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Conceived and designed the experiments: UJJ MSC. Performed the experiments: UJJ. Analyzed the data: UJJ YBP SRK. Contributed reagents/materials/analysis tools: YBP. Wrote the paper: UJJ SRK MSC.
Persimmon Leaf (PL), commonly consumed as herbal tea and traditional medicines, contains a variety of compounds that exert antioxidant, α-amylase and α-glucosidase inhibitory activity. However, little is known about the in vivo effects and underlying mechanisms of PL on hyperglycemia, hyperlipidemia and hepatic steatosis in type 2 diabetes. Powered PL (5%, w/w) was supplemented with a normal diet to C57BL/KsJ-db/db mice for 5 weeks. PL decreased blood glucose, HOMA-IR, plasma triglyceride and total cholesterol levels, as well as liver weight, hepatic lipid droplets, triglycerides and cholesterol contents, while increasing plasma HDL-cholesterol and adiponectin levels. The anti-hyperglycemic effect was linked to decreased activity of gluconeogenic enzymes as well as increased glycogen content, glucokinase activity and its mRNA level in the liver. PL also led to a decrease in lipogenic transcriptional factor PPARγ as well as gene expression and activity of enzymes involved in lipogenesis, with a simultaneous increase in fecal lipids, which are seemingly attributable to the improved hyperlipidemia and hepatic steatosis and decreased hepatic fatty acid oxidation. Furthermore, PL ameliorated plasma and hepatic oxidative stress. Supplementation with PL may be an effective dietary strategy to improve type 2 diabetes accompanied by dyslipidemia and hepatic steatosis by partly modulating the activity or gene expression of enzymes related to antioxidant, glucose and lipid homeostasis.
Persimmon (diospyros kaki) is a widely cultivated fruit in East Asia, and the persimmon leaf (PL) is commonly used for herbal tea and traditional medicines in South Korea, Japan and China. PL contains proanthocyanidins (also called condensed tannins), flavonoids and other compounds, which have a variety of pharmacological actions [1]–[7]. Flavonoids isolated from PL have antioxidant [1], hypotensive [2] and anti-allergic effects [3] and proanthocyanidins, the major polyphenol in PL, have anti-hypertensive and vasorelaxant effects [4]. Some in vitro studies have suggested that PL may also have beneficial effects on diabetes. For example, components from PL inhibited α-amylase, α-glucosidase and protein tyrosine phosphatase 1B activity [5]–[7], and stimulated glucose uptake in HepG2 cells and 3T3-L1 adipocytes [6]. However, there is relatively little known regarding the in vivo efficacy of PL for diabetes.
Type 2 diabetes, the most common type of diabetes, is one of the fastest growing and most costly metabolic disorders in the world. It is accepted that changes in lifestyle, such as increased fat intake and/or physical inactivity and decreased vegetable, fruits and whole grain intake, are responsible for the increasing the incidence of type 2 diabetes. Insulin resistance is a major underlying factor contributing to the development of type 2 diabetes, which can result in hyperglycemia, dyslipidemia, or hepatic steatosis. The liver is a key metabolic buffering organ that controls glucose and lipid homeostasis, and, in particular, hepatic insulin resistance can cause hyperglycemia through reduced glycogen synthesis and storage and a failure to suppress glucose production and release into the blood. In addition, hepatic steatosis is linked to insulin resistance, although whether the excessive accumulation of lipids in the liver is a cause or a consequence of insulin resistance still remains unclear [8]. Since hyperglycemia- and hyperlipidemia-induced reactive oxygen species is one of the major contributors of insulin resistance [9], the identification of antioxidant foods, which can improve insulin sensitivity, is crucial for the amelioration of type 2 diabetes and its complications.
We previously reported that powdered PL improved lipid profiles and suppressed body weight gain in rats fed a high-fat diet [10]. In this study, we investigated the anti-diabetic effect of PL in type 2 diabetic db/db mice that have an exacerbation of insulin resistance and hepatic steatosis [11]. We also examined the potential mechanisms of action, particularly focusing on the gene expression and activity of enzymes involved in glucose and lipid metabolism and oxidative stress in the liver as well as the lipid content in the feces.
PL was prepared as described previously [10]. PL was harvested in Sangju (Korea) and dried in the shade for a week. The leaf was powdered and passed through 60 mesh sieves. The total fiber and phenolic contents were analyzed by AOAC method and a modified Folin-Ciocaleu colorimetric method, respectively [12], [13]. For determination of total phenolic content, a solution containing extract or standard solution of gallic acid was mixed with Folin-Ciocalten reagent. After 6 min, 7% sodium carbonate solution was added to the mixture. The resulting solution was incubated for a further 90 min before absorbance reading was spectrophotometrically read at 760 nm. The total phenolic content was expressed as mg of gallic acid equivalents/g of powdered PL. The total flavonoid content was determined according to Moreno et al. [14] and was expressed as mg of quercetin equivalents/g of powdered PL. The total fiber, phenolic and flavonoid contents in the PL were 630 mg/g, 11.49 mg/g, 1.59 mg/g respectively.
Male C57BL/KsJ-db/db (db/db) mice were purchased from Jackson Laboratory (Bar Harbor, ME) at 5 weeks of age and maintained under standard light (12 h light/dark) and temperature conditions (22±2°C). The twenty db/db mice were fed a pelletized commercial chow diet for 2 weeks after arrival, and then the db/db mice were divided into two groups (n=10). Thereafter, the control group of db/db mice were fed a standard semisynthetic diet (AIN-76) [15], [16], while another group of db/db mice were fed a standard semisynthetic diet with the powered PL (5 g/100 g diet, w/w) for 5 weeks. The mice had free access to food and water ad libitum. At the end of the experimental period, the mice were anesthetized with ketamine after withholding food for 12 hours, and blood samples were taken from the inferior vena cava to determine the plasma biomarkers. In addition, the liver was removed after the blood was collected, then rinsed with a physiological saline solution, and immediately stored at −70°C. All procedures were approved by the animal ethics committee of Kyungpook National University (Approval No. KNU-2011-28).
Every week after 12 hours of fasting, the blood glucose concentration was monitored in the venous blood from the tail vein using a glucometer (Arkary, Japan). HOMA-IR was calculated according to the homeostasis of the assessment as follows (Eq. 1) [17]:
The blood was collected in a heparin-coated tube and centrifuged at 1,000×g for 15 min at 4°C. The plasma insulin and adiponectin levels were determined using an insulin RIA kit (Diagnostic Systems Laboratories, USA) and a sandwich ELISA kit (R&D system, USA), respectively. The plasma free fatty acid concentration was measured using an enzymatic non-esterified fatty acid kit (Wako, Osaka, Japan). Meanwhile, the plasma triglyceride, total cholesterol, and high-density lipoprotein (HDL)-cholesterol concentrations were measured spectrophotometrically using a commercial kit (Sigma Chemical Co.). The paraoxonase (PON) activity was assayed spectrophotometrically using the method described by Mackness et al. [18], which measured the increase in absorbance for 90 s at 405 nm and 25°C.
The feces from each group were collected daily for one week, and the hepatic and fecal lipids were extracted using the procedure developed by Folch et al. [19]. The levels of cholesterol and triglyceride in the liver and feces were analyzed with the same commercial kit as used in the plasma analysis.
The hepatic glycogen content was determined as previously described by Seifter et al. [20] with modification. Briefly, the liver tissue was homogenized in 5 volumes of an 30% (w/v) KOH solution and dissolved at 100°C for 30 min. The glycogen was determined by treatment with an anthrone reagent (2 g anthrone/1 L of 95% (v/v) H2SO4) and measuring the absorbance at 620 nm.
The hydrogen peroxide levels in liver were measured by Wolff's method [21]. FOX 1 (Ferrous Oxidation with Xylenol orange) reagent was prepared as the following mixture: 100 µM xylenol orange, 250 µM ammonium ferrous sulfate, 100 mM sorbitol, and 25 mM H2SO4. Fifty microliters of test sample was added to 950 µL FOX 1 reagent, vortexed, and incubated at room temperature for a minimum of 30 min at which time color development is virtually complete. The absorbance was read at 560 nm and the standard was linear in the 0~5 µM concentration range. The hepatic thiobarbituric acid-reactive substances (TBARS) concentration, as a marker of lipid peroxide production, was measured spectrophotometrically by the method of Ohkawa et al. [22].
The livers were removed from the mice and fixed in a buffer solution of 10% formalin. Fixed tissues were processed routinely for paraffin embedding, and 4-µm sections were prepared and stained with hematoxylin eosin (H&E); stained areas were viewed using an optical microscope with a magnifying power of ×200.
The hepatic cytosolic, mitochondrial and microsomal preparations were performed according to Hulcher and Oleson [23] with a slight modification, and the protein concentration was determined using Bradford's method [24].
