoplasmic reticulum stress and the inflammatory basis of metabolic disease," Cell, vol. 140, no. 6, pp. 900–917, 2010. View at Publisher · View at Google Scholar · View at Scopus
- P. Casas-Agustench, M. Bulló, and J. Salas-Salvadó, "Nuts, inflammation and insulin resistance," Asia Pacific Journal of Clinical Nutrition, vol. 19, no. 1, pp. 124–130, 2010. View at Google Scholar · View at Scopus
- J. F. Navarro-González, C. Mora-Fernández, M. Gómez-Chinchón, M. Muros, H. Herrera, and J. Garcia, "Serum and gene expression profile of tumor necrosis factor-α and interleukin-6 in hypertensive diabetic patients: effect of amlodipine administration," International Journal of Immunopathology and Pharmacology, vol. 23, no. 1, pp. 51–59, 2010. View at Google Scholar · View at Scopus


text:
Zipslack, Windows not being buddies
Hello Slackers,
I'm attemping to install slack. But that penguin must've been in an oil slick or something because he's slipping from my grasp.
The problem is (I am trying to use windows XP as a tool for downloading and installing my linux slack, but) slack is ignoring windows files/folders. This sounds bad, but if you understand zipslack read on.
I downloaded zipslack and unzipped onto a FAT32 partition (from windows XP). Then I downloaded x1, kde1 and ap1 using windows, I put them into a "slakware" folder under "linux" (such that x1, kde1 and ap1 were all folders containing the *.tgz files and so forth).
Then I boot linux by using a ms-dos boot disk, and running linux.bat from my second hard drive. Linux.bat is so :
\linux\loadlin \linux\vmlinuz root=/dev/hdb1 ro
I had tried using rw but I was getting warnings, and the problem persisted anyway.
My fstab is :
/dev/hdb1 / umsdos defaults 0 0
/root/swapfile swap swap defaults 0 0
none /dev/pts devpts gid=5,mode=620 0 0
none /proc proc defaults 0 0
My mtab is :
/dev/hdb1 / umsdos rw 0 0
From a windows point of view there is a "--LINUX-.---" file in every linux folder, which is obviously part of the filesystem. But when I use windows to add files/folders to the linux install, linux is completely unaware of any change. Hence I cannot use windows to download and add packages to my linux build :(
What's the go ? Do I need to remount /hdb1 or something ?
You need to run the umssync program to update the --LINUX-.--- files when you copy files to the linux directories from DOS/Windows. Details
can be found with a man umssync. I'm not sure why this isn't happening
on bootup, as umssync should be running as part of your /etc/rc.d/rc.S script.
James Dixon.
Right you are, thanks for that
Yes, seconds after I installed slack I set to "configuring" it. It was fun playing the "guru" but the sham turned around and bit me quick.
I re-installed and I'm going to be a bit more cautious.
Thanks again.
|All times are GMT -5. The time now is 08:23 AM.


text:
Mike Avery Joins the Valpo Coaches Show
Men's soccer head coach Mike Avery joins the Valpo Coaches Show this week. The Crusaders return home Saturday to face the 24th-ranked Milwaukee Panthers (9-1-1) at Brown Field at 7 p.m.
Next week's show will feature women's soccer head coach John Marovich. Fans can submit questions for possible use on the show by tweeting @ValpoAthletics.


text:
Opening statements began in the 1st-degree murder trial of John Oldson Tuesday. Oldson is accused of killing Catherine Beard in Ord in 1989.
The prosecution started by giving their version of events, saying that Beard turned down Oldson's sexual advances. They said "this is the story of a man who was rejected. He couldn't handle it, and he killed her." The state also noted that Oldson changed his story every time he was interviewed by law enforcement.
The defense countered that there are witnesses who collaborate Oldson's story. They also noted that no forensic evidence has ever tied Oldson to Beard's death and that their forensics expert will testify that the victim's injuries are consistent with being struck by a vehicle.
The state called a total of six witnesses Tuesday, including Beard's sister and close friend, as well as law enforcement officials and individuals who saw Beard the night she disappeared.
Beard's close friend was on the stand the longest Tuesday and recounted that Oldson asked her, "What's going to happen if her body comes floating down the river? Who do you think they're going to blame? Me!"
Court reconvenes Tuesday at 9 a.m. with the prosecution calling its other witnesses.


