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The role of the gluco-incretin hormones GIP and GLP-1 in the control of β cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R–/– but not in Gipr–/– mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on β cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a β cell autonomous secretion defect when both receptors are inactivated.
Insulin secretion is controlled by the pancreatic β cell glucose sensor but also by sensors that are located at other anatomical sites and that send hormonal or nervous signals to the β cells. The gut endocrine cells, which secrete the gluco-incretin hormones GIP and GLP-1 after absorption of nutrients, particularly glucose (1, 2), represent such a secondary control system. The gluco-incretin hormones play different roles in the control of whole-body glucose homeostasis. Their best-described effect, however, is the potentiation of glucose-stimulated insulin secretion (3, 4), an action that requires binding of the hormones to specific β cell G-coupled receptors that activate the adenylyl cyclase pathway (5, 6). This insulinotropic effect, which is responsible for approximately 50% of the insulin secreted after meal absorption, becomes progressively blunted in the development of type 2 diabetes (1, 7) as a result of a decrease in the secretion of these hormones as well as a decreased response of the β cells to their action (8).
Apart from the stimulation of insulin secretion, both GIP and GLP-1 have additional physiological effects as a result of expression of their receptors in several other tissues. Most notably, GIP may control fat metabolism, as suggested by the presence of its receptor in adipose tissue. GLP-1, on the other hand, has been studied in greater detail because of the preservation of its insulinotropic effect in type 2 diabetes, thus suggesting its potential use in the treatment of this disease (9, 10). Clinical trials have thus shown that in addition to stimulating insulin secretion and normalizing blood glucose and hemoglobin A1C, GLP-1 also reduces the rate of gastric emptying and increases satiety, thus leading to a reduction in body weight (11). Studies in rodents have further described that GLP-1 can increase β cell mass, probably through a combination of transcriptional activation of key genes involved in β cell differentiation and function, such as Pdx-1, Glut2, glucokinase, and insulin (12–16), and by providing protection against apoptosis (17). Recently we have also demonstrated that an important site of GLP-1 action is on the hepatoportal glucose sensor. This sensor is activated when a glucose gradient is established between the portal and peripheral blood, for instance after meal absorption, or experimentally by direct portal vein glucose injection. Using this last protocol, we demonstrated that the activated sensor increases glucose clearance by peripheral tissues through a mechanism independent of insulin action (18, 19). Glucose detection by this sensor requires, in addition to GLUT2 (20), the presence of an activated GLP-1 receptor, as demonstrated by the use of KO mice lacking the GLP-1 receptor or by infusion of the GLP-1 antagonist exendin-(9–39) in the portal vein, which completely prevents its activation (21).
The physiological importance of the gluco-incretin receptors has been further studied by gene inactivation in the mouse. KO mice lacking the GIP receptor showed impaired tolerance to oral glucose load but not to intraperitoneal glucose injection (22). High-fat feeding for 3 weeks induced a marked increase in the glycemic excursions after meal absorption. However, inactivation of this receptor gene protected mice from obesity induced by a high-fat diet, and transfer of this mutation in ob/ob mice reduced their body weight (23). KO mice lacking the GLP-1 receptor had a marked intolerance to oral glucose absorption but only a mild intolerance to intraperitoneal glucose injection and displayed normal feeding behavior (24). However, in these mice, absence of GLP-1 receptors was compensated by upregulation of both GIP plasma levels and GIP action on pancreatic islets. Also, lack of GIP receptor led to higher sensitivity to GLP-1 in pancreatic islets (25–27). Thus, inactivation of each receptor caused only mild impairment in whole-body glucose and energy homeostasis, which may be due to compensatory overexpression of the other incretin hormone. Therefore, inactivation of both receptors should lead to a stronger defect in whole-body glucose homeostasis.
Here, we studied mice with inactivation of either each gluco-incretin receptor or both. We show that these hormones control insulin secretion through three different mechanisms. First, they have additive insulinotropic effects on β cells during oral glucose tolerance tests. Second, in the absence of the GLP-1 receptor, there is suppression of the first phase of insulin secretion measured in vivo, but not in the isolated islets, indicating a role for this receptor in the function of glucose sensors that are located outside the endocrine pancreas and that control first-phase secretion. Third, absence of both receptors causes a β cell autonomous insulin secretion defect at a site distal to plasma membrane depolarization.
The mouse GIP receptor gene was cloned from a 129/SV mouse genomic library (Stratagene, La Jolla, California, USA) using human GIPR cDNA as a probe (28) and mapped by restriction enzyme analysis (see Figure Figure1).1). The targeting vector was made by cloning a 4.5-kb BglII fragment of sequence 5′ of the mouse Gipr gene and a 3.5-kb AflII-BamHI fragment covering exons 6–10 into pBluescriptKS (Stratagene) and inserting a neomycin-resistance cassette in place of the first six exons. Two copies of the HSVtk cassette were cloned 5′ of the BglII fragment. E14 ES cells were transfected as described (29), and positive clones were identified by Southern blotting using HindIII-digested genomic DNA and a 200-bp StuI-NheI probe external to the vector. Chimeric C57BL/6 mice were obtained by morula aggregation as described (30), and subsequent F1 mice bred to generate a Gipr–/– line. Glp-1R–/–Gipr–/– double-KO mice were obtained by crossing Glp-1R–/– and Gipr–/– mice and subsequently crossing the double heterozygotes to obtain Glp-1R+/+Gipr+/+ (WT) and Glp-1R–/–Gipr–/– (double-KO) mice on the same C57BL/6 × SV129 hybrid background. Both single- and double-KO mice were obtained in the expected mendelian ratios. Glp-1R–/–Gipr–/– mice and their single-KO controls, Glp-1R–/–Gipr+/– and Gipr–/–Glp-1R+/– (referred to in the text as Glp-1R–/– and Gipr–/– mice, respectively), were obtained as siblings, by crossing Glp-1R–/–Gipr–/– mice with Glp-1R–/–Gipr+/– or Glp-1R+/–Gipr–/– mice.
Mice were maintained on a 12 hours light/12 hours dark cycle, with free access to water and standard laboratory chow (Provimi Kliba, Penthalaz, Switzerland). Animals were treated in accordance with our Institutional Guidelines and with the authorization of the Service Vétérinaire Cantonal.
After a 16-hour overnight fast, age- and sex-matched 14- to 16-week-old mice received glucose by intragastric gavage (3 mg/g, as a 66% solution) or by intraperitoneal injections (1 mg/g, as a 10% solution). Blood samples were obtained from tail-tip bleedings, and blood glucose levels were measured with a Glucometer (Glucotrend Premium; Boehringer Mannheim GmbH, Mannheim, Germany). Glycemic areas under the curve (AUCs) were measured from time 0 to 120 minutes, after subtraction of basal glycemia from each time point. Plasma insulin levels were determined by ELISA (Mercodia AB, Uppsala, Sweden).
For measurement of pancreatic insulin content, pancreata were quickly dissected, weighed, and homogenized in acid ethanol. Insulin was measured by RIA (Linco Research Inc., St. Charles, Missouri, USA). Pancreata were perfused in situ on mice starved overnight (31), with basal and stimulatory glucose concentrations of 1 and 16.7 mM, respectively. Secreted insulin was measured by RIA (30). Statistical analysis was based on the comparison of the AUCs for first and second phases of secretion from WT and mutant mice using a Student's t-test (two-tailed distribution, two-sample equal variance).