The glucokinase (GK) activity was determined using a spectrophotometric continuous assay as described by Davidson and Arion [25] and Newgard et al. [26] with a slight modification, in which the formation of glucose-6-phosphate was coupled to its oxidation by glucose-6-phosphate dehydrogenase and NAD+ at 37°C. The glucose-6-phosphatase (G6Pase) activity was determined using the method of Alegre et al. [27] with a slight modification. The reaction mixture contained 40 mmol/L sodium Hepes (pH 6.5), 14 mmol/L glucose-6-phosphate, 18 mmol/L EDTA, both previously adjusted to pH 6.5, 2 mmol/L NADP+, 0.6 IU/mL mutarotase, and 0.6 IU/mL glucose dehydrogenase. The phosphoenolpyruvate carboxykinase (PEPCK) activity was monitored in the direction of oxaloacetate synthesis using the spectrophotometric assay developed by Bentle and Lardy [28] with a slight modification. A 1 mL final volume of the purified enzyme was pipetted with a reaction mixture (pH 7.0) containing 77 mmol/L sodium Hepes, 1 mmol/L IDP, 1 mmol/L MnCl2, 1 mmol/L dithiothreitol, 0.25 mmol/L NADH, 2 mmol/L phosphoenolpyruvate, 50 mmol/L NaHCO3, and 7.2 units of malic dehydrogenase into a Eppendorf tube. The enzyme activity was then measured for 2 min at 25°C based on a decrease in the absorbance at 340 nm. The fatty acid synthase (FAS) activity was measured according to the method of Carl et al. [29] by monitoring the malonyl-CoA-dependent oxidation of NADPH at 340 nm, where the activity was represented by the oxidized NADPH nmol/min/mg protein. The phosphatidate phosphohydrolase (PAP) activity was determined using the method of Walton and Possmayer [30]. The carnitine palmitoyl transferase (CPT) activity was determined according to the method of Markwell et al. [31] and the results were expressed as nmol/min/mg protein. The fatty acid β-oxidation was determined using the method of Lazarow [32] by monitoring the reduction of NAD to NADH at 340 nm, where the activity was expressed as the reduced NAD nmol/min/mg protein. The 3-hydroxy-3-methylglutaryl-coenzyme reductase (HMGR) activity was measured in the microsomes with [14C]-HMG-CoA as the substrate based on a modification of the method of Shapiro et al. [33], where the activity was expressed as the synthesized mevalonate pmol/min/mg protein. The acyl CoA: cholesterol acyltransferase (ACAT) activity in the microsomes was determined by the rate of incorporation of [14C]-Oleoyl CoA into cholesterol ester fractions, as described by Erickson et al. [34], where the activity was expressed as the synthesized cholesteryl oleate pmol/min/mg protein. Superoxide dismutase (SOD) activity was spectrophotometrically measured by the inhibition of pyrogallol autoxidation at 420 nm for 10 min according to the method of Marklund and Marklund [35]. One unit was determined as the amount of enzyme that inhibited the oxidation of pyrogallol by 50%. Catalase (CAT) activity was measured using Aebi's [36] method with a slight modification, in which the disappearance of hydrogen peroxide was monitored at 240 nm for 5 min using a spectrophotometer. A molar extinction coefficient of 0.041 mM−1cm−1 was used to determine CAT activity. Glutathione peroxidase (GPX) activity was measured using the spectrophotometric assay at 25°C, as described previously by Paglia and Valentine's [37] method with a slight modification. The reaction mixture contained 2.525 mL of a 0.1 M of Tris-HCl (pH 7.2) buffer, 75 µL of 30 mM glutathione, 100 µL of 6 mM NADPH, and 100 µL of glutathione reductase (0.24 unit). One hundred microliters of the solution was added to 2.8 mL of the reaction mixture and incubated at 25°C for 5 min. The reaction was initiated by adding 100 µL of 30 mM H2O2 and the absorbance measured at 340 nm for 5 min. A molar extinction coefficient of 6.22 mM−1cm−1 was used to determine GPX activity.
Total RNA was isolated from the livers by the guanidine thiocyanate-phenol method of Chomzynski and Sacchi [38]. For Northern blotting, the total RNA (20 µg) was separated on a 0.9% agarose gel containing 2.2 M formaldehyde and transferred to Nytran-Plus membranes (Schleicher & Schuell, Dassel, Germany). The membranes were then hybridized with a [32P]-labeled cDNA probe, washed at room temperature with 2× sodium chloride sodium citrate (SSC) containing 0.1% SDS followed by two washes at 65°C with 0.2× SSC containing 0.1% SDS, and exposed to X-ray film with an intensifying screen at −70°C. Thereafter, DNA probes were prepared from the mouse liver RNA using RT-PCR with the following primers: for GK, 5'-TTCACCTTCTCCTTCCCTGTAAGGC-3' and 5'-TACCAGCTTGAGCAGCACAAGTCG-3'; for G6Pase, 5'-AAGACTCCCAGGACTGGTTCATCC-3' and 5'-TAGCAGGTAGAATCCAAGCG CG-3'; for PEPCK, 5'-TGCTGATCCTGGGCATAACTAACC-3' and 5'-TGGGTACTCCTTCTGGAGATTCCC-3'; for Cu/Zn SOD, 5′-AGGATTAACTGAAGGCGAGCAT-3′ and 5′-TCTACAGTTAGCAGGCCAGCA G-3′; for CAT, 5′-ACGAGATGGCACACTTTGACAG-3′ and 5′-TGGGTTTCTCTTCTGGCTATGG-3′; for GPX, 5′-AAGGTGCTGCTCATTGAGAATG-3′ and 5′-CGTCTGGACCTACCAGGAACTT-3′; and for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 5'-TTGAAGGGTGGAGCCAAACG-3' and 5'-AGTGGGAGTTGCTGTTGAAGTCG-3'. The intensities of the mRNA bands were quantified using a Bio Image Whole Band Analyzer (50S, B.I. System Co., USA) and subsequently normalized based on the intensity of the respective GAPDH mRNA bands. For real-time PCR, complementary DNA was synthesized using Moloney murine leukemia virus reverse transcriptase (Fermentase, Burlington, ON, Canada), random hexamers, deoxyribonucleoside triphosphates, and 5 µg of total RNA. After first-strand complementary DNA synthesis, the RNA expression was quantified by a real-time quantitative PCR using SYBR green PCR reagnets (Applied Biosynstems, Foster City, CA) and the SDS7000 sequence-detection system (Applied Biosystems). Transcripts of the housekeeping gene GAPDH in the same incubations were used for normalization. The primer sequences were as follows: for ATP-citrate lyase (ACL), 5′–CAGCAAGCACTGTCAGAATA–3′ and 5′–TTAAAACTTGCATTCCCTTC–3′; for CPT, 5′-ATCTTCTAATCCCACCCAGT-3′ and 5′-AAAGCACCCATTACTTGAGA-3′; for diacylglycerol transferase (DGAT), 5′-ACTCCATCATGTTCCTCAAG-3′ and 5′-CTCTGCTTGTGAGAAGGAAC-3′; for PAP, 5′-GGGTTCTACTGTGGAGATGA-3′ and 5′-TGACAGTAGCTGTGATGATGA-3′; for peroxisome proliferator activated receptorγ (PPARγ), 5′–AGAGTCTGCTGATCTGCGAGC–3′ and 5′–TTCCTGTCAAGATCGCCCTC–3′; for stearoyl-CoA desaturase-1 (SCD-1), 5′–TAAGCTCAGTCTCACTCCTT–3′ and 5′–AAAAGATTTCTGCAAACCAA–3′.
All data were presented as the mean ± S.E. Statistical analyses were performed using the statistical package for the social science software (SPSS) program. Student's t-test was used to assess the differences between the groups. Statistical significance was considered at p<0.05.
First, we examined the effect of PL on hyperglycemia and insulin resistance in type 2 diabetic db/db mice. All db/db mice were diabetic when the experiment began, as indicated by the fasting blood glucose level (≥21.06 mmol/L) (Fig. 1A). The supplementation of PL suppressed the increase of the fasting blood glucose level from the 3rd week to the 5th week in the db/db mice. The plasma insulin level was not affected by PL supplementation, while PL improved HOMA-IR in the db/db mice (Fig. 1B&C). Furthermore, PL did not alter the plasma leptin level, yet it significantly increased the plasma adiponectin level (Table 1). There was no significant difference in food intake, body weight and body fat mass between the groups (data not shown).
To examine how PL ameliorated hyperglycemia, we determined the activity of the hepatic glucose-regulating enzymes, their gene expression and glycogen content (Fig. 1D–F). The GK activity and mRNA expression as well as glycogen content were significantly higher in the liver of the PL-supplemented db/db mice compared to the control db/db mice. In contrast, the supplementation of PL significantly lowered the activity of hepatic gluconeogenic enzymes, G6Pase and PEPCK. However, no difference was observed in the mRNA expression of hepatic G6Pase and PEPCK between the groups (data not shown).
Next, we evaluated the effect of PL on dyslipidemia and hepatic steatosis in the db/db mice. The plasma triglyceride and total cholesterol concentrations were significantly lower in the PL group than in the control group, whereas the plasma HDL-cholesterol concentration was significantly higher in the PL group (Table 1). Thus, an increased HTR and decreased atherogenic index were observed in the PL group. Furthermore, PL supplementation significantly lowered hepatic triglyceride and cholesterol contents compared to the control db/db mice, and liver weight was significantly lower in the PL group (Fig. 2A&B). Histological analysis of the liver also revealed lower numbers and size of hepatic lipid droplets in the PL-supplemented db/db mice compared to the control db/db mice (Fig. 2C).
To clarify the mechanism in which PL decreased the plasma and hepatic lipids levels, we examined the hepatic lipid-regulating enzyme activity and gene expression along with fecal lipids levels. The activity of the hepatic lipogenic enzymes, FAS, PAP, HMGR and ACAT, were significantly lower in the PL-supplemented db/db mice compared to the control db/db mice (Fig. 2D&E). PL also down-regulated mRNA expression of lipogenic transcription factor (PPARγ) and its target genes (ACL, SCD1, DGAT, PAP) in the liver (Fig. 2G). Moreover, the supplementation of PL significantly increased the fecal triglyceride and cholesterol content (Fig. 2H). The fatty acid oxidation as well as CPT activity and mRNA level were markedly lower in the PL group compared to the control group (Fig. 2F&G).
We next examined the effect of PL on hepatic lipid peroxidation, hydrogen peroxide levels, and antioxidant enzymes activities and their mRNA expression, which influence the regulation of glucose and lipid metabolism in the db/db mice. The lipid peroxidation and mitochondrial hydrogen peroxide levels were significantly lower in the liver of the PL-supplemented db/db mice compared to the control db/db mice (Fig. 3A&B). Hepatic GPX activity and mRNA expression was not different between the groups; however, SOD and CAT activities and their mRNA expression were significantly increased by PL supplementation (Fig. 3C&D). Furthermore, PL significantly increased the activity of PON in plasma (Table 1).
Type 2 diabetes is a metabolic syndrome with diverse pathological manifestations and is often associated with abnormal glucose and lipid metabolism. Previously, we reported that the supplementation of PL that is rich in fiber and phenolic compounds suppressed the body weight gain and lowered plasma and hepatic lipid levels in rats fed a high-fat diet [10]. Furthermore, several in vitro studies showed the possible beneficial effect of PL on glucose regulation. For example, PL inhibited enzymes involved in the digestion of carbohydrates (α-amylase and α-glucosidase) and the regulation of insulin signaling (protein tyrosine phosphatase 1B) [5]–[7]. However, no report has been published on the in vivo anti-diabetic effects of PL in type 2 diabetes. In this study, we firstly demonstrated that dietary supplementation of PL for 5 weeks ameliorated hyperglycemia, dyslipidemia and hepatic steatosis in type 2 diabetic mice, at least in part, by regulation of hepatic glucose and lipid metabolism and antioxidant status.