text:
iPhone 4G: Apple asks Gizmodo to return 'lost' prototype
Tech website Gizmodo has confirmed that Apple has contacted it asking for its âiPhone 4â prototype back, which was found in a bar close to Appleâs Palo Alto headquarters.
The technology blog released video footage of a suspected iPhone 4G âprototypeâ on Monday, after Engadget revealed pictures of the device on Friday.
A post then revealed that Appleâs General Counsel Bruce Sewell had contacted them, formally requesting that the iPhone be returned to them.
The letter stated: 'It has come to our attention that Gizmodo is currently in possession of a device that belongs to Apple,
'This letter constitutes a formal request that you return the device to Apple. Please let me know where to pick up the unit.'
Gizmodo also revealed the name of the unfortunate Apple employee who lost the iPhone prototype, who is believed to work on the iPhoneâs baseband software, which enables the device to make calls.Â
It is believed that the engineer had been testing the iPhone on a night out, before leaving the device on a stool in the Gourmet Haus Staudt bar.
The customer who found the iPhone reportedly managed to use the iPhone for a short time before Apple remotely disabled the device via the MobileMe service.
The man apparently attempted to contact Apple to report the missing device once he realised that he was in possession of a prototype, but says his calls were effectively ignored.
Gizmodo paid a reported $10,000 for the iPhone 4G exclusive.


text: In 2009 I went to travel all over China for a month with my friend Brian. We basically made a big circle around China and visited close to a dozen of the provinces there. We saw everything from the modern skyscrapers in Shanghai to the rice patty fields in remote villages. One of the places we ventured to was Huangshan or "Yellow Mountain" in the Anhui province. It was absolutely amazing. We climbed thousands of steps for around 4-5 hours, just in time to see the sunset. Then we went to bed and woke up at 5am the next morning (while it was pitch black outside) to hike another 2 miles to the edge of a cliff to see this spectacular sunrise. To say it was cold is an understatement, it was freezing, but it was absolutely worth it! I'm sure I will be sharing more pictures from my trip to China here but if you would like to see the rest of them they can all be found on China set on Flickr, enjoy!


text:
Your Housecleaning Checklist
Streamline housecleaning by sticking to a list. There's freedom in knowing exactly what to clean and when to clean it. No more time wasted stressing about cleaning or fretting over what you've missed. Just check, check, check each item off as you go. Done!
The following is a sample list courtesy of Amanda Thomas, founder and domestic expert at Moxie Girl Household Assistants. Feel free, of course, to adjust rooms, tasks, and frequencies to your specific household's needs.
continue reading below
- Dust furniture and wall hangings
- Change bed linens
- Clean floor
- Dust light fixtures and wall hangings
- Clean counters, sinks, and cabinet fronts
- Clean mirrors
- Clean shower/tub
- Scrub and wipe down toilet
- Change towels
- Empty trash
- Clean floor
- Tidy and wipe off countertops
- Clean microwave, toaster, and coffeepot inside and out
- Wipe down all appliances
- Spot-clean cabinet fronts
- Launder cloths and towels
- Put sponges and dish brushes through dishwasher cycle, if possible (and if they are dishwasher-safe)
- Clean floor
Living Room
- Dust furniture and wall hangings
- Clean floor
- Dust furniture and wall hangings
- Clean floor
MONTHLY (Entire Home)
- Dust ceiling fans and window treatments
- Wipe down doors, knobs, and light switches
- Spot-clean walls
- Dust baseboards
- Dust window sills and tracks
- Wipe out inside of fridge
ANNUALLY OR SEMIANNUALLY (Entire Home)
- Wipe out inside of kitchen cabinets and pantry
- Wipe out inside of bathroom cabinets
- Dust high ledges
- Wash windows
- Have carpets cleaned
- Go through closets and kids' rooms, and donate unused items
Cleaning Shortcuts You Need to Know
Are You the Queen of Clean? Find Out!
Discover your cleaning personality and get cleaning tips and tricks that suit your style. Plus, read what other BHG.com users have to say about cleaning.
Share your take on this idea!
Upload your photo here.
Upload your photo here.