Islets were isolated by hand-picking after collagenase digestion of pancreas (32) and were maintained overnight in RPMI 1640 medium supplemented with 10% FCS, 10 mM HEPES, pH 7.4, 1 mM sodium pyruvate, 100 U/ml penicillin-streptomycin, 50 μM β-mercaptoethanol, and 11 mM glucose.
For perifusion experiments, batches of 30 islets were placed in parallel perifusion chambers at 37°C and perifused at a flow rate of 1 ml/min with a Krebs-Ringer solution (KRBH) containing 0.5% BSA. Islets were first equilibrated for 30 minutes in KRBH supplemented with 2.8 mM glucose and then stimulated during 10-minute periods in high glucose concentrations (11.1 or 16.7 mM) with chemicals as indicated. Fractions were collected every minute. At the end of each perifusion, islets were pelleted by centrifugation and lysed in acid ethanol for assessment of insulin content by RIA. Results are presented as insulin secreted (ng/ml) per minute normalized to islet insulin content.
For static incubations, islets were preincubated for 1 hour in 1 ml KRBH supplemented with 2.8 mM glucose, in 12-well plates. Then, islets were transferred to new plates containing 1 ml KRBH supplemented with 16.7 mM glucose and chemicals as indicated. For insulin measurements, batches of 10 islets were incubated for 15 minutes in the absence or presence of isobutylmethylxanthine (IBMX) 100 μM and/or forskolin 10 μM. Insulin in media and islets was then measured as described before. For cAMP measurements, batches of 20 islets were incubated for 15 minutes in the presence of 250 μM IBMX and were then lysed in ice-cold 0.1 M HCl. cAMP was measured using a kit (Amersham Biosciences Europe GmbH, Freiburg, Germany).
Data are expressed as mean ± SE. Statistical analyses were performed using the Excell 2000 or Origin 6.0 (Microcal Software Inc., Northampton, Massachusetts, USA) software. Data were analyzed using unpaired t-test or one-way ANOVA.
We generated mice with inactivation of the Gipr gene by replacing exons 1–6 with a neomycin cassette (Figure (Figure1a).1a). Transmission of the mutant allele was confirmed by Southern blot analysis using a 3′ probe, external to the targeting vector (Figure (Figure1b).1b). We then intercrossed Gipr–/– mice with Glp-1R–/– mice to obtain Glp-1R–/–Gipr–/– (double-KO) mice. Controls were derived from littermates of double-KO mice and single-KO mice.
To confirm the absence of the hormone receptor from pancreatic islets of each set of mutants, we measured the insulin secretion from isolated islets incubated in the presence of either hormone. Figure Figure1c1c demonstrates that inactivation of each receptor led to suppression of the insulinotropic action of the respective hormone, and inactivation of both receptor genes abolished the effects of both hormones.
Double-KO mice were fertile and exhibited no gross behavioral abnormalities. Their body weight was similar to that of control mice, and their fed and fasted blood glucose concentrations were normal (Table (Table1).1). The plasma insulin levels of fasted females tended to be lower in the KO mice as compared to controls, although the difference sometimes did not reach statistical significance (see Figures Figures2b2b and and3d).3d). In males no statistically significant differences were observed in plasma insulin levels in the fasted state (Figure (Figure22d).
To evaluate the impact of gluco-incretin receptor gene inactivation on disposal of a glucose load, we performed oral glucose tolerance tests. Female mice with a single-receptor gene inactivation showed glucose intolerance as revealed by a significant increase in the AUC of the glucose tolerance test (AUC glucose) (Figure (Figure2a).2a). Female mice with double-receptor KO displayed greater intolerance, with an AUC glucose approximately twice that of WT and 40–50% higher than in single-KO mice (Figure (Figure2a).2a). Glucose intolerance in single-KO mice was associated with a 34–43% lower plasma insulin level measured at 15 minutes after glucose injection compared to WT control mice (Figure (Figure2b).2b). Double-KO mice exhibited an even lower insulin response (–57% vs. WT; –24 to –34% vs. single-KO mice) (Figure (Figure22b).
In male mice, glucose intolerance was less marked, with AUC glucose for double-KO mice increased by 17–40% as compared to single-KO mice, and by 50% as compared to WT mice (Figure (Figure2c).2c). The corresponding insulin responses were significantly blunted, with a 60% reduction as compared to WT mice and a 40% reduction as compared to the GLP-1 receptor KO mice (Figure (Figure2d).2d). These data indicate an additive insulinotropic action of GIP and GLP-1 during an oral glucose load. The incretin effect of each hormone seemed to be of similar magnitude in females when comparing the AUC glucose and AUC insulin in single-receptor KO mice. In light of these criteria, the incretin effect of GIP was more important than that of GLP-1 in male mice.
Oral, but not intraperitoneal, glucose administration induces the secretion of gluco-incretin hormones. To evaluate whether single or combined suppression of the GIP and GLP-1 receptors also led to altered glucose tolerance and insulin secretion when secretion of these hormones was not stimulated, we performed intraperitoneal glucose tolerance tests (IPGTTs). Male mice with single- and double-receptor gene KO showed normal basal glycemia as well as normal glucose tolerance after intraperitoneal glucose injection, at both 14–16 and 40 weeks of age (Figure (Figure3,3, a and b). Thus glucose tolerance was not impaired in male KO mice.
In 14- to 16-week-old single- and double-KO female mice, basal glycemia was normal (Figure (Figure3c).3c). However, single-KO mice had greater glycemic excursions after intraperitoneal glucose injection (AUC glucose 40–45% higher than in WT mice), and double-KO mice had still higher AUC glucose, approximately twice that of WT and 40% higher than single-KO mice (Figure (Figure33c).
Glucose intolerance in single- and double-KO female mice was associated with changes in plasma insulin concentration (Figure (Figure3d).3d). Remarkably, the 2-minute plasma insulin peak, which represents first-phase insulin secretion, was totally absent in the double-KO mice as well as in mice lacking the GLP-1 receptor, but was present in the Gipr–/– mice (Figure (Figure3d).3d). The 30-minute peak insulin levels were significantly reduced in the single-KO mice, but the reduction was not statistically significant in the double-KO mice (Figure (Figure33d).
To evaluate whether glucose intolerance could be associated with peripheral insulin resistance, we performed hyperinsulinemic euglycemic clamp experiments in double-KO and WT female mice. Insulin was infused at either high (18 U/kg/min) or intermediate (6 U/kg/min) rates. In both conditions, double-KO mice had normal insulin sensitivity compared to WT mice, as revealed by identical glucose infusion rates to maintain euglycemia (84.1 ± 6.4 vs. 75.5 ± 5.4 mg/kg/min in double-KO and control mice, respectively, at high insulin infusion rate, and 60.5 ± 3.4 vs. 60.1 ± 6.0 mg/kg/min, in double-KO and control mice, respectively, at intermediate insulin infusion rate; n = 5–6).
To determine the insulin-secretory capacity of the endocrine pancreas of the mutant mice, we first performed pancreas perfusion experiments. In our setting, the pancreas is still connected to the duodenum and has normal connections to the local autonomic nervous system. Moreover, the hepatoportal glucose sensor should be exposed to the perfusate, which is introduced via the aorta (30). Glucose-induced insulin secretion in perfused pancreata from control female mice showed a strong first-phase secretion (Figure (Figure4,4, a and d). Perfusion of pancreata from GIP-receptor KO mice showed a first phase of secretion that was not significantly different from that of control pancreas (Figure (Figure4,4, a and d). In contrast, as compared to WT pancreas, Glp-1R–/– and double-KO pancreas perfusions revealed a markedly blunted first phase of insulin secretion (50 ± 7 vs. 17 ± 7 and 11 ± 3 in control vs. Glp-1R–/– and double-KO pancreata, respectively, Figure Figure4,4, b–d). The second phase of insulin secretion was significantly decreased in single-KO but not in double-KO pancreata, similar to the observation on second-phase secretion in IPGTTs. Notably, those defects occurred despite normal pancreatic insulin contents in single- and double-KO mice (Table (Table2).2). The excellent correlation between these results and those from the IPGTT indicate that the factors responsible for the loss of first-phase insulin secretion in the double-KO and GLP-1 receptor-KO mice remain in the perfused-pancreas setup.