db/db mice are a widely used genetic model of type 2 diabetes since they exhibit most of the human characteristics of type 2 diabetes, including hyperglycemia, dyslipidemia and insulin resistance [11]. A recent study suggests that defects in hepatic insulin signaling contribute to the development of diabetes in C57BL/KsJ-db/db mice [39]. The liver is a major insulin-sensitive organ responsible for maintaining glucose and lipid homeostasis. A failure of insulin to increase hepatic glucose utilization and to suppress hepatic endogenous glucose production is a major factor contributing to hyperglycemia in diabetes [40]. The key enzyme responsible for the regulation of glucose utilization is GK that catalyzes glucose phosphorylation as the first step of storage of glucose as glycogen and glucose disposal by glycolysis [41]. Conversely, PEPCK and G6Pase are rate-controlling enzymes of gluconeogenesis in the liver [42]. We found that in the db/db mice, the supplementation of PL significantly decreased the fasting blood glucose level and HOMA-IR index, which primarily reflects hepatic insulin resistance [43]. These changes were accompanied by decreases in hepatic G6Pase and PEPCK activity and increases in hepatic GK activity along with glycogen content. Thus, these observations suggest that PL can promote hepatic insulin sensitivity and thus effectively regulate the activity of enzymes involved in hepatic glucose homeostasis, leading to lower blood glucose level in db/db mice.
The regulation of GK activity is primarily due to changes in the transcription of its gene [44]. We also found that the change in GK activity by PL was accompanied by its increased transcriptional level. In contrast, the gene expression of hepatic G6Pase and PEPCK was not affected. Similarly, a lack of regulation of G6Pase and PEPCK gene expression was reported following treatment with some phenolic compounds in rat hepatocytes, despite a significant reduction in glucose production and enhanced hepatic GK mRNA expression [45]. In addition, it is known that the suppression of hepatic glucose production by metformin results from the inhibition of G6Pase activity along with an increase in glycogen stores with minimal effects on the gluconeogenic gene expression in the livers of rats [46], [47]. Thus, we think that PL may act mainly by suppressing the activity of hepatic gluconeogenic enzymes independent of the transcriptional repression of gluconeogenic genes. Since elevated GK expression led to a reduced endogenous glucose production in the liver [48], it is possible that the observed decrease in activity of gluconeogenic enzymes in PL-supplemented db/db mice is related to the inhibition of the substrate flux through GK activation.
On the other hand, some studies have raised concerns about the manipulation of GK activator for diabetes treatment since a decline in glucose level in response to hepatic GK overexpression is accompanied by an increase in circulating lipids and hepatic lipogenesis [49], [50]. However, several lines of evidence suggest that hepatic GK activation does not alter plasma and hepatic lipid metabolism in normal and high-fat fed animals [49], [51]. The present results also showed that PL induced a marked decrease in triglyceride and cholesterol accumulation in the liver, together with the inhibition of activity of hepatic lipogenic enzymes involved in the synthesis and esterification of fatty acid (FAS, PAP) or cholesterol (HMGR, ACAT), which may subsequently reduce the formation of lipid droplets within hepatocytes and the secretion of triglycerides and cholesterol into the blood. Simultaneously, this effect could be related to the down-regulated expression of several lipogenic genes (ACL, SCD1, PAP, DGAT) as well as key transcription factor (PPARγ) in the liver. Normally, PPARγ is expressed at very low levels in the liver, but its expression is dramatically increased in animal model with insulin resistance and hepatic steatosis such as db/db mice [52]. The genetic deletion of hepatic PPARγ protected against hepatic steatosis in high fat diet-induced obese mice [53]. We also found that PL appeared to facilitate fecal excretion of triglycerides as well as cholesterol in the db/db mice, in accordance with our previous data on high-fat fed rats [10]. Accordingly, PL seemed to lower plasma and hepatic lipid accumulation by decreasing hepatic lipogenesis and increasing fecal lipids. Since inhibition of FAS induces an increase in hepatic malonyl-CoA which is a potent inhibitor of CPT [54], [55], a key enzyme involved in mitochondrial fatty acids uptake for oxidation [56], the reduced activity of hepatic fatty acid oxidation and CPT could be a secondary consequence of the decrease in hepatic FAS activity. Also, the reduced fatty acid oxidation might be associated with activated glucose utilization and a reduction in glucose production in the liver [57].
In addition to its role in regulating lipogenesis, it is known that PPARγ is required for transcription of the PEPCK gene in adipocytes [58]. PPARγ agonists such as pioglitazone and rosiglitazone were potent inducer of PEPCK gene transcription and enzymatic activity in adipose tissue of obese Zucker rats [59], [60]. Moreover, hepatocyte specific PPARγ-knockout mice showed reduced serum glucose level and PEPCK mRNA expression [53]. However, liver-specific disruption of PPARγ in leptin-deficient mice dramatically increased basal endogenous glucose production [61]. Also, PPARγ agonist, troglitazone, inhibited the expression of PEPCK gene by a PPARγ-independent, antioxidant-related mechanism, and other PPARγ agonists, including rosiglitazone and ciglitazone, had little effect on PEPCK gene expression in hepatocyte [62], suggesting that the regulation of PEPCK by PPARγ is cell-specific [63]. We also observed that PEPCK mRNA expression was not altered by PL supplementation, although the PL down-regulated hepatic PPARγ and its target lipogenic genes expression. In fact, the regulation of PEPCK gene transcription coordinated by the action of a number of transcriptional factors and various hormones, including insulin, glucocorticoids, retinoic acid, thyroid hormone, and cyclic AMP [64]–[66]. Thus, it is possible that the PEPCK gene expression in PL-supplemented db/db mice was controlled by cooperative interaction of multiple transcription factors and hormones involved in PEPCK gene regulation.
Oxidative stress has been implicated in the pathogenesis of diabetes and other metabolic syndrome, including fatty liver disease and cardiovascular disease. In particular, the mitochondria is a major source of reactive oxygen species (ROS), and the ROS generated from the mitochondria damages proteins, DNA, and lipids in the membrane components, which results in mitochondrial dysfunction [67], [68]. Under normal physiological conditions, ROS are continuously produced, and oxidative damage induced by ROS can be prevented by antioxidant enzymes, where superoxide anion is rapidly converted by SOD into hydrogen peroxide, which is eliminated by CAT and GPX. However, an imbalance between ROS production and antioxidant capacity can induce cell damage associated with diabetes. Increased ROS levels were observed in the liver of db/db mice [69] and the expression of the antioxidant gene was down-regulated in the liver of type 2 diabetic rats [70]. In contrast, overexpression of SOD or CAT protected against hepatic oxidative injury in the livers of db/db mice [68] or HepG2 cells [71]. We found that PL up-regulated the mRNA expression of SOD and CAT in the liver. In parallel with the enhanced antioxidant gene expression, hepatic SOD and CAT activity was increased in the PL-supplemented db/db mice, suggesting that the elevated SOD and CAT expression may be regulated at the transcriptional level. Thus, the decreased level of mitochondria hydrogen peroxide in the liver of PL-supplemented mice may be attributed to the improved hepatic antioxidant capacity, which may contribute to the decreased hepatic lipid peroxidation and provide protection against hepatic oxidative stress in type 2 diabetes.
We also found that PL significantly increased the plasma PON activity as well as the plasma HDL-cholesterol and adiponectin levels. Plasma PON is another antioxidant enzyme contained in plasma HDL, which protects LDL and HDL from oxidation by ROS, and possesses other multiple anti-atherogenic activities [72]. Serum PON activity is low in patients with diabetes and it has potential as a marker for atherosclerosis in diabetes [73]. Along with this enzyme activity, HDL-cholesterol is an independent predictor of atherosclerotic cardiovascular complications. Furthermore, the adiponectin concentration is positively correlated with HDL cholesterol and negatively associated with HOMA-IR, independent of age and BMI, in type 2 diabetic subjects [74]. Taken together, our findings suggest the potential protective effects of PL on atherosclerotic cardiovascular complications in type 2 diabetes.
In conclusion, our results show that dietary PL improved hyperglycemia by alterations in activity and/or mRNA expression of hepatic enzymes involved in glucose utilization and glucose production (Fig. 4). Furthermore, PL ameliorated dyslipidemia and hepatic steatosis through a combined decrease in hepatic lipogenesis and an increase in the excretion of fecal lipids, which seemed to be related to the enhanced responsiveness of the liver to insulin (Fig. 4). The beneficial metabolic effects were also related to decreased plasma and hepatic oxidative stress as well as increased adiponectin secretion (Fig. 4). Thus, we believe that PL is a promising anti-diabetic compound that will be helpful for improving type 2 diabetes, although further study is required to identify its active components that mediate the hypoglycemic, hypolipidemic and hepatoprotective effects of PL.
This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST) (No. 2011-0000920 and No. 2011-0022387). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Apple's new iPad Pro is an impressive machine, intended to replace your powerful laptop and become part of your work and leisure life. And it's also a bit borked.
Reports have been coming in from a number of users saying that any time they plug in their tablet it won't respond to the wake button or any touches. Charging is something we have to do with our techy devices quite regularly, so this could be a bit of an issue.
The company had admitted that some units are becoming totally unresponsive after charging and is advising users to try a hard reset to bring it back to life. This involves pressing the home button and the sleep/wake button for around 10 seconds. Hold it until you see the Apple logo, provided the tablet isn't completely broken which would be a separate issue.
While the issue doesn't seem widespread it is unusual for Apple to concede that one of their devices has a problem. And while the solution is fairly simple, it's something which is less than ideal - what if someone was using the tablet for work and plugged it in to get some extra charge, effectively losing whatever they were working on. And this in a device which could cost up to a staggering €1300.