text:
Cushing's suspension could cost him down the road
Published: May 11th, 2010 | Tags: Brian Cushing, Houston Texans
In addition to the stigma of possibly being stripped of his 2009 NFL Defensive Rookie of the Year award, there's another issue for Texans LB Brian Cushing: How does this affect his wallet?
As it pertains to the rookie award, it actually has no effect at all. Cushing's rookie contract included a $2.219 million bonus for which the ROY award was just one of a few performance-based goals that served as a trigger. Even without the award, Cushing met other incentives that triggered that bonus.
That said, there are more lucrative escalators in the contract that could be affected — and could cost Cushing as much as $2.6 million.
These escalators increase the value of the contract if Cushing plays 80 percent of the team's defensive snaps and makes the Pro Bowl in three of the first four years of the contract. He reached both of those goals as a rookie, but his four-game drug suspension for the start of the 2010 season also disqualifies him from next year's Pro Bowl and makes it highly unlikely that he will reach the 80 percent mark in total plays. That means he'd have to reach those goals in 2011 and again in 2012 to earn that $2.6 million in the fifth year — an uphill climb for what seemed like a very attainable goal just a few months ago.
— Gil Brandt


text:
Pierced work, in metalwork, perforations created for decorative or functional effect or both; the French term for such work is ajouré. Both hand-operated and mechanical tools such as saws, drills, chisels, and punches are used. The principal present-day exponents of this ancient technique are perhaps Asiatic Indian craftsmen. In European metalwork—apart from its functional and decorative use on handles, lids, covers, finials, and the like—pierced work is most often associated with such articles as locks and keys, iron and steel caskets, and guns, as well as with jewelry and other small objects. In the 18th century, however, it enjoyed a period of great popularity, when certain pieces of domestic silver—for example, cake baskets, sugar basins, and coasters—consisted almost entirely of intricate pierced-work patterns. A new tool was developed in order to pierce Sheffield plate in this manner. See also opus interassile.
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CHICO — Malik Hopkins is making up for lost time.
In just his second year of wrestling, the Chico High senior is the top-ranked grappler in the 285-pound division for the Northern Section.
Hopkins started wrestling because of former Panthers assistant Joe Rios, who died in 2012.
"I knew him from Pop Warner football," Hopkins said. "He told me if I came out for wrestling, he'd buy me my first pair of wrestling shoes. After he passed away, I decided I was going to honor what he held up to me. I pretty much did it for him."
A fifth-place finish at the Northern Section Masters Wrestling Championships as a junior was just the beginning.
His senior year has been even better. The 6-foot-3, 245-pound Hopkins is ranked No. 22 in the state as he's primed to get the one thing that eluded him on the football field — a section title.
"To see the growth and the progress he's had in the sport in such a short time is unbelievable," said Rollins, who added Panthers football coach Jason Alvistur raved about Hopkins' athleticism before he joined the wrestling team. "He wasn't kidding. He's really an athlete, a true, true athlete."
In football, Hopkins excelled for the Panthers playing both left tackle on offense and defensive end as he earned first-team honors to the all-section football team.
He has taken his football mentality over to the mat as he preferred playing defense because he likes "hitting people."
"The defensive instincts kick in during wrestling — attack, attack, attack. I don't like winning by points. I like pinning people," said Hopkins, who has done that 22 times among his 27 victories this season.
That mentality has paired well with his other attributes.
"He picks up things quickly. You can show him something and he can be doing it in the next match," Rollins said. "He's got speed, strength, quickness. That's what makes him so dangerous from all positions. For him, I don't see a weakness. He's really good on his feet. He gets away from everyone. On top, he's just brutal with guys."
That gives Hopkins a chance to wrestle in college if he wants, Rollins added.
"He sees whatever it takes to get him an education. He gets what he needs to do with his life," Rollins said, noting that Hopkins was "elected captain hands down. To me, it's just a testament to who he is. He's the kind of guy who walks into a room and people have respect for."
Hopkins has in turn found respect for his second sport.
"It's been more than I expected," Hopkins said. "I thought it'd be just something to stay in shape for football. Two years wrestling, and people are already looking at me. It's pretty exciting."
Connect with Sports Writer Joseph Shufelberger at www.twitter.com/JShufelberger and read his blog at http://www.norcalblogs.com/norcalsports.