We next evaluated the kinetics of insulin secretion in islet-perifusion experiments. Figure Figure5a5a shows insulin secretion from control and single-KO islets when glucose concentration was raised to 11.1 or 16.7 mM. The kinetics of secretion in single-KO islets was indistinguishable from that of control islets, with a very rapid onset of secretion at high glucose concentration and suppression of secretion when glucose levels returned to basal values. Although there was no clear separation of first- and second-phase insulin secretion in the present experiments, as is usually the case in mouse islets (33), the initial rapid secretory response over the first 5 minutes of high-glucose perfusion is considered to represent the first phase of insulin secretion. The total amount of insulin released from single-KO islets was indistinguishable from those of control islets at 11.1 or 16.7 mM glucose (Figure (Figure5c).5c). Moreover, as shown in Figure Figure5d,5d, the ratio of insulin to DNA content of the different types of islets was identical.
Perifusion of double-KO islets (Figure (Figure5b)5b) revealed a pattern of insulin secretion characterized by a rapid initiation of secretion over the first 5 minutes of high-glucose perifusion, suggesting a normal first phase of insulin release. However, this secretion was of reduced amplitude, and the total amount of secreted insulin from the double-KO islets was markedly reduced (Figure (Figure5c)5c) despite a normal islet insulin/DNA ratio (Figure (Figure55d).
To evaluate whether the secretory defect in double-KO islets occurred upstream or downstream of the depolarization event, we stimulated insulin secretion by K+-induced depolarization. Figure Figure5e5e shows a markedly reduced secretory response to K+ in double-KO mice, strongly suggesting that there is a major defect distal to plasma membrane depolarization.
The above data thus demonstrate that in the absence of a single hormone receptor, first-phase and total insulin secretion were normal. In the absence of both receptors, onset of secretion was kinetically normal but total secretion was markedly reduced and associated with a defect in glucose signaling at a step distal to plasma membrane depolarization. This defect could result from reduced intracellular cAMP levels, to a defect in the insulin-secretory pathway as a consequence of alterations in the expression of genes controlling exocytosis of insulin granules, or both.
To distinguish between these alternatives, we first tested whether the secretory defect was observed when the perifusion experiments were performed in the presence or absence of IBMX combined or not combined with forskolin. As shown in Figure Figure6a,6a, the secretory response to 16.7 mM glucose was similarly reduced in double-KO islets whether IBMX was included in the perifusate or not. Moreover, the addition of forskolin in the presence of IBMX strongly stimulated insulin secretion in response to 16.7 mM glucose, and the insulin secretion rate was similar in double-KO and control islets (Figure (Figure6b).6b). In Figure Figure6,6, c and d, in static incubations, we measured insulin secretion from control and double-KO islets and their intracellular cAMP levels. The results show that secretion from double-KO islets incubated with or without IBMX was markedly reduced as compared to secretion from control islets. Furthermore, addition of forskolin to the incubation medium strongly increased secretion in both control and double-KO islets, and secretion was quantitatively identical from both types of islets. These results are similar to those obtained in perifusion experiments (see Figure Figure6,6, a and b). The intracellular cAMP levels from islets incubated in the presence of 16.7 mM glucose and IBMX were identical in control and double-KO islets (Figure (Figure6d),6d), suggesting that the difference in cAMP levels cannot explain the reduced secretory activity in the mutant islets. In the presence of forskolin and IBMX, cAMP levels were strongly elevated in both types of islets (Figure (Figure6d),6d), conditions in which insulin secretion was normalized in double-KO islets (Figure (Figure6c).6c). Together, these data suggest that impaired insulin secretion in double-KO islets was not due to lower cAMP levels but rather to a reduced sensitivity to this second messenger.
To evaluate whether the secretory defect was restricted to cAMP-controlled mechanisms, we performed islet-perifusion experiments in the presence or absence of carbachol. As shown in Figure Figure6e,6e, the secretory defect observed in double-KO islets perifused with high glucose concentrations was suppressed when the islets were perifused in the presence of carbachol, an activator of the G-coupled muscarinic receptors.
Despite their secretory defect, double-KO islets exhibited no obvious abnormality in insulin content (Table (Table2),2), size range, gross morphology, and distribution of insulin- and glucagon-producing cells (data not shown). Hence, double-KO islets have a β cell autonomous defect in stimulated insulin secretion that is probably due to the absence of both GLP-1- and GIP-receptor signaling. However, strikingly, first-phase insulin secretion was not suppressed in GLP-1 receptor KO islets and only moderately in double-KO islets. This suggests that the blunted first-phase insulin secretion obtained via IPGTT and in the perfused pancreas may reflect an integrative response, including glucose sensors located outside the endocrine pancreas.
We and others previously demonstrated that a glucose sensor was located in the hepatoportal vein region. This sensor controls insulin secretion, through autonomic nervous connections (34). Using different mouse models, we demonstrated that this sensor required GLUT2 gene expression and the presence of an activated GLP-1 receptor (20, 21) for normal function. Our present data suggest that this sensor could be involved in the control of first-phase insulin secretion, since GLP-1 receptor KO mice lack first-phase secretion during an IPGTT and in perfused pancreata but not in perifused isolated islets.
Thus, to test the involvement of the hepatoportal sensor in the control of first-phase insulin secretion, we performed two sets of experiments. First, we measured insulin secretion in RipGlut1Glut2–/– mice. These mice have a nonfunctional hepatoportal sensor due to GLUT2 gene inactivation; however, they have normal biphasic glucose-stimulated insulin secretion, as assessed in islet-perifusion experiments, due to the transgenic expression of a GLUT1 transporter in their β cells (33). Figure Figure7a7a shows that the 2-minute peak of plasma insulin normally induced by an intraperitoneal glucose injection was absent from RipGlut1Glut2–/– mice. Similarly, when evaluated in the perfused pancreas, this first peak of insulin secretion was almost completely blunted (Figure (Figure77b).
In a second set of experiments, we inactivated the hepatoportal glucose sensor in control mice by portal vein infusion of the GLP-1 receptor antagonist exendin-(9–39). The perfusion rate was chosen so as to block the function of the hepatoportal sensor without interfering with blood glucose levels (0.5 pmol/kg/min), as previously described (21). Thirty minutes after initiation of the perfusion experiments, mice were injected intraperitoneally with glucose. Figure Figure7c7c shows the glycemic profiles over the time course of the experiments, and Figure Figure7d7d shows the plasma insulin levels measured at time 0, at the initiation of peptide or saline infusion (time 60 minutes), and 2 and 15 minutes (time 92 and 105 minutes) after the injection of glucose. The basal insulinemic levels (0 and 60 minutes) were similar in the saline- and antagonist-perfused mice. The first peak of insulin secretion (2 minutes after glucose injection, time 92 minutes) reached 75 ± 11 μU/ml for the saline-infused mice and 30 ± 2 μU/ml for the exendin-(9–39)–infused mice. Fifteen minutes after injection (time 105 minutes), the plasma insulin concentrations were reduced to the same level in both groups. Thus, the above data demonstrate that inhibition of the hepatoportal glucose sensor by GLUT2 gene inactivation or exendin-(9–39) portal infusion dramatically reduced first peak insulin secretion after intraperitoneal glucose injection.