subset: commoncrawl


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Currently 5.00/512345 Rating: 5.0/5 (Total votes: 1)
Rating: 5.0/5 (Total votes: 1)
Homebrew developer KazoWAR has released a new version of NDS Music Player, an alternative audio player for the DS that uses Nintendo's own SSEQ sequence format, allowing users to play tracks from commercial games.
Developer's note:
NDS Music Player is a homebrew that uses fincs' SSEQ Player to play SSEQ music off of ROMs on your SD card. You need to run SPSMaker on your computer to generate a SPS file for each game. The SPS files contain info for the game's SDAT files to make loading the music way faster than reading the sdat data directly from the ROM.


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"Fire is a language all its own. It's magical. Mysterious."
In pursuit of a healthy cuisine, chefs are adding vegan
Julia Child and I became good friends late in her life, when I moved to Boston and met her in person for the first
On special occasions and holidays, we want great food and we want fun. For chef Attila Bollok at Barton G. Los Angeles, every day
The only part of Thanksgiving better than the dinner itself is the next day, when we feast on leftovers. Sandwiches made with sliced turkey
Fried chicken, oh how you are loved. Crisp on the outside, moist inside and savory-sweet, fried chicken is solidly on the list of favorite
Here's the challenge. Create a daily spa menu with 1,000-1,200 calories. Do not use refined sugar or salt. Use fresh fruit, vegetables, low-fat animal
I've lived in Italy off and on since the 1970s, eating my way up and down the peninsula, shopping the markets, raising the vegetables


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House Sitter in Phoenix
House Sitting: I have been House Sitting for over five years for friends, family, and even friends of friends of friends. I have taken care of five animals at one time and the longest I have house sat was for three weeks. I follow specific instructions regarding pets, plants, and house cleaning and am no stranger to detailed schedules. I understand well that each animal and plant is taken care of differently for each family. I can walk the animals, play with them, feed them, wash them, etc. all depending on the needs of both the family and of the animal. I know the numbers to each vet office in the Phoenix Metropolitan area, but will go to the closest/preferred vet if the case arises. I possess a valid drivers license as well and can provide my own transportation. PAYMENT: I can work either over-night stays at the house, or once-a-day visits. The amount of animals does not affect price, but distance does. Overnight: Within a 25-mile distance from 24th and Thomas, $20 a day. Further than 25-mile, $25 Once-a-day: Within a 25-mile distance from 24th and Thomas, $15 a day. Further than 25-mile, $20 THINGS YOU SHOULD KNOW ABOUT ME: "I am an 18 year-old Female currently attending Arizona State University." This statement might strike as a red flag. Yes, I am a teenager and yes, I attend a well-known "party school." Nevertheless, I am focused solely on school work and my job. I am double-majoring in Biological Sciences and Chemistry and minoring in Marketing. I was an Honors Student in High School taking only AP and Honors Classes, graduated in the top 20%, and has over ten Academic medals. My hobbies are many. I love drawing, DIY projects, Pinterest, Piano, or reading. I'm a morning person, and go to bed early. I like to take morning jogs and sometimes get enough energy to hike a mountain (but I would have to be feeling really adventurous for that). I also work at a well-know discounted Retail, and do community service around-the-clock. REFERENCES: Upon Request.
House Sitter Details
|Email Address
|Phone Number
|602-653-... Confirmed
|Years of Experience
|Provider Type
Collect Mail
Feed Pets
Care For Plants
Take Out Trash/Recycling
|Daily Rate
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Don't believe all the negative that you read about santa rosa extended stay! I recently stayed here for 18 days while on business in Santa Rosa. Upon checking in I found the guest services very helpful friendly and attentive. My room was absolutely awesome. A small studio setup. Very masculine in design which I welcomed. WiFi worked great as did the smart flat panel Samsung. I especially liked the extra pillows on the bed. Great touch. They even allowed me to store my trailer onsite which saved me storage fees! Very accessible all the major highways-especially the 101. A great place for business travelers - I will definitely stay here again.
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After taking charge of this morning's training session with first-team coach Chris Hughton, director of football Pleat looked forward to Wednesday's game at Coventry.
"We will all focus our minds on the immediate future," Pleat said.
"There is no future in the past. That is sad, but true. We've just got to try to stabilise things as players will have all sorts of thoughts going through their heads.
"We've just got to be positive and get back on the winning trail, which breeds confidence. We'll pull through it. Decisions have been made and the club has to go on and be strong.
"Every game is important. We want to win games and would like to have a Carling Cup run. We want to do all the things that the supporters want for us.
"It will take a big effort. Everyone has to be true to themselves and I'm sure we can improve things."
What the fans think
Daniel Wynne, chairman of the Tottenham Hotspur Supporters' Trust, said: "I think the inevitable had to happen. I initially thought five games was not enough to judge, but after Saturday that changed."
Jim Duggan, editor of the Top Spurs website, said: "It was a tough decision but it was the correct one."
Messages on the internet chat forum "Spurs Web" generally supported the decision.
"I feel sorry for Hoddle but the board was right to let him go. He just simply lost control of things." - "Dragan"
"His playing memories aren't tarnished by his incompetence as a manager." - "Nuttynoah"
"Disgraceful decision. Six games is a joke. Sing for Glenn on Wednesday. The legend deserves it." - "Bobby Mimms"
"It is probably the right move but it still feels like somebody has just died." - "Big Dave"
- More about:
- Chris Hughton
- Coventry
- Newcastle United


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Members of Local 54 of UNITE-HERE in Atlantic City were among the union supporters who picketed Wednesday in front of the Service Employees International Union, or SEIU, headquarters in Washington, D.C.
SEIU has been fostering a "hostile takeover" of its union, assisting in the secession of members and attempting to raid UNITE-HERE jurisdictions, according to UNITE-HERE.
New York-based UNITE-HERE said about 300 members were picketing, some holding signs that read, "Shame on you SEIU!"
Ramona Oliver, a spokeswoman for the SEIU, said UNITE-HERE's claims are "clearly not factual." The SEIU represents about 2 million health care, building cleaning and janitorial workers nationwide.
Local 54 President Bob McDevitt said he is upset that SEIU president Andy Stern has not tried to support Local 54 as it prepares to renegotiate its contracts with 10 of the gaming halls in Atlantic City this summer.
Stern was previously in the resort in March, championing a new Gaming Workers Council to help dealers represented by the United Auto Workers union win contracts with their respective casinos.
The division between SEIU and UNITE-HERE has been mounting.
A group of UNITE-HERE members unhappy with the union's direction broke away last month and formed a new union, Workers United, which is affiliated with the SEIU.
The new union has been accused of being a "front group" for Stern and his attempts to raid UNITE-HERE, although Workers United leaders maintain that they are autonomous.
The struggle between the two groups has played out at Harrah's Chester, a casino and racetrack outside Philadelphia.
Last year, UNITE-HERE's Philadelphia Joint Board negotiated a contract to represent service workers at the casino.
But this year, the Philadelphia Joint Board decided to leave UNITE-HERE and join Workers United.
In mid-February, McDevitt said, 550 of 600 workers at Harrah's Chester signed cards to remain with UNITE-HERE and join Local 54 instead.
Elana Levin, a spokeswoman for Workers United, said the union had not heard of that event taking place.
"Local 54 has conspired with management at (Harrah's Chester) to deny workers the right to choose," Richard Minter, organizing director of the Philadelphia Joint Board, said in a statement.
A Harrah's spokeswoman was unable to talk about union representation at the casino.
E-mail Erik Ortiz:


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We help you find a Eastleigh accordion tutor. Accordion tuition are an excellent method to learn a stimulating new hobby, pick up a new skill and attain confidence with accordion. Please use our service to find Eastleigh accordion tutors and determine which suits your requirements so you can start your accordion lessons in Eastleigh immediately!
First Tutors: Music is the best way to find Eastleigh accordion teachers in the UK, helping you find Eastleigh accordion tuition close to you and Eastleigh tutors to assist with any instrument such as piano, violin or guitar. We can help you find Eastleigh accordion lessons or a Eastleigh accordion teacher to prepare for accordion exams and develop your accordion skills! Our search will order Eastleigh accordion teachers local to you by their hourly charges and distance from you.
If you are a accordion tutor and would like to offer accordion tuition services in Eastleigh or throughout the UK, please register with First Tutors: Music or find out more about us here. Becoming a Eastleigh accordion tutor is a brilliant way to improve your own skills through providing accordion lessons while helping others, all in your local Eastleigh area!


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This has been superseded by my Vanity Names add-on.
- Compatible XF Versions:
- 1.2
- 1.3
- 1.4
- Visible Branding:
- No
This is a relatively simple addon that will change your member URL's from:
If the username isn't available in the data passed to the link builder, then the addon will fetch it to the database. This is configurable via an option, as it may substantially increase queries.Code:members/<username>
Credits to http://mcbrawl.com for paying for development of this add-on.
This is a free add-on with no branding, however any payments for it's development are welcomed (but not necessary) via paypal at firstname.lastname@example.com
Unmaintained Username URL Parameter 1.0.6
Use the username instead on the user id...


text: To get from Messina to Lentini by train you can catch one of the 7 trains that everyday travel between these two cities. The first train to Lentini leaves from Messina at 05:25 and the last train departs at 20:05. If you choose a local train the trip lasts on average 01:44 hours. For your trip from Messina to Lentini by train you can choose to leave from one of Messina main stations: Messina Centrale On Wanderio you can compare all schedules, fares and railway companies to Lentini and book the best itinerary starting from Messina.