text:
This is leeched, and I am aware of it, it just move textures from you're Nexon/Combat Arms/game folder and edits them and makes almost eveything white, heres a screenie of what it does!
Virus Scan!
Virustotal. MD5: 1b29db0906df24675a51eb2e2e1df45d
The download is below, I know it's scetchy because it is a .exe, but bare with me....


text: Girls' horoscope T-shirt Item H0490 Color: WHITE Size: All sizes are US sizes. 2 3 4-5 6-7 8 10 12 14 Size Charts Quantity: 1 2 3 4 5 6 7 8 9 Prices do not include taxes. Add to Bag Wishlist Add to Bag Add To Wishlist share: size & fit Product Details This T-shirt features every sign of the zodiac calendar and was inspired by our limited-edition horoscope tee collection that we designed especially for mom (so the two of you can be twins if you want!). Bonus: You can check off the box under the appropriate sign with a permanent marker...now that's what we call personali-tee! Cotton. Machine wash. Import. Item H0490.


text:
In MLS Fantasy Soccer: Manager a win or a loss can be decided by as little as one point. And when it comes to moving up in the overall rankings, every decision you make becomes even more costly.
I've mentioned this move to some of my Twitter followers in the past, but now it's time to share this little trick with you.
Above is a snapshot of my team prior to the start of this round (Round 16), with a few exceptions. The changes below did not affect the formation or substitution order.
- Camilo Sanvezzo (IN) ---> Diego Fagundez (OUT)
- Nathan Sturgis (IN) ---> Andrew Farrell (OUT)
- Patrice Bernier (IN) ---> Dillon Powers (OUT)
- Camilo Sanvezzo ---> (Captain)
If you look closely you'll notice that I have Amobi Okugo starting as my fourth midfielder. It may seem odd that I purposely left Chris Tierney and Landon Donovan on my bench, but I assure you it's all for good reason.
Here's how the trick works...
MLS Fantasy – Substitution Trick
If I make zero manager substitutions once the round begins, then at the end of the round Tierney will automatically be subbed into my lineup for Okugo. But, since Donovan is playing on a later date, I can go ahead and sub him in for Okugo before his game begins.
Now, this may not seem like a huge deal, but it gives you the ability to see how one player performs before deciding who to play. Let's say Tierney has a pretty good game (8-10 points), but instead of starting Okugo, I started Donovan. Those points are now lost for good, unless of course, one of my other starters misses their game.
Tierney got an assist (+3) and an attacking bonus (+1) against Vancouver, but he also got -2 for goals conceded and a -1 for yellow card. That left him with a total of three points. But if New England had gotten a clean sheet, Tierney would've ended up with nine points. And instead of subbing Donovan in for Okugo (which is what I did), I would've left Tierney in and Donovan would've remained on my bench.
- This trick will ONLY work if the two players involved are playing games on different days (e.g. Saturday and Sunday)
- You HAVE to start someone who isn't playing at all, whether it's due to injury, suspension, a bye week etc.
- Your #1 sub (Chris Tierney) has to be playing IN the first game day of that round
- Your #2 sub (Landon Donovan) has to be playing AFTER the first game day of that round
TIP: As long as there are games being played on two different dates in each round, you can use this trick every time. It's best to use on high risk/high rewards players, like forwards. You can also use it to get more points out of your Captain/Vice-captain.
Poll of the Week: Last week I gave you the option to choose between three midfielders and pick which one would have the highest score at the end of Round 16. Midway through the round, the point totals look like this;
- Russell Teibert – 5 points
- Patrice Bernier – 4 points
- Diego Valeri – 3 points
The poll is still open for voting, so with one game each left to play, do you still think Diego Valeri is going to be the top scorer this week? Or will one of the other two guys claim the top spot among this group of midfielders? Vote now.


text:
brag about (someone or something)
brag about (someone or something)
To boast about someone or something, perhaps to an excessive or unwarranted degree. I can't stand being around Marcus ever since his company became such a massive success. The guy just can't stop bragging about it! You're my daughter, and you have such good grades—of course I'm going to brag about you!
See also: brag


text:
Washington, D.C.—Nevada Senator Harry Reid released the following statement on tomorrow's 57th anniversary of the Brown vs. Board of Education decision, which struck down racial segregation in public schools:
"The Brown vs. Board of Education decision was a major step toward education equality in America, and launched a Civil Rights movement that changed the face of our nation. But while the Brown decision changed the law of the land, it didn't immediately change the reality of education inequality in America. That process continues today as we work to ensure every child in Nevada and across America has equal access to a world-class education regardless of race, family income or birthplace.
"We thank the countless activists, lawyers, parents and students who put themselves at risk to fight for equality and justice. It was their work and sacrifice that led to the Brown decision, which ended legal segregation in our schools. Those advocates for integrated, diverse schools pursued their beliefs even when they weren't popular, and fought to ensure that this country lived according to its founding principle: that all people are created equal."