The present study revealed that the gluco-incretin hormones GIP and GLP-1 control glucose homeostasis and insulin secretion through multiple mechanisms.
After oral glucose administration, the glycemic excursions were observed to be increased in single-receptor KO as compared to control mice and to be even higher in double-KO mice. This was associated with correspondingly lower plasma insulin levels measured 15 minutes after the glucose loads. These data are best explained by the additive effect of GIP and GLP-1, secreted by gut endocrine cells after glucose absorption, and whose insulinotropic action requires binding to their cognate receptors at the β cell surface. This interpretation is also in agreement with the data (Figure (Figure1c)1c) showing suppressed insulinotropic action of these hormones on the islets isolated from the single- and double-KO mice. Also notable are the normal basal glycemic levels observed in the double-KO mice. Indeed, one of the initial reasons to generate and study these mice was to evaluate whether suppression of both gluco-incretin hormone receptors would lead to a more pronounced defect in glucose homeostasis as compared with single-receptor gene inactivation. However, the present data demonstrate that suppression of the action of both hormones does not lead to a diabetic phenotype, indicating that even if the insulinotropic action of these hormones is very powerful, their physiological role is not critical for normal glucose homeostasis. Their role may nevertheless become more important when the organism is faced with more challenging conditions, such as high-fat or high-carbohydrate diet feeding, as reported for the Gipr–/– mice (22).
Intraperitoneal glucose injections revealed mild intolerance in female mice with single-receptor gene inactivation and a more severe intolerance in the double-KO mice. Intolerance was the result of a defect in insulin secretion and not of a decreased sensitivity to insulin action as assessed by hyperinsulinemic clamp studies.
The defects in insulin secretion observed during intraperitoneal glucose injections were twofold. First, there was a reduction in the level of insulin observed at 30 minutes. This reduction was similar in both Gipr–/– and Glp-1R–/– mice. In double-KO mice, the reduction at 30 minutes did not reach statistical significance. While the reason for this lack of significant reduction is not known, it may suggest the presence of compensatory mechanisms enhancing insulin secretion when both receptors are inactivated. Second, first-phase secretion, measured as the 2-minute plasma insulin peak, was absent in Glp-1R–/– and double-KO mice but present in control and Gipr–/– mice. These patterns of first and second peak of insulin secretion were strikingly similar when tested in the perfused pancreas. In our experimental setting, the pancreas is perfused in situ from the aorta—that is, with all its anatomical connections preserved, including those to the local autonomic nervous network and to the stimulated hepatoportal glucose sensor.
In perifusion experiments, although we usually do not observe clear separation between the first and second phase of secretion, we consider the strong secretory response over the first 5 minutes of glucose stimulation to be the first phase. This first phase is, for instance, lost in Glut2–/– islets, whereas a second phase, which starts a few minutes later, is still detected (35). Here, first-phase secretion in islets from single-receptor KO mice was kinetically and quantitatively normal. In double-receptor KO islets, initiation of insulin secretion displayed a normal kinetics, but the amplitude of this first peak was decreased. Thus the defect in first-phase secretion described in vivo and in the perfused pancreas was not observed when studying isolated islets.
What could explain the absence of first-phase insulin secretion in Glp-1R–/– KO mice in IPGTT and perfused pancreas experiments when it is present in the perifused islets? We know from our previous studies that the GLP-1 receptor is also present in extrapancreatic glucose sensors, in particular those present in the hepatoportal vein area (21). This sensor controls several physiological functions, including the stimulation of insulin secretion through an autonomic nervous system pathway (34). We have demonstrated that the function of this sensor is suppressed when the GLP-1 receptor is absent, as in Glp-1R–/– mice or when inactivated by the antagonist exendin-(9–39). It has also been reported that the hepatoportal sensor was not sensitive to GIP (36). We have obtained direct evidence that inhibiting the hepatoportal sensor in control mice by exendin-(9–39) portal vein infusion strongly reduced the first peak of insulin secretion during an IPGTT. This first peak was not completely suppressed, however, indicating either that there was a partial pharmacological blockade or that other sensors, possibly related to glucose-sensitive nervous fibers of the enteric nervous system, play a role in controlling first-phase secretion, or a combination of both.
Further support for the hypothesis that the hepatoportal sensor contributes to the triggering of first-phase secretion was obtained by studying RipGlut1Glut2–/– mice. These mice have no endogenous GLUT2 gene but express a transgenic GLUT1 in their β cells that normalizes the kinetics of insulin secretion as assessed in islet-perifusion experiments (33). However, the hepatoportal sensor of these mice is no longer functional in the absence of GLUT2 (20). Strikingly, first-phase insulin secretion was absent during an intraperitoneal glucose challenge or in perfused pancreas experiments. Thus, inactivation of the hepatoportal sensor, or of a similar sensor present outside of the endocrine pancreas, also leads to suppression of in vivo first-phase insulin secretion. Kirchgessner and co-workers have also demonstrated that neurons from the enteric nervous system located in the pancreas are glucose responsive and express the KATP channels (37), implying a role in glucose signaling. These sensors may be activated during the pancreas-perfusion experiments.
These results thus suggest that glucose sensors located outside the endocrine pancreas participate in the control of in vivo first-phase insulin secretion. These sensors are probably connected to the pancreatic β cells through the autonomic or enteric nervous system. The hepatoportal sensor, in particular, may be one of the early glucose detectors involved. Indeed, its location in the portal vein, where ingested glucose first transits, may be ideal for a rapid stimulation of insulin secretion.
These sensors show similarities with pancreatic β cells by expressing key molecules involved in glucose sensing. Because of their role in the control of the first phase of insulin secretion, the disappearance of which is an early sign of diabetes development, their dysfunction may represent an initial pathogenic event.
Islet-perifusion studies also revealed a striking reduction in the rate of insulin secretion from double-KO islets. This occurred even though islet morphology and insulin content were normal. Our data demonstrated that a major defect was at a step distal to membrane depolarization, since perifusion of islets in high concentrations of K+ led to a much weaker secretory response as compared with control islets. This suggests a defect in either Ca2+ entry or the mechanisms controlling exocytosis of insulin granules.