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A charming cottage in the old town area of Staithes just north of Whitby, The Bay Tree Cottage is a mere 2 minute stroll from the beach and perfect for a long weekend break, as a summer holiday retreat or a cosy winter bolt hole. This luxurious cottage is beautifully designed throughout, featuring 3 stunning double bedrooms including a newly refurbished master bedroom with en-suite Jacuzzi bath, and a seating area with outstanding views. Relax outside in the sunny secluded patio area with BBQ ideal for al fresco drinks and dining, or inside in front of the log burning stove.
Further luxury touches include a superb Shaker style kitchen with double range cooker and for those vistors keen on fishing, we supply a collection of fishing rods, crab lines and basic tackle. Children can enjoy great rock pooling down on Staithes beach when the tide is out, and the surrounding coast and North York Moors offers ample opportunities for bird watching, walking, cycling and more. The many delights of Whitby are within easy reach - the cottage is perfect for Whitby Festival breaks.
Stairs lead up to the first floor and bedrooms/ bathrooms including:-
An outside patio dining area is a real 'suntrap' and is equipped with garden furniture.
Midweek bookings (minimum 2 night stays) are available on request.
We are also adjacent to Kindly Light cottage and so can accommodate larger groups of up to 11 people if required.
Bay Tree Cottage is ideal for a seaside and countryside break being so close to Yorkshire coast and the moors. The cottage is situated in the traditional fishing village of Staithes. This area is rich in history - discover Captain James Cook and explore secret alleys and caves. Whitby, Runswick Bay, Sandsend and the North York Moors National Park are all within easy reach.
OLD JACK'S BOAT, the popular Children's TV programme on CBeebies is set in Staithes, and features Bernard Cribbins as 'Old Jack' and his dog, Salty. The programme is set in the cobbled streets and quaint cottages in the village as Jack and his friends tell stories of adventures in his old fishing boat - The Rainbow.
Book Mon to Fri in September, was £500 now £480
Offer expires 30th Sep 2017
This offer cannot be used in conjunction with any other offer
Book 3 nights Fri to Mon in September, was £405, now £380
Offer expires 30th Sep 2017
This offer cannot be used in conjunction with any other offer


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|Legal answers
|Legal guides
|School name
|Stanford Law School
|JD - Juris Doctor
|Brown University
Posted by anonymous
Dan provided a much-needed sense of calmness from start to finish. He constantly kept things in perspective and helped convey the "bigger picture", even when all I could focus on were my immediate fears. He was always available to answer my questions, even though they were probably very irrelevant to the case. His answers were always in-depth and I never walked away with doubts remaining. His knowledge of the law seemed to be without any flaw. His professional relationships with the courts and court officials proved invaluable. His impeccable ethics made myself and my family trust him completely. Even more impressive, it would seem that even the judge and opposing DA were aware of and respected his ethic. I may not have any other experiences to compare Dan to, but I cannot imagine a better criminal defense attorney. I would highly recommend Dan Barton to anyone in need of a criminal defense attorney.
Posted by anonymous
Dan is compassionate, knowledgeable, and personable. He knows the law and will use it to your advantage, ever working to keep a potentially uncomfortable situation as calm and as under control as possible, I hope to never need his services again, but now consider him a friend. I highly recommend him to anyone who does need his services.
Posted by anonymous
You cannot argue with results. Dan genuinely bonds with his client no matter what psychological state they may have fallen into due to pending criminal charges. His research and intelligence skills are superb. He's a very likeable guy. One of the few criminal defense attorneys you can trust right off the bat.
Jeffrey Hammerschmidt, Criminal defense Attorney
Relationship: Other
I endorse this lawyer. I have worked with Mr. Barton on the California State Bar Criminal Law Advisory Commission. He is very knowledgeable about criminal law. It is clear from my discussions with him that he is passionate about representing clients at the highest level.
Rolf Kruger, Family Attorney
Relationship: Worked together on matter
I endorse this lawyer. I often refer matters to Dan Barton when my client's are in need of a criminal defense attorney with complex issues. I have referred numerous clients to Mr. Barton and my client's have had excellent results.
600 University Avenue.
Palo Alto, CA, 94301


text:
Question about Teac P-A688 Turntable
I will add a picture of the configuration of the turntable
Posted by Allen on
above is a generic video that applies to almost all belt driven turntables including yours that will show how to install the belt and a few other things. if it keep coming off they can help you size a new one.
Posted on Feb 12, 2009
SOURCE: I have freestanding Series 8 dishwasher. Lately during the filling cycle water hammer is occurring. How can this be resolved
a 6ya expert can help you resolve that issue over the phone in a minute or two.
best thing about this new service is that you are never placed on hold and get to talk to real repairmen in the US.
the service is completely free and covers almost anything you can think of (from cars to computers, handyman, and even drones).
click here to download the app (for users in the US for now) and get all the help you need.
Posted on Jan 02, 2017
Tips for a great answer:
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Jan 01, 2014 | Teac P-A688 Turntable
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What do you think? Do you believe in God? Does the article change anything you believe?
I believe in God.
Asked by booklover545 at 3:09 PM on Sep. 18, 2012 in Religious DebateLevel 38 (104,764 Credits)
Answer by momto2boys973 at 10:05 PM on Sep. 18, 2012
Answer by RyansMom001 at 7:19 PM on Sep. 18, 2012
Answer by adnilm at 3:12 PM on Sep. 18, 2012
I think the more we learn, the harder it is to believe in the existence of any gods. At very least, it rules out the possibility of the god of the Abrahamic tradition as creator and ruler. Considering all we currently know about the universe, and to compare it to the god of the bible who is at once the creator, omniscient, omnipotent, omnibenevolent and omnipresent, it seems more than a bit unlikely. It doesn't add up. Whether people will begin to see it that way, and let go of their superstitions, is (unfortunately, in my opinion) as equally unlikely as the possibility of the existence of such a supernatural being.
Answer by jsbenkert at 4:09 PM on Sep. 18, 2012
Answer by sahmamax2 at 4:46 PM on Sep. 18, 2012
Answer by 3libras at 3:11 PM on Sep. 18, 2012
Change YES, as we learn more and more in regards to the Natural world around us there is less and less need for "super natural" entities to explain them. Will it ever completely disappear, No but some religions will certainly take some heavy blows from their unwillingness to change from prehistoric notions.
Answer by KristiS11384 at 5:30 PM on Sep. 18, 2012
Answer by bandgeek521 at 6:27 PM on Sep. 18, 2012
Answer by anng.atlanta at 3:29 PM on Sep. 18, 2012
Answer by Sebbiemama at 7:04 PM on Sep. 18, 2012
Next question in Religious Debate
Is religion so fragile that it can't stand up to scrutiny?
Next question overall
(Religion & Beliefs)
Working on CoExist Month for my Facebook Page... I need your help (ALL...


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Does Selphyl Work?
Can Injecting Your Blood Into Your Face Make You Look Younger?
A new procedure called the Selphyl System (self-fill, get it?) is purporting to "rejuvenate" patients (like the woman at right) by drawing blood, then using a centrifuge to separate the components out. Then, the platelets and fibrin are injected back into the face.
Supposedly, your body reacts to the injections by producing a bunch of collagen, thereby making your face appear fuller over time. Results take three weeks to develop and last for up to 18 months, and the procedure costs about $1,100. Not for me, but I can see it creating a lot of interest. What do you think?


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For sale by Yemi alaran-VERIFIED SELLER VERIFIED25 Jan 12:44 pmIsolo, Lagos
Window 8.1 Edition. Processor: Intel Core CPU M 520 @2.40GHZ (RAM) : 3.00GB. System type:64-bit Operating system, x64-based processor. 150GB Hard Drive. Supplied without the Power Cord.
Call: [to get phone number click on show number button] to arrange for inspection
Location: Okota, Lagos.
Stay safe!
Watch out for:


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In reply to Daniel Dennett's attack on "belief in belief", Patrick Appel wrote the following: I consider myself an agnostic or pantheist depending upon how you define such labels but still have an acute nostalgia for my Catholic upbringing. I find the certainty of some atheists and most fundamentalists deeply grating. In reply, one of [Read More…]
On The Alleged Intolerance Of The New Atheists Towards "Faitheists"
July 26, 2009 by Leave a Comment
Like Camels With Hammers and Patheos Atheist on Facebook!


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République du CanadaTimeline: Scenario: Futatsuiwa of Sado
|Canadian Krone
The Republic of Canada was a nation in Vinland. It was turned into a republic in 2020. When the United States collapsed in 2035, Canada took the advantage and invaded parts of New England and annexed all the former states above New York. Canada has some influence over the former nation, along with Mexico, Russia, China, and Japan.


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The other day I was searching for some java applications for my Nokia phone, when I found this neat little app called 'Snaptu'. What it is, is basically a placeholder for other apps, including popular social networks (Facebook, Twitter, LinkedIn), your favourite tech blogs (Mashable, TechCrunch, Ars Technica and LifeHacker), sports updates, news, weather and pretty much anything else you would want to be informed of.
Now the beauty of this app, is that :
- It's cross-platform and runs on most mid-range phones, so you don't need to be sporting the latest QWERTY or touchscreen device to use it.
- It's completely free of cost.
- All the 'apps' have very elegant, clean interfaces, focussing on usability.
The third point is probably the most important. What I mean is, that these apps are standalone applications, not just links to their respective websites. So if you're using say, the Facebook app, you'll see a nice home screen with large icons telling you about your notifications, messages, requests etc. Similarly, the twitter app makes tweeting, replying, searching, following and all your twitter activities really simple. Same goes for the blogs, where you'll see all recent posts' topics in a highly-readable interface; click on it and you can access the whole article.
While on the topic of mobile apps, also check out eBuddy and Nimbuzz – both are multi-protocol chat clients for your mobile device, both are cross platform, free and support all popular chat accounts. Go ahead and give these a try, you'll be surprised with what your phone is capable of !