text:
found a new home!
Plenty of my friends are looking
for one too. Find a pet to adopt.
I am already neutered, up to date with shots, and good with cats.
Tucker, a Cerritos Siamese kitten was adopted! Here's how you can benefit by looking at adoption as an option to buying a Siamese for sale in Cerritos, or seeking a Siamese kitten from a breeder in Cerritos.


text:
Here and There has been compared to such Jim Jarmusch films as "Stranger Than Paradise," and "Lungulov" does emulate Jarmusch's deliberate pace, minimal dialogue, deadpan humor and strong sense of place. In fact, Belgrade is the movie's most compelling character, its tattered charm underscored by back-street New York locations that oddly evoke Eastern Europe. show more
Here and There deserves all the attention it can get for its limited release. Beautifully executed, the semi-autobiographical film is set between the director's adopted New York and his native Belgrade, Serbia. show more
Borderline clichéd, and it makes getting a US visa seem way too easy. But I can think of much worse ways to spend an hour and a half than watching this absurdist comedy. show more


text:
Please add the kdump(1) utility to freebsd-utils. This program renders the binary log files produced by ktrace(1) into human-readable format; I don't think it's an exaggeration to say that ktrace is useless without kdump.
We are aware of it. In mean time, please use kdump from http://ftp.debian-ports.org/debian/pool-kfreebsd-i386/main/f/freebsd-hackedutils/freebsd-hackedutils_6.1-3_kfreebsd-i386.deb http://ftp.debian-ports.org/debian/pool-kfreebsd-amd64/main/f/freebsd-hackedutils/freebsd-hackedutils_6.1-3_kfreebsd-amd64.deb We hope kdump will be buildable from freebsd-utils after switch to 8.0 upstream series. See also http://lists.debian.org/debian-bsd/2009/11/msg00003.html, the netstat is now ready in our SVN ... Petr