The decreased secretory response to high glucose concentrations and IBMX of double-KO as compared to control islets could not be due to reduced intracellular cAMP levels. Indeed, in these stimulatory conditions the cAMP levels were identical in both types of islets. However, addition of forskolin, which strongly increased the intracellular cAMP levels, led to similar rates of secretion from both types of islets.
The second messenger cAMP acts via two pathways in β cells: first, by activation of protein kinase A, which phosphorylates GLUT2, the KATP and Ca2+ channels (38–40), and as yet unidentified substrates; and second, by binding to the cAMP sensor protein cAMP-GEF2 or Epac2, which forms a complex with Rim2 and activates Rab3, a component of the exocytotic machinery (41, 42). Affinity for cAMP of protein kinase A is in the nanomolar range (43), whereas it is in the micromolar range for cAMP-GEF2 (41). Thus, the defect in secretion observed at low intracellular cAMP levels may be due to a selective defect in the protein kinase A pathway that would be overcome by the stimulation of the cAMP-GEF2-Rim2 pathway when intracellular cAMP levels are strongly increased by forskolin. An additional effect of forskolin could nevertheless also be on the blockade of Kv channels (44), which would increase insulin secretion (45).
The defect in protein kinase A action may result from a decreased expression of protein targets whose expression are under the control of the GIP and GLP-1 receptors. Indeed, stimulation of GLP-1 and GIP receptors not only potentiates insulin secretion but also stimulates the proliferation and differentiation of pancreatic β cells as well as the expression of β cell genes such as Pdx-1, proinsulin, Glut2, and glucokinase. GLP-1 and GIP receptors increase gene transcription via activation of cAMP-responsive elements binding proteins (46) but possibly also through the MAPK pathway (47). Finally, since carbachol stimulation led to the same rate of glucose-induced secretion in control and double-KO islets, this further supports the suggestion that there is a specific downregulation of cAMP-regulated proteins and not a general defect in the secretory machinery.
In summary, our study demonstrates the additive effect of gluco-incretin hormones in the stimulation of insulin secretion after oral glucose absorption. Permanent absence of both gluco-incretin hormone receptors led to glucose intolerance in female mice due to a defect in insulin secretion with no impairment of insulin sensitivity. GLP-1 receptor expression, at glucose sensors located outside the endocrine pancreas, was shown to be required for the in vivo control of first-phase insulin secretion. Finally, inactivation of both incretin hormone receptors induced a β cell autonomous defect in stimulated insulin secretion; a major part of this defect is located at a site distal to plasma membrane depolarization. The altered expression of genes implicated in the control of insulin exocytosis may underlie the latter defect. Future studies will be required to identify these genes. These may represent important effectors of gluco-incretin hormone action and may be involved in the pathogenesis of type 2 diabetes.
We thank Wanda Dolci, Montserrat Gonzalez, and Olivier Dupont for expert technical assistance, and P. Kopp and J.-F. Spetz (Friedrich Miescher Institute) for technical assistance in generating the Gipr–/– mice. This work was supported by grants of the Swiss National Science Foundation to B. Thorens and C.B. Wollheim. I. Franklin was supported by the European Commission (HPRN-CT-2000-00082).
Mark Ibberson's present address is: Serono Pharmaceutical Research Institute, Geneva, Switzerland.
Mario Pende's present address is: INSERM U508, Hôpital Necker, Paris, France.
Rémy Burcelin's present address is: Centre Hospitalier Universitaire Rangueil, UMR 5018, Toulouse, France.
Conflict of interest: The authors have declared that no conflict of interest exists.
Nonstandard abbreviations used: area under the curve (AUC); Krebs-Ringer solution (KRBH); isobutylmethylxanthine (IBMX); intraperitoneal glucose tolerance test (IPGTT).
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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|Find A Doctor:
|Online or call:1-800-247-9580
|Contact Us:
Medical Specialties
The Healthy Aging Program at Atlantic Health System suggests the following helpful resources to help seniors find information on Medicare, Medicaid and long-term care insurance.
Medicare is a joint federal-state funded government health insurance program for people age 65 or older, as well as many people living with disabilities. It consists of the following parts:
Medicare Advantage Plans
A Medicare Advantage Plan (like an HMO or PPO), sometimes called "Part C" or "MA Plans," are offered by private companies approved by Medicare. These plans provide Part A and Part B coverage, may include prescription coverage (Part D) and offer extra coverage, such as vision, hearing, dental, and/or health and wellness programs. Each Medicare Advantage Plan can charge different out-of-pocket costs and have different rules for how you get services, like whether you need a referral to see a specialist or if you have to go to only doctors, facilities, or suppliers that belong to the plan.
For general information about Medicare and up-to-date information regarding the health plans available in your area, call 1-800-MEDICARE (1-800-633-4227), available 24 hours a day, seven days a week.
Medicaid provides health insurance to people who are aged, blind or disabled who meet specific standards for financial income and resources. It pays for hospital services, doctor visits, prescriptions, nursing home care and other health care needs.
To apply for Medicaid, contact your local county Board of Social Services office:
Essex County Department of Citizen Services, Division of Welfare
Newark, NJ
Morris County Office of Temporary Assistance
Passaic County Board of Social Services
Paterson, NJ
Somerset County Board of Social Services
Sussex County Division of Social Services
Union County Division of Social Services
Warren County Division of Temporary Assistance and Social Services
Belvidere, NJ
Long-term care insurance is a policy you pay for that will provide some coverage for extended health care in assisted living facilities and nursing homes. Medicare and most Medigap insurance policies do not pay for extended health care in facilities such as assisted living or skilled nursing facilities/ nursing homes. Some people purchase long-term care insurance to help supplement the cost of their care. Premiums range in monthly cost and the range of coverage can depend on the level of care the policyholder chooses.
National Clearinghouse for Long-Term Care Information
State Health Insurance Program (SHIP)
FamilyWize Prescription Discount Card
A resource of the United Way of Northern NJ, FamilyWize provides a free discount card.
MedReturn Drug Collection
MedReturn Drug Collection units are available statewide to assist with the proper disposal of unwanted or expired household and prescription medications. Many bins are located at local police departments. Visit website or contact local police department for a location near you.
The Partnership for Prescription Assistance
Pharmaceutical Assistance to the Aged and Disabled (PAAD) and Senior Gold Resource Center
PAAD provides assistance with the payment of prescriptions to people 65 years of age or older or disabled individuals who meet income guidelines; Senior Gold assists those whose income exceeds PAAD limits.
Senior Medicare Patrol of New Jersey
Senior Medicare Patrol provides consumer counseling and advocacy to resolve billing errors and disputes or make referrals to law enforcement for suspected cases of Medicare fraud, waste or abuse. This federally funded statewide program is coordinated by Jewish Family and Vocational Service of Middlesex County.
Milltown, NJ 08850
State Health Insurance Program (SHIP)
U.S. Department of Health & Human Services – Affordable Care Act information
Federal agency provides health information and essential human services. Website provides current information about the Affordable Care Act (ACA).