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Flocked nasal swab versus nasopharyngeal aspirate for detection of respiratory tract viruses in immunocompromised adults: a matched comparative study
Several studies have compared nasal swabs to the more invasive nasopharyngeal aspirate (NPA) for detection of respiratory viruses. Mostly, the comparisons have been performed on immunocompetent children with upper respiratory tract symptoms. The results range from a relatively poor sensitivity for the swabs to an even higher sensitivity than for the NPA. We aimed to investigate the sensitivity of a flocked nasal swab (fNS) on immunocompromised adults with febrile neutropenia.
During 16 months, adults with a hematological disorder presenting with febrile neutropenia were enrolled in the study. Paired samples of the fNS and NPA were collected in the outer part of the nasal cavity and the nasopharynx, respectively. The samples were analyzed regarding a panel of 15 respiratory viruses by means of quantitative polymerase chain reaction. Furthermore, as an indirect measure of cell yield by either method, the copy number of the human beta actin gene was also determined. Cohen's kappa was calculated as a measure of agreement of the results obtained from either method. Wilcoxon signed-rank test was used for comparison of cell yield.
A total of 98 paired samples from a total of 89 patients were collected. Twenty of the pairs had virus detected in at least one of the specimens; 11 in both, 7 in NPA only, and 2 in fNS only. For the fNS, the overall sensitivity for any virus and for rhinovirus only was 65% and 78%, respectively. NPA was significantly superior to the fNS in collecting epithelial cells.
We found the overall sensitivity of 65% to be too low to replace NPA with this sampling technique in this patient category.
A number of studies have compared different sampling techniques for detection of viruses in the upper respiratory tract in immunocompetent children
Between January 2008 and May 2009 adults with any hematological disorder presenting at the Karolinska University Hospital, Stockholm, for febrile neutropenia (auricular temperature >38.0°C twice or ≥38.5°C at one occasion, and an absolute neutrophil count ≤500 cells/mm3) were asked to participate in this study. The patients were allowed to participate more than once provided that an afebrile period of at least three weeks separated the episodes of febrile neutropenia. At admission, the patients received empirically administrated broad-spectrum antibiotics; ceftazidime or piperacillin-tazobactam.
Collection and storage of material
The collection was made within 72 hours from onset of fever. The fNS with a nylon fiber tip (COPAN, art. no. CP552C) was inserted at least 20 mm and rotated inside each nostril. Then, the NPA was obtained by insertion of a sterile catheter (no. 8, Mediplast, Sweden) into the posterior nasopharynx and pulled back while applying gentle suction. Finally, 2-3 mL of sodium chloride was sucked into the trap. Both specimens were obtained without instillation of any solution into the nostrils. The specimens were stored without any medium in room temperature and transported to the laboratory within six hours. The NPA was stored in its collection tube in minus 80°C. The fiber tip of the fNS was put in 500 μL RPMI 1640 (Sigma-Aldrich, St. Louis, MO) and shaken for 30 minutes. The suspension was stored in minus 80°C.
Detection methods
A total of 400 μL of each sample was extracted and then analyzed regarding presence of nucleic acids from adenovirus, bocavirus, coronavirus, enterovirus, influenzavirus A+B, metapneumovirus, parainfluenzavirus 1-3, rhinovirus, and RS-virus. The extraction method and the quantitative polymerase chain reaction (qPCR) assay are previously described
After giving written informed consent the patients were enrolled. The study was approved by The Regional Ethical Review Board in Stockholm that handles applications for research at Karolinska University Hospital.
Statistical methods
Positivity by either method was used as gold standard for presence of viruses. Cohen's kappa was calculated as a measure of agreement of the results obtained from either method
A total of 98 episodes of febrile neutropenia occurring in 89 patients were included in the study. Based on episodes, the mean age was 55 ± 15 years (43 females, 57 ± 13 years; 55 males, 53 ± 16 years) and the median neutrophil count <100 cells/mm3 (<100-500). As underlying hematological disorder, acute leukemia and myelodysplastic syndrome predominated (n = 42, 43%) followed by non-Hodgking lymphoma (n = 33, 34%) and myeloma (n = 13, 13%). The remaining diagnoses were chronic lymphocytic leukemia (n = 6, 6%) and Hodgking's lymphoma (n = 4, 4%). In total, 49 (50%) of the patients were on antiviral prophylaxis with aciclovir. The patients were sampled within one day from admittance (n = 54, 55%), but due to practical obstacles, in 32 (33%) and 9 (9%) of the cases, the samples were collected on the second and third day after admittance, respectively. In total, 98 paired samples collected with fNS and NPA respectively, were obtained. A total of 20 of the pairs had virus detected in one or both of the specimens; 7 exclusively in NPA and 2 exclusively in fNS (Table
Table 1
Detection of viruses in NPA and fNS specimens compared with total viral findings by either method
No. of samples in which virus was detected by:
Total no.
Sensitivity a for fNS (%)
Mean difference b in Ct values (range)
Agreement c between NPA and fNS (95% CI d )
Both methods
NPA only
fNS only
3.2 (-2.0-6.5)
0.86 (0.68-1.05)
2.2 (5.6-9.9)
Influenza A
Influenza B
Any virus
5.1 (-2.0-15.5)
0.66 (0.44-0.87)
NOTE. NPA, nasopharyngeal aspirate; fNS, flocked nasal swab; Ct, cycle of threshold; CI, confidence interval.
a Percentage of positive samples from fNS in relation to the total number of pairs with positive results from any of specimens.
b The Ct value for the flocked nasal swab minus the corresponding Ct value for NPA.
c Cohen's kappa: >0.8, almost perfect agreement; 0.6-0.8, substantial agreement; 0.4-0.6, moderate agreement; <0.4, poor agreement.
d CI, confidence interval.
The amount of cells yielded by NPA approximated by ACTB copy numbers was significantly larger than by fNS with a mean difference of 4.2 × 105 cells/mL (
We compared the efficacy to collect specimen for viral detection between fNS and NPA. According to Landis and Koch's
Thus, the difference in sensitivity for the fNS and NPA could have several reasons; biological and technical. One obvious biological reason is the fact that two different anatomical sites are investigated; one technical explanation could be that suction is superior scratching for collecting adequate amount material. The production of mucus that transports the viral nucleic acids in an anterior direction to the fNS's sampling site may be an important parameter. In this patient category, the lack of a competent immune response could reduce the mucus-production. Taking the above into account, the depth of the sampling with the fNS probably plays an important role. However, a deeper penetration could cause even more discomfort than does the NPA.
In contrast to our findings, several groups have reached good sensitivity using the fNS in the outer part of the nose and concluded it comparable to NPA
This study has several limitations. The time interval between fever onset and sampling varied between the patients, and they did not necessarily have respiratory tract symptoms. Furthermore, the patients suffered from different underlying diseases. However, this reflects the clinical reality and as both sampling methods were used at the same time point in the same patient, the comparison is still valid. The foremost important limitation is the low number of positive samples on which the calculation of sensitivity is based. However, the upper limit in the 95% confidence interval for the overall sensitivity was 85% which is still a questionable value for replacing an established method.
In summary, the NPA was superior to the fNS in collecting epithelial cells. Furthermore, we also found lower sensitivity for the fNS than for NPA in detecting respiratory viruses in these immunocompromised adults. For detection of rhinovirus it was slightly better, but still not appropriate, according to our judgment, for clinical use in this patient category. With an insertion depth comparable to what other groups have used we found lower sensitivity for the fNS than previous investigators. Less mucus production and consequently less anterior transport of viral nucleic acid in immunocompromised individuals may explain this finding.
On the basis of our findings, fNS sampling of the nares for viral detection in immunocompromised individuals cannot be recommended until further large studies have revealed more promising results.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
All authors have been active in the interpretation of data, the writing of the manuscript and the process of its internal revision as well as the final approval for submission. Furthermore, LÖ has contributed to the study regarding overall design, inclusion of a portion of the patients, acquisition of clinical data, and analysis of data. MW has contributed with laboratory design, compilation, and analysis of data. MRÖ contributed to the study regarding laboratory design, performance of the laboratory work and interpretation of raw data. ON has contributed to the overall design, inclusion of a portion of the patients, and analysis (including statistics) of data. KB was involved in the overall design, and analysis of data. TT contributed to the study regarding initiation and overall design, inclusion of a portion of the patients, acquisition of clinical data and analysis of data.
We thank all involved patients. We are indebted to the nurses and study nurses at the Hematology Center and the Department of Emergency, Karolinska University Hospital, for their dedication to the study. We acknowledge the staff at the Department of Clinical Microbiology at Karolinska University Hospital. Grants were received from the Stockholm City Council/Karolinska Institutet and from the Swedish Children's Cancer Foundation.
A comparative study of nasopharyngeal aspirate and nasal swab specimens for the diagnosis of acute viral respiratory infection
Comparative study of nasopharyngeal aspirate and nasal swab specimens for detection of influenza
Comparing nose-throat swabs and nasopharyngeal aspirates collected from children with symptoms for respiratory virus identification using real-time polymerase chain reaction
Comparison between pernasal flocked swabs and nasopharyngeal aspirates for detection of common respiratory viruses in samples from children
Comparison of flocked and rayon swabs for collection of respiratory epithelial cells from uninfected volunteers and symptomatic patients
Comparison of four nasal sampling methods for the detection of viral pathogens by RT-PCR-A GA(2)LEN project
Comparison of nasopharyngeal aspirate and nasal swab specimens for detection of respiratory syncytial virus in different settings in a developing country
Comparison of nasopharyngeal aspirate and nasopharyngeal swab specimens for respiratory syncytial virus diagnosis by cell culture, indirect immunofluorescence assay, and enzyme-linked immunosorbent assay
Comparison of respiratory virus detection rates for infants and toddlers by use of flocked swabs, saline aspirates, and saline aspirates mixed in universal transport medium for room temperature storage and shipping
Development and implementation of a molecular diagnostic platform for daily rapid detection of 15 respiratory viruses
Nasal swab versus nasopharyngeal aspirate for isolation of respiratory viruses
Nasopharyngeal swabs and nasopharyngeal aspirates equally effective for the diagnosis of viral respiratory disease in hospitalized children
Rapid painless diagnosis of viral respiratory infection
RSV testing in bronchiolitis: which nasal sampling method is best?
Respiratory viruses, a common microbiological finding in neutropenic children with fever
Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center
The measurement of observer agreement for categorical data
Most human metapneumovirus and human respiratory syncytial virus in infant nasal secretions is cell free
Pre-publication history
The pre-publication history for this paper can be accessed here:


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Bookstore | NONFICTION | TECHNOLOGY & ENGINEERING | ENGINEERING
I am not a climatic scientist; I am an experienced electrical engineer, drawn to study this subject by the peculiarity of the news I was observing. And it became obvious, very quickly, that something weird was going on. So I began to collect data, news, and other factual information that gradually became available. I have now assembled a wide range of proven, factual details on global warming (which became climate change when warming stopped in 1998 and temperatures began to drop), the claims and counter claims that have been published over the years, and some of my own observations arising from an engineering point of view. My purpose is to put all of the facts I have assembled in one location, for ease of observation and analysis, and to show the absolute foolishness involved.
Others who also became interested have seen much of this information before, reported as individual elements or events, and responded to one at a time. In each case, global warming enthusiasts have responded to each individual weakness reported with the comment that, "yes, that was one little problem … but with all things considered, man-made global warming is `settled science.'" It will be interesting to see their responses to the entire range of factual information as developed by reputable scientists and engineers, some of which are listed below, when all are presented in detail and absolutely refute the idea that, "man-made global warming is `settled science.'"
· Surface and marine temperature measurements - - totally lacking in the accuracy necessary to detect the small variations involved. We show that, absolutely.
· Global temperatures have not affected the amount of carbon dioxide in the atmosphere -- they have no relationship to each other. We present data to show that absolutely. Global warming cannot possibly be causing an increase in CO2. Human's activities are exonerated, absolutely.
· Satellite measurements have been shown to be highly inaccurate - all records since their installation in 2000 are exposed as highly erroneous. Reports from the Great Lakes area helped that.
· The terrible environmental disasters created by global warming, as presented by UN reports. are shown to be untrue.
· The glaciers haven't disappeared, as reported - failing sensors missed an area the size of California.
· The "scientists" engaged in improper activities to change temperature-record data to suit their contentions have been exposed; details are shown, absolutely. Russia helped with the revelations.
· The global-temperature data from the four responsible agencies do not agree. The agencies do not share expertise, and the differences in their data, one to the other, differ more than the small variations in contention. The average yearly temperature rise from the year 1850 to that of 2008 was only 1.38 ºF. The existing sensor locations will not allow that degree of accuracy.
· Temperatures were higher 1000 years ago, than they have been in the twentieth century. The "scientists" efforts are shown as they struggle to lower the temperatures of those early years.
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Playing Ubisoft's "Watch Dogs," arguably the most-hyped game of the year, give players an incredible sense of power as they step into the role of Aiden Pearce, a professional hacker seeking revenge after a job leads to the death of a close family member. Originally slated to release alongside the new Xbox One and PlayStation 4 to catch holiday season sales, Ubisoft made the risky decision to push the game's release date back to Tuesday -- only raising the bar that it had to hit.
It delivers on its promise to provide players with a hacker's playground -- an endless buffet of data and smaller quests to keep you occupied for hours, even without touching the main storyline of techno-vengeance.
Which, sadly, is a good thing. Because while "Watch Dogs" is very fun to play, it hardly tugs at the heartstrings or gets your brain clicking in quite the way that many people wanted it to. Set in a version of Chicago that's been enabled with a smart grid -- networked cameras with facial recognition among other things. In light of the leaks by former National Security Agency contractor Edward Snowden, as well as growing calls for companies to reveal just how much data they collect from their customers, the sort of nonchalant hacking that players engage in as Pearce should be ripe for better commentary. Ubisoft had all the components to make something more than a fun game and continue the elevation of the video game as a narrative device. Certainly, at the very least, for a pointed sidequest or two about morality. Instead, there's only, at best, a cursory discussion of what a wired society gains and loses by being so plugged in.
"Watch Dogs" does come with a moral compass score of some kind -- reputation -- but it doesn't rely on what you do with information that comes your way. Instead, your reputation can be improved by injuring cops rather than killing them, or deciding not to mow down pedestrians with your car, "Grand Theft Auto" style. A good reputation convinces the people of Chicago that you're doing things for the greater good; a bad one will likely get the cops on your tail. And sure, you can build in your own ideas of data morality -- I, for example, decided against hacking the bank account of a person that the game told me was a) making $28,000 per year and b) was recently diagnosed with lymphoma. (I know. I should expect a medal for that.) But the game doesn't really address any of that.
The weaker story is a shame, because the game itself is really fun; fun enough, even, to balance a somewhat anemic narrative. Players can run around as they wish in the connected Chicago, wielding an all-powerful smartphone instead of a gun -- though you can wield that, too -- in order to reach their objectives. That makes it all the more disappointing that the story game skims over a chance to really examine the ethics behind what it means to be the triggerman behind a hacking attack.
And, man, can you ever attack. Your magic phone lets you tap into the smart grid of cameras and traffic lights, explode underground pipes and short out transformers, all by getting them within your line of sight. Sure, it makes you feel a little over-powered. But it's sure fun to be able to manipulate your surroundings so easily, especially when you're just starting in the game. There's no learning curve here, really, just a superphone that immediately lets you knock out the power at a major city landmark with very little effort. From there, you only get more powerful, getting the opportunity to specialize Pearce's skill set to make him better at getting into combat or at making MacGyver-like aid devices to help you sneak past your enemies instead.
There's also quite a bit of driving in the game, which frankly makes you happy that Ubisoft opted to make all that hacking so easy to do. The best parts of the game are when you get into a good rhythm of driving, hacking and occasionally shooting your way through a mission that makes you feel like you've earned all the skill that you wield. Multitasking also gives the game the opportunity to show off its next-gen credentials. On both the Xbox One and PlayStation 4 copies provided by Ubisoft to The Post, the game looks good, though admittedly not quite as good as it looked in its initial Electronic Entertainment Expo demo in 2012.
"Watch Dogs" does deliver on its next-gen potential, however, with its multiplayer missions -- something I'll have to test out more thoroughly now that the game is open to more people -- to let you collaborate on attacks, go head-to-head, play a sort of digital capture the flag, hold drag races or free roam with friends to wreak some merry havoc.
All that balances out the fact that you're not really thinking about the morality of anything you're doing, in character. In fact, you pretty much have to create your own drama. Even Pearce's storyline, which should be ripe for wringing out drama, isn't all that well-crafted. Pearce himself is too neutral a protagonist -- so distant that he becomes hard to relate to even when you're controlling him. He wrestles with some weighty issues through the game, but I never felt all that invested in his moral dilemmas because they never really aligned with the ones I was feeling as a player.
That missed opportunity bruises an otherwise strong game that's launching to high expectations. But, overall, "Watch Dogs" is a strong game, and certainly one worth picking up if you have a PlayStation 4 or 3, Xbox One or 360, or want to grab it on PC. Just don't expect it to spark too many philosophical discussions.


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Nevada vs. San Francisco - Postgame Notes
University of Nevada Men's Basketball
Dec. 15, 2012
University of Nevada Men's Basketball
Postgame Notes
- Nevada improved to 7-4 after defeating San Francisco (5-3) 59-51 today.
- Nevada's fourth-year head coach David Carter is now 69-43 at Nevada. The 69 wins are ninth most in school history.
- The 59 points for Nevada is a season low as is the 51 by USF. The 51 points is the fewest points allowed by Nevada this season. The previous low was 56 to Cal Poly on Tuesday.
- Nevada has won three in a row for the second time this season.
- The Wolf Pack is 6-1 at home after today's victory.
- For the second game in a row Nevada held a double figure rebounding advantage 45-30. On Tuesday the Pack outrebounded Cal Poly 47-31. On the offensive backboards Nevada held a 14-7 advantage today.
- The two teams combined to go four-for-38 from behind the arc. Nevada was two-for-23 and USF two-for-15.
- Deonte Burton scored a game-high 14 points. It is seventh time he led the Pack in scoring and sixth time he posted a game-high.
- Kevin Panzer and Jordan Burris each had seven rebounds for Nevada. It was the third time that each led the team in rebound which is tied with Cole Huff for the most by a Nevada player this year.
- Burris was the other Pack player in double figures finishing with 11 points. Since being inserted into the starting lineup the last four games he has scored in double figures three times. Tuesday he totaled 13.
- For the seventh time this season the Pack bench outscored its opponent, 16-7.
- Malik Story had his streak of seven games scoring in double figures snapped finishing with seven.
- Burton and Story have started all 78 games of their Nevada careers.
- Nevada hosts Cal State San Marcos on Friday at 7 p.m.