text:
Lecicarbon A Suppository
Last Updated on eMC 27-Apr-2015 View changes | Aspire Pharma Ltd Contact details
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and breastfeeding
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
1. Name of the medicinal product
Lecicarbon A Suppository
2. Qualitative and quantitative composition
Each suppository of Lecicarbon A Suppository containsSodium hydrogen carbonate 0.500 g, sodium dihydrogen phosphate 0.680 g.Lecicarbon A Suppository contains (3-sn-Phosphatidyl)cholin (= soybean oil, lecithines, as phosphatides, 36 mg phosphatides per suppository).For a full list of excipients, see section 6.1.
3. Pharmaceutical form
Suppository.Lecicarbon A Suppository is a cream coloured, homogenous, torpedo shaped suppository; packed in PVC/PE blisters of five, with batch number and expiry date embossed.
4. Clinical particulars
4.1 Therapeutic indications
All forms of frequent constipation (habitual or chronic constipation), especially where the rectal emptying reflex is weak, constipation due to low-fibre food or insufficient exercise (bedridden patients), to ease bowel movements after operations or labour before child birth.Lecicarbon A Suppository can be used to evacuate the bowel prior to surgery or diagnostic procedures (e.g. x-rays, rectoscopy and before childbirth). Lecicarbon A Suppository can also be added if other laxatives have proved ineffective.
4.2 Posology and method of administration
PosologyUnless otherwise directed, insert one suppository into the rectum when needed. If necessary, this can be repeated after 30 60 minutes.The dosage is the same in adults, children and infants, taking care to use the appropriate type of suppository.Lecicarbon A Suppository is safe to use for long periods and are not habit-forming.
Method of administrationRemove from the packaging by separating one suppository from the strip. Grasp the plastic tabs in both hands and pull apart. Insert one suppository into the rectum. Insertion is made easier if the suppository is first dipped into water. Do not use oil or petroleum jelly as a lubricant.For a child, it may be necessary to press the two halves of the child's bottom together to avoid the suppository being immediately expelled.The onset of action is between 15 and 30 minutes.
4.3 Contraindications
This medicinal product must not be used in cases of ileus (intestinal obstruction), in case of all anal and rectal region diseases that can lead to an excessive absorption of carbon dioxide, especially in children and infants, and in case of hypersensitivity against soybean, peanut or to one of the excipients of Lecicarbon A Suppository. In the presence of toxic megacolon (pathological enlargement of the end of the large intestine due to various causes) the product should only be used with explicit permission of the treating physician. This medicinal product contains (3-sn-Phosphatidyl)cholin (= Soybean oil, lecithines). If you are allergic to peanut or soya, do not use this medicinal product.
4.4 Special warnings and precautions for use
None known and not likely in view of the pharmacological properties.
4.5 Interaction with other medicinal products and other forms of interaction
None known.
4.6 Fertility, pregnancy and breastfeeding
PregnancyLecicarbon A Suppository may be used during pregnancy after a careful risk to benefit evaluation of the treating physician. Based on current knowledge the effect of the expanding volume of the carbon dioxide may be negligible.BreastfeedingLecicarbon A Suppository may be used during breastfeeding. The developed carbon dioxide will not be excreted in the human breast milk.
4.7 Effects on ability to drive and use machines
None known.
4.8 Undesirable effects
Rarely Soya Lecithin has been known to cause allergic reactions.The insertion of the suppository can very occasionally cause a slight burning sensation, which quickly disappears.
4.9 Overdose
Not known.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Carbon dioxide producing drugs, ATC code: A06AX02Lecicarbon A Suppository functions by a physical induction of reflex bowel evacuation caused when carbon dioxide is liberated when the suppository contacts moisture.Carbon dioxide (CO2) is the main constituent of the gaseous products of metabolism which are formed on digestion of the intestinal contents. Of all the intestinal gases, it is the one which causes the most intense stimulation of movement of the rectum.Lecicarbon A Suppository overcomes constipation according to the same principle, exclusively via the supply of CO2 which is slowly released in fine bubbles from the suppositories after they are inserted into the rectum. The CO2 activates the intestinal movement and triggers the evacuation process within 15 30 minutes, without causing irritation, cramps or other side effects.
5.2 Pharmacokinetic properties
If any hydrogen carbonate is not converted to carbon dioxide it may be absorbed and excreted as hydrogen carbonate ions in the urine. Any absorbed phosphate will also eventually be excreted in the urine.
5.3 Preclinical safety data
Preclinical studies were not conducted. Systemic toxic effects are not to be expected. Carbon dioxide is a physiological intestinal gas.
6. Pharmaceutical particulars
6.1 List of excipients
• (3-sn-Phosphatidyl)cholin (= soya lecithin, phosphatides),• hard fat and• silica, colloidal anhydrous.
6.2 Incompatibilities
None stated.
6.3 Shelf life
18 months.
6.4 Special precautions for storage
Do not store above 25 °C.
6.5 Nature and contents of container
Each suppository is contained in a twin layer PVC and foil shell. The shells are supplied in strips of 5 or 6 suppositories in a cardboard carton.Original Pack Sizes containing 10, 30 or 100 suppositories of Lecicarbon A Suppository.Hospital Pack Sizes containing 50x10 or 500 suppositories of Lecicarbon A Suppository.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
athenstaedt GmbH & Co KGAm Beerberg 135088 Battenberg (Eder)Germany
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text
Aspire Pharma Ltd
4 Rotherbrook Court, Bedford Road, Petersfield, Hampshire, GU32 3QG, UK
Medical Information Direct Line
+44 (0)1730 231148
+44 (0)1730 231148
Customer Care direct line
+44 (0)1730 231148
Before you contact this company: often several companies will market medicines with the same active ingredient. Please check that this is the correct company before contacting them. Why?
Active ingredients
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text:
I had an extra 10x10 frosted chocolate cake that I didn't use today. What could I turn it into. I have a daughters birthday in two weeks, another one in 4 weeks and a son in 5 weeks. That son is also graduating. Anyone have any suggestions. I worked on a book cake that took me all day (I'm so slow). Now it's late and I don't have any ideas. Don't want to waste the cake and don't want to turn it into cake balls. Anyone have any creative juices flowing this late at night???
0 replies