subset: commoncrawl


text: Performics named Overture Strategic Provider Published on November 19, 2003. Most Popular Chicago--Performics, an online search engine marketing company, announced it has been designated as an official Overture Strategic Provider. Overture Services, Pasadena, Calif., a search engine company, has given that designation to only a few search engine marketing companies as part of its overall Ambassador Program. In this article: BtoB


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The suburban stay-at-home mom is rapidly becoming one of the most sexualized demographics in Western culture, and for good reason. With yoga, healthy diets, and skin tight clothing all being marketed to women well into their 40s, the American MILF has never been hotter. Meanwhile, they spend the majority of their day taking care of snot nosed babies while trying to find outlets for their sexual boredom.
In her article The 40-Year-Old Reversion, Amy Sohn talks about the ways in which a group of 40-something mothers deal with the boredom and monotony of raising children while being in their sexual peak. Though it kind of sounds like a bunch of bored housewives complaining, it's actually pretty hot. The stories are supposed to be cringe inducing tales of substance abuse and infidelity, but because I work in porn I only cringed shortly before I started masturbating.
They essentially tell the tale of a bunch of well-to-do 40 year olds behaving like twenty-something hipsters. She notes that with people casually doing drugs, giddy over how rebellious it feels and drunk women stumbling out of a party – the only thing that has changed since their 20s is the baby sitter they had to hire.
I've never been much of a partier but I've been around a lot of people who do. Now that we're all approaching late adulthood it's kind of sad to watch them attempt to relive their glory days while the younger people they party with look at them and self-reflect on their direction in life.
Sohn's article is the precursor to a book, roughly about the same topic. I probably won't read it because I'm still technically in my 20s and I don't give a shit about a bunch of old, rich, white people and their fake problems. I just thought it was cool to read about horny MILFs flashing their new boob jobs in restaurants and talking about getting fingered in the back of their minivans while on business trips.


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JEAN LAFITTE, La. – Republican presidential nominee Mitt Romney toured a flood-ravaged area of the Louisiana bayou on Friday in the aftermath of the hurricane that disrupted his party's national convention in Florida.
Accompanied by his wife, Ann, the candidate rode in an SUV past submerged gas stations and flooded homes in this Mississippi River delta community near New Orleans. In some places, the water was several feet deep.
Romney got out of the vehicle and had an informal roadside conversation with Louisiana Gov. Bobby Jindal and U.S. Sen. David Vitter, both Republicans.
"I'm here to learn and obviously to draw some attention to what's going on here so that people around the country know that people down here need help," he told Jindal.
PHOTOS: Romney's post-Isaac tour
Jindal told the former Massachusetts governor about relief efforts by the Red Cross, Salvation Army and other organizations. Romney inquired about how many people were out of their homes or in shelters. "Did the water come from the sky, or the rivers, or the ocean?" he asked. The answer could not be heard.


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Point Loma's Modern Times landed on RateBeer's list of "Top New Brewers in the World."
Based on reader reviews, Modern Times ranked among the top 10 out of 2,600 breweries that opened last year. The site cited two of brewery's ales, Blazing World, an American amber ale, and Fortunate Islands, an American pale wheat ale. Both, RateBeer maintained, are "already near the tip-top of their respective style categories."
The complete list:
Pressure Drop, London
Modern Times, Point Loma
Trappistenbrouwerij De Kievit, Zundert, Netherlands
Rhinegeist, Cincinnati
Trillium, Boston
Weird Beard, London
J.W. Sweetman, Dublin
Bevog Brewery, Bad Radkersburg, Austria
Siren, Finchampstead, Berkshire, England
Arizona Wilderness Brewing, Gilbert, Ariz.


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Washington, DC— Jim Manley, spokesman for Nevada Senator Harry Reid, released the following statement today in advance of a key Senate cloture vote to move to debate on Wall Street accountability legislation:
"Today, Republicans face a major choice: Will they stand up for the American people, and join us to hold Wall Street accountable for the reckless gambling that cost 8 million Americans their jobs and millions more their economic livelihood? Or will they follow the marching orders they've been getting at their secret, closed-door meetings with Wall Street executives, and continue to protect Wall Street?
"We remain eager to work with Republicans who are sincere about reforming Wall Street, and we are hopeful for bipartisan agreement on this important effort. But there are no two ways about it: a vote against even opening debate on holding Wall Street accountable is a vote to protect Wall Street."
This Month


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SEEKINGBand to Join.
I have been playing for 4 years. I have a pearl set, and a premier. I play Rock N Roll, Metal, classic rock.
- Screen name:
- CowboyFromHell626
- Member since:
- Sep 17 2006
- Active over 1 month ago
- Level of commitment:
- Committed
Gene Kruppa, Neil Peart,Vinnie Paul, Scott tTravis, Tommy Lee, Steven Adler, Chris Adler, Jimmy Degrasso, Dennis Chambers, Tony Royster Jr., and many more.
Pearl set, two basses, three toms, two floor toms, four crash cymbals, ride, two hi-hats, two chinas all Sabian, Remo heads.And i have a Premier set.


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Hello everybody and invitation
I am living in Libya and I am heading FOSSiL (Free and Open Source Software in Libya) group. We are preparing for Linux Day in Libya. It will be on January 24, 2009 in Tripoli (the capital of Libya) in the center of the most prestigious places in the center of Tripoli. It is the "That Al-Imad" complex where a lot of companies (such as Eni-Gas, Tamoil, Repsol, Libyan Foreigner Bank, ...) are located. We will have workshop and lectures running in parallel. If any of you have a note, lecture, information, or anything that he fells it is worth to be announced during the day, please send it to me. I am appreciating very much your inputs.
Thank you very much
M. Osama A. Alghwell
Hi malghwall
Welcome at LQ
A advice delete you're personal email , if not it just asking for spam
Thanks, but I received no info, neither docs. So, is it possible to received something?
What info did youi like to have about LQ you find it here on this side.
General info search the internet
The event will be the first in Libya. This event will be an introduction for "FOSS" applications for the Libyan society. That is why we are looking to make it very promising. So, I am asking if there is an article, presentation, document, or any material any of you thinks it will be good to be mentioned for better introducing FOSS.
Thank you
|All times are GMT -5. The time now is 09:03 AM.