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2009 Volkswagen Routan - Consumer Review
Average Consumer Rating
Total Reviews
SEL Passenger Minivan (4.0L V6 6-speed Automatic)
Build Quality
Reliability Value
Build Quality
Reliability Value
VW reputation intact
By late74C on
Vehicle2009 Volkswagen Routan SEL 4dr Minivan (4.0L 6cyl 6A)
ReviewJust purchased my new VW Routan last weekend as part of a cash for clunker deal. Have an SEL w/trim pkg 3 and navi. This will be our 3rd minivan since '90 (a '90 and '97 Dodge Gr Caravan) and so far like this one the best, lot's of little extras, comfy seats, great power and ride. Only rated it an '8' on reliability as we had a 'no-start' situation this past Monday but this is the reason for the review -- VW's roadside assistance arranged a tow to the dealer who handled it quickly -- it turned out to be loose connections in the master fuse panel. We have multiple cars so it was no bother as well as they updated the navi system once a complete check of electrical was done. Great job VW!
Best FeaturesPower (for a minivan) from 4.0L, nice interior and seats, remote start, navigation and backup camera, smooth ride, those checking out minivans should check out a Routan
Worst FeaturesHopefully no more gremlins, but nice to know VW offers high level of customer care as well as 3 year free maintenance
Recommend (0) (0)
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|Message view
|« Date » · « Thread »
|« Date » · « Thread »
|Costin Manolache <cmanola...@yahoo.com>
|Re: [5.0] Monitor servlet
|Wed, 05 Mar 2003 15:44:36 GMT
Remy Maucherat wrote: > Hi, > > I proposed that to Costin a few days ago, but got not so enthusiastic > comments. > The idea would be to add a new monitor servlet to the manager webapp. It > would generate data similar to http://www.apache.org/server-status. It > would mostly (exclusively ?) use JMX to retrieve the components > statistics. I'm not so enthusiastic for few reasons. We still have a lot of work to do in our core area - and it seems the ammount of time most people have is limited. +1 on extending the manager servlet to also display monitoring data, and to use the new JMX model - if 5.0 will use recommend using JMX to control tomcat, the manager should be an example of that instead of using the internal APIs. /manager is also close to /server-status ( or /jkstatus ). There are 3 JMX consoles available ( each JMX impl. has one ). A generic console would be nice - but it doesn't belong to tomcat ( maybe in commons). > That's not a high priority task for me, but something I'd like to get > done eventually, and I'm looking for some feedback. I understand that > there are existing agents for JMX that can be used to provide more > powerful remote access to the statistics (HTTP, RMI, etc), but these > tools do not have the ability to give a user a quick and comprehensive > look at the Tomcat status (although they allow much more complex > operations, and it's not my objective to replace them). For remote statistics - I added a small experimental remote-JMX mechansim for mod_jk ( which obviously can't support direct JMX ), and I plan to extend it and merge it in modeler. IMO any generic JMX effort should be in commons ( modeler or a different component ). Costin --------------------------------------------------------------------- To unsubscribe, e-mail: email@example.com For additional commands, e-mail: firstname.lastname@example.com
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text: I started to make one of these, and when i finally got the needle all the way through, it cooled to fast and now my needle is stuck in it. So i have squered (sp?) a poor little guitar playing alien through the head. Any suggestions on how to get it out?


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|Product Profile
They pack that crunch that we all love in our potato chips, along with a cheesy and bacon flavor that adds to the appeal of these snack chips. These chips are loaded with flavor. TGI Friday's Cheddar & Bacon Potato Skins snack are made from real potatoes and real potato skins to give you thick, crunchy chips that deliver big cheddar and bacon taste.


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Vogue 7090; ca. mid to late 1960s; One-Piece Dress. Semi-fitted, straight dress with pockets in side front seams has softly folded standing collar; full-length shirt sleeves or sleeveless.
Featured in Vogue Patterns Counter Catalog December 1967
Links to reviews/blog posts Edit
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Gallery Edit
[insert your photos of this pattern made up]
Wishlist Edit
[insert your username, and make sure your preferences allow for people to contact you via e-mail. Do not list your email address here!]


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|SVU, Episode 1.20
|Production number: E0924
First aired: 5 May 2000
| Written By
Michael R. Perry
Directed By
Alexander Cassini
The police apprehend a man who appears to be one of the two people involved in an old rape case where the victim was a famous TV reporter.
Plot Edit
Television reporter Sarah Logan refuses to let her recent rape get her down and talks about her experiences on the air which leads to the arrest of a young man that the police feel is responsible by Benson and Stabler, as Munch finds himself forming a bond with Sarah.
Summary Edit
Episode summary
Cast Edit
Main cast Edit
- Christopher Meloni as Detective Elliot Stabler
- Mariska Hargitay as Detective Olivia Benson
- Richard Belzer as Detective John Munch
- Michelle Hurd as Detective Monique Jeffries
- Dann Florek as Captain Donald Cragen
Recurring cast Edit
- Reiko Aylesworth as A.D.A. Erica Alden
- Peter Francis James as Judge Kevin Beck
- Josh Pais as Attorney Robert Sorensen
Guest cast Edit
- Jennifer Esposito as Sarah Logan
- Daniel Sunjata as Bomb Squad Officer
- Jayce Bartok as P.K.
- Kristen Lee Kelly as Krieger's Date
- Christopher Evan Welch as William Lexner
- Patrick Fitzgerald as Tommy McConaugh
- Juan Carlos Hernández as Prison Source
- Michael Medico as EMT
- Richard Petrocelli as Buck
- Richard V. Licata as Bartender
- Christa Scott-Reed as Producer
- Sandra Daley as Rosa Farris
- Chris Fischer as Firefighter
- Jason Field as Mark Krieger
References Edit
Quotes Edit
"I don't think she suffered much."
"She suffered."
"I mean she was killed instantly."
"I know what you mean."
- - Bomb Squad officer and John Munch
"Got a name for this guy?"
"Tommy something ... Irish."
"There are, like, two million Irish in New York, P.K."
"Good luck."
- - John Munch, P.K., and Monique Jeffries
Background information and notes Edit
- This is one of the few episodes that features Detective John Munch as the lead detective.
- Actor Daniel Sunjata appears for the first time in an episode from Law & Order: Special Victims Unit. In this episode he plays a Bomb Squad Officer, but starting with the third season episode "Prodigy" he would appear as recurring character CSU Technician Burt Trevor.
Episode scene cards Edit
Apartment of
Apartment of "P.K."
Rikers Island
Supreme Court
Supreme Court
Welton Apartments
| Previous episode:
| "Remorse"
Law & Order: Special Victims Unit
Season 1
| Next episode:


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text:
- regard
I. noun
Etymology: Middle English, from Anglo-French, from regarder
Date: 14th century
1. archaic appearance
a. attention, consideration <due regard should be given to all facets of the question> b. a protective interest ; care <has no regard for her health> 3. look, gaze 4. a. the worth or estimation in which something or someone is held <a man of small regard> b. (1) a feeling of respect and affection ; esteem <she soon won the regard of her colleagues> (2) plural friendly greetings implying such feeling <give him my regards> 5. a basis of action or opinion ; motive 6. an aspect to be taken into consideration ; respect <is a small school, and is fortunate in this regard> 7. obsolete intention II. verb Etymology: Middle English, from Anglo-French regarder to look back at, regard, from re- + garder to guard, look at — more at guard Date: 14th century transitive verb 1. to consider and appraise usually from a particular point of view <is highly regarded as a mechanic> 2. to pay attention to ; take into consideration or account 3. a. to show respect or consideration for b. to hold in high esteem 4. to look at 5. archaic to relate to intransitive verb 1. to look attentively ; gaze 2. to pay attention ; heed Synonyms: regard, respect, esteem, admire mean to recognize the worth of a person or thing. regard is a general term that is usually qualified <he is highly regarded in the profession>. respect implies a considered evaluation or estimation <after many years they came to respect her views>. esteem implies greater warmth of feeling accompanying a high valuation <no citizen of the town was more highly esteemed>. admire suggests usually enthusiastic appreciation and often deep affection <a friend that I truly admire>.
New Collegiate Dictionary. 2001.


text:
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text:
NEW YORK (AP) A key Episcopal panel defied conservatives Thursday, saying that Episcopal leaders should not cede authority to overseas Anglicans who want the church to halt its march toward full acceptance of gays.
The Episcopal Executive Council said that Anglican leaders, called primates, cannot make decisions for the American denomination, which is the Anglican body in the United States.
"We question the authority of the primates to impose deadlines and demands upon any of the churches of the Anglican Communion," the council said in a statement, after a meeting in Parsippany, New Jersey.
The worldwide Anglican Communion has moved toward the brink of splitting apart since its U.S. branch, the Episcopal Church, consecrated its first openly gay bishop, V. Gene Robinson of New Hampshire, in 2003.
In February, Anglican leaders demanded that Episcopalians allow a panel — that would include Anglican conservatives from other countries — to oversee conservative Episcopal parishes in the U.S. Episcopalians also were given until Sept. 30 to unequivocally pledge not to consecrate another openly gay bishop or authorize official prayers for same-sex couples.
The Executive Council did not speak directly to the other demands in its statement Thursday, but said it has struggled "to embrace people who have historically been marginalized."
"Today this struggle has come to include the place of gay and lesbian people and their vocations in the life of the church," the council wrote.
The document approved by the 38-member panel of clergy and lay people is not the final word from the U.S. church. Episcopal bishops will give the denomination's official response during a meeting Sept. 20-25 in New Orleans. The prelates strongly indicated at a March gathering that although they wanted to stay in the communion, they considered the demands unacceptable.
The 77 million-member communion is a loose association of churches that trace their roots to the Church of England. Each Anglican province is self-governing and the communion's spiritual leader, Archbishop of Canterbury Rowan Williams, has no direct authority to force a compromise.
But in a series of emergency summits and private negotiations over the last four years, Williams has worked to prevent a schism. Under pressure from Episcopal leaders, he has agreed to attend the bishops' meeting in New Orleans.
Last month, he announced that neither Robinson nor conservative Bishop Martyn Minns, head of a group of breakaway U.S. Episcopal parishes aligned with the Anglican Church of Nigeria, would be invited to a once-a-decade Anglican assembly called the Lambeth Conference. Minns' group, the Convocation of Anglicans in North America, was formed by Nigerian Archbishop Peter Akinola to counter the liberal-leaning U.S. denomination on its home turf.
In a recent interview with Time magazine, Williams said a split is not inevitable. But he said the communion "feels very vulnerable and very fragile, perhaps more so than it's been for a very long time."
A split would be a financial hardship for the communion. The small but wealthy Episcopal Church provides a significant chunk of the communion's budget. Even with a schism, Episcopal leaders say they are committed to maintaining their missions work with overseas Anglicans.
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