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After 17 hours, Devega jury still deliberating
Posted May 15, 2014
Raleigh, N.C. — After nearly 17 hours of deliberations this week, a Wake County jury on Friday will enter its fourth full day of deciding the fate of a Raleigh man who could face the death penalty for the shooting deaths of two people more than six years ago.
The seven men and five women are considering 11 verdicts against 32-year-old Armond Devega, who is charged with two counts of first-degree murder, one count of attempted first-degree murder and eight counts of armed robbery in a series of crimes in 2008.
Anthony Dwayne Scarborough, 32, was fatally shot Feb. 13, 2008, during a home invasion in which prosecutors say Devega sought retribution because he thought Scarborough set him up to be robbed.
They say Devega also shot and killed Stephanie Powell Anderson, 39, during an April 10, 2008, robbery at a gas station in north Raleigh.
Devega has denied any involvement in the crimes – defense attorneys say there's no fingerprints or DNA – but Wake County prosecutors say he's guilty beyond a reasonable doubt. Ballistics evidence, they say, links him to the crimes, and witnesses, a family member and his ex-girlfriend all identified him as the culprit.
The jury started deliberating Tuesday morning and has since asked to examine and re-examine evidence, including frame-by-frame reviews of surveillance video from several of the robberies.
On Thursday, they asked to see security footage from a June 6, 2008, robbery at a Bojangles' on Durant Road and also video from a sporting goods store on Sept. 10, 2008, where Devega says he was during a robbery at Mexico Lindo check-cashing service on Wake Forest Road.
In that case, Modesta Fernandez-Lucas survived after being shot shot several times.
Jurors – allowed only to see the videos in open court – sat intently, leaning in from the jury box, looking deliberate and repeatedly asking for a replay of portions of video.
Jurors also asked for and were granted to view timesheets from Devega's job as an electrician's assistant. Prosecutors contend he didn't show up for work on the days of the crimes.
If Devega is found guilty of either first-degree murder charge, jurors will also hear testimony in a sentencing phase of the lengthy trial – now in its 12th week – before deciding his punishment.


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NetWellness is a global, community service providing quality, unbiased health information from our partner university faculty. NetWellness is commercial-free and does not accept advertising.
Thursday, September 21, 2017
Mouth Diseases
Tongue Bump and Gland Hurts
i have a large painful bump underneath the skin in the top of my tongue on the right side towards the tip. its about a half inch in size. also a gland i think under my jaw on the right side hurts. it has been like this for about a day now. what could this be?
There are a number of things that this set of symptoms could be.
- The tongue bump could be nothing more than trauma from biting the tongue.
- You may have a hematoma (bruise) that is presenting as a nodular swelling.
- You may also have a fibroma or fibrous tissue as a result of continuous tongue biting, and a small fibrous nodule has developed.
- You also may have a small lymph node that is swollen; again, a small nodular occurrence on the dorsum of the tongue.
- The swollen gland under the jaw may be a lymph node that is swollen or it may be a salivary gland that is swollen.
I would recommend that you have it evaluated by your dentist or physician to rule out an infection or other possible pathologic problems. There are many things it could be, and without examining the sites, I can only speculate on what is actually going on. Your dentist or primary care provider will be able to sort through these things and rule out any major problems
Richard J Jurevic, DDS, PhD
Formerly, Assistant Professor of Biological Sciences
School of Dental Medicine
Case Western Reserve University


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All Strip Clubs in Helsinki, Finland
Strip clubs in Helsinki. The City of Helsinki offers a variety of Bars, Pubs, Clubs, Nightclubs, Cafes and Restaurants making it easy to locate a venue which best suites your taste in foods, day or nightlife entertainment form and budget. The parting doesn't start till after 10pm, so get yourself some food beforehand and then hit the town, and the strip clubs in Helsinki of course.


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PRZOOM - /newswire/ -
Oceanside, CA, United States, 2007/11/16 - International corporate and personal concierge service to serve South Florida areas.
Excellence Property & Lifestyle Management, a high-end corporate and personal concierge service, has opened its doors in Palm Beach. Led by Russell Colodny and Victoria Brewer, the turnkey property management and concierge service is designed to help people in the Palm Beach and Jupiter areas with personal, corporate, and real estate/home services. Excellence Property & Lifestyle Management also offers various packages of lifestyle management services to individuals and companies, ranging from day-to-day tasks such as general up-keep of the home to more specialized jobs like helping newcomers relocate to South Florida, providing personal shopping or party planning services, staging a home for sale, and customizing luxury travel itineraries.
At the core of Excellence Property & Lifestyle Management is its Home Management Program, ideal for part-time residents as they open and close their properties for the season. Specifically, the company inspects and maintains homes, offering solutions from detailed weekly evaluations to performing preventative maintenance.
We have been in the real estate development, construction, and hospitality industries for many years, and our partners are carefully selected based on this experience. Our licensed and insured sub-contractors handle everything from maintaining your vehicle while youre here or away to a complete remodeling. Whether youre looking for a kitchen update or someone to get your home ready for the holidays, we handle it all for you, delivering, Confidence with One Call, explains Excellences Vice President and Style Maven, Victoria Brewer.
In addition to the new Palm Beach location, Excellence Property & Lifestyle Management (excelplm.com) has an office in Geneva, Switzerland. Inge Leutscher, founder and president of EXCELLENCE International, has 25 years experience in the luxury concierge and consulting industry and brings a worldwide network of partners and associates to South Florida via the new U.S.-based location.
Agency / Source: ScorePR.com / Innova Communications, Inc.
Availability: All Metropolitan Area
Traffic Booster: [/] Quick PRZOOM - Press & Newswire Visibility Checker
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text:
At King's, we value and nourish ideas. Discussions flow effortlessly and take you to unexpected places. Connections are made in classrooms, corridors and social spaces. From these interactions and shared experiences comes a supportive and engaged community that happens naturally, where academic pursuits blend with a vibrant campus life to create a truly satisfying educational experience.
firstname.lastname@example.com | 902 422-1271 ext. 259


text:
It only takes a minute to get started. Fill out our simple sign up form and login to the website.
This step is voluntary but will seriously increase your chances of getting interest from other Christian members on the site. Write a little something about yourself, your hobbies and attach a nice photograph of yourself.
Utilise our website's sophisticated search to encounter members who match your desired requirements. Or just look through listings of Christian singles and encounter members that attract you.
Discovered someone who appeals to you? Send a letter to them or just a wink and take it from there. With a little luck you'll be on your way to a lifetime of happiness.
It's quick and simple


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Mr. A. M. Lythgoe, instructor in Egyptology, will give the second lecture on "The Excavations carried on by the Hearst. Egyptian Expedition, 1899-1905" this evening at 8 o'clock in the Fogg Lecture Room. The special topic of the lecture will be "The Cemeteries of Girga."
The lecture will be open to the public.
Want to keep up with breaking news? Subscribe to our email newsletter.
Read more in NewsUniversity Calendar


text:
Oregon State's specialists
Updated 8:43 pm, Friday, December 28, 2012
PK Trevor Romaine
Vitals: #12, 5-11, 200, So.
Notable: Has been a starter in both seasons. Named All-Pac 12 honorable mention after converting 14 of 16 field goals, including current streak of 10 straight. Set school single-season record with 48 PATs this season. Kicked off 76 times with 34 touchbacks. Tied for third on the team with six special-teams tackles.
P Keith Kostol
Vitals: #48, 6-3, 189, So.
Notable: Walk-on who averaged 42.1 yards with three touchbacks and 22 fair catches on 55 kicks. Booted a career-best 61-yarder at UCLA. Eight of his kicks have been more than 50 yards.
Sports Channel
KR Terron Ward
Vitals: #28, 5-7, 195, So.
Notable: Produced 13 kick returns for 308 yards for 23.7-yard average per return. His longest kick return was 39 yards.
PR Jordan Poyer
Vitals: #14, 6-0, 190, Sr.
Notable: Accounted for nine of OSU's 12 punt returns this season, amassing 51 yards and a 5.7 yard per return average and the longest punt return of the season at 24 yards.


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SAN DIEGO (CNS) - The City of San Diego's new interim chief operating officer has released a video urging employees to continue working hard despite some of the recent news regarding Mayor Bob Filner.
[Video: Ekard's message to city employees]
The two-minute, 30-second video with Walt Ekard was posted on the city's website on Thursday.
"Our city is going through a rough time right now, and reading the news every day can be demoralizing," Ekard said. "But we have an important job to do, and we need to be focused on the task at hand."
Ekard, who retired last year as the County of San Diego's chief administrative officer, joined Filner's administration last week as part of a management shake-up that followed allegations that the mayor has sexually harassed women.
He was also accused of berating a top official in the City Attorney's Office and ordering police to remove him from a closed session meeting of the City Council.
The Filner administration is also under investigation for a policy change on a Kearny Mesa apartment complex after the developer donated $100,000 to the city, according to published reports. The money was later returned.
Ekard, who was widely praised during his tenure as the county's CAO, previously served Filner in an advisory role. His hiring has been viewed as an attempt by the mayor to steady the ship.
"Over the next few months, we'll be focusing on continuing to move this city forward, in spite of whatever distractions there might be," Ekard said.
He promised to improve internal communications so that "all employees have an opportunity to know where we are and where we're going as an organization." The Filner administration's communications efforts have been criticized since he took office.


text:
Hillis finds the end zone
Michael Fabiano | Tags:
Peyton Hillis just scored on an 18-yard run against the Chiefs. He's rushed for 43 yards on five carries and is well on his way to a huge fantasy performance.
In Arizona, Kurt Warner threw a 12-yard touchdown pass to Larry Fitzgerald to put the Cardinals ahead of the Rams by two scores. Tim Hightower scored the first touchdown on a short run.
And in the most meaningless touchdown in fantasy football history, 49ers OT Joe Staley recovered a fumble in the end zone against the Jets.
Guidelines: Fan feedback should be within the guidelines for the NFL community. These guidelines will be used to identify those comments that will be removed from display on the site. Please keep your comments relevant to the topic, not abusive or combatant towards other fans, and don't share any personal details. To report inappropriate comments, click the "X" that appears in the top right corner when your mouse is hovered over the chosen comment.
Comments may be no longer than 2000 characters and will post to the site shortly after submitting.


text:
- 100+ majors in 7 undergraduate schools and colleges
- 50 master's degree programs; 22 doctoral programs; M.D. program
- 4 pre-professional options (pre-medical, pre-dental, pre-vet, pre-law)
- Fully accredited by the New England Association of Schools and Colleges (NEASC) -- Read accreditation letter (PDF)
- Undergraduate: 10,267
- Graduate: 1,462
- Medical: 461
- Post-Baccalaureate Certificate: 23
- Non-Degree (CE): 892
- 1,600 full and part-time faculty
- 88% of full-time faculty hold a Ph.D. or the highest degree in their field
- Undergraduate student-faculty ratio: 15/1
- 4,660 undergraduate course offerings
- Average undergraduate class size: 30
- 98% of classes are taught by faculty (only 2% of classes are taught by graduate assistants)
Experience-based Learning
- 91% of seniors report being engaged in research, an internship or other experience-based learning/high impact practice during their time at UVM
- 38% of seniors report involvement in research with faculty mentor*
- 600 study abroad options in 70 countries; 32% of undergraduates studied abroad
- 99 service learning courses
Campus Life
- Undergraduates enrolled from 48 states
- More than 800 international students from over 65 countries
- 96 student veterans
- Over 200 student clubs and organizations, including a nationally recognized debate team and a student-run newspaper, radio station, TV station, rescue squad, legal services and many more academic, artistic, musical, cultural, ethnic, political, and religious clubs; 30 service clubs promoting health, literacy, and/or justice
- 54 club sports, some engaged in intercollegiate competition, and around 20 intramural teams
- 18 NCAA Division I Athletics teams (8 men's and 10 women's)
- Over 5,500 on-campus students live in 9 residential complexes with access to over a dozen dining facilities
- 75% of first-year students will live in a learning community (starting Fall 2017)
History and Tradition
- Founded 1791
- Fifth oldest university in New England (after Harvard, Yale, Dartmouth and Brown)
- First institution of higher education to declare public support for freedom of religion
- First university to admit women and African-Americans into Phi Beta Kappa honor society
- Called UVM for Universitas Viridis Montis, Latin for "University of the Green Mountains"
- Motto: "Studiis et Rebus Honestis" — "For studies and other honest pursuits"
- School colors: Green and gold
- Mascot: Catamount
Location -- Burlington, Vermont
- Burlington, Vt. (city population, 40,000; metro area population, 150,000)
- 220 miles northwest of Boston, 285 miles north of New York City and 90 miles southeast of Montreal
- Located on Lake Champlain -- a stunning lake with 587 miles (945 kilometers) of shoreline.
- 25 to 60 minutes to ski resorts, including Bolton Valley, Stowe, Sugarbush, Mad River Glen and Smuggler's Notch
- Named a top city for outside activities, the arts, safety and overall quality of life by Outside, The Huffington Post, Travel + Leisure, The New York Times, Arts & Entertainment, Traveler and other national media.
- Burlington's Church Street marketplace and mall feature national chains such as Lululemon, Athleta, Patagonia, Banana Republic, L.L. Bean, Urban Outfitters, GAP, Eddie Bauer, Abercrombie & Fitch, Macy's and Starbucks, as well as many locally owned stores and boutiques.
- 460-acre campus
- Libraries: Bailey/Howe (main library), Dana (medical library), Cook (physical sciences)
- Specialized facilities include: Lakeside Rubenstein Ecosystem Science; Stafford Center for Microbiology and Molecular Genetics; FAHC medical center; nine natural areas, including Mt. Mansfield summit; Weybridge Morgan Horse Farm; four research farms supporting animal and dairy science, horticulture, and maple research
Admitted Student Profile
Class ranking* of students admitted for Fall 2017
- Top 10%: 42%
- Top 25%: 78%
- Top 50%: 98%
*27% attended high schools reporting exact class rank.
SAT/ACT Score Ranges for Middle 50% of Admitted Students
Applications for Fall 2017
- First-year: 21,786
55% of first-year applicants applied early action
Campus Safety (Clery Act)
- The University of Vermont's annual security report includes statistics for the previous three completed calendar years concerning reported crimes that occurred on campus; in certain off-campus buildings owned or controlled by UVM; and on public property within, or immediately adjacent to and accessible from the campus.
- The report includes institutional policies concerning alcohol and drug use, crime prevention, the reporting of crime, sexual assault, and other important information and resource referrals. You can obtain a copy of this report at the Police Services website.


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Start : Wednesday, August 08, 2012 12:00 PM
End : Wednesday, August 08, 2012 01:00 PM
Add To Your Calendar
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text:
HR strives to support sound compensation practices across the university community. Use the following information to gain an understanding of the university's compensation philosophy and get a sense of the terms used to express different aspects of employees' compensation packages.
The University of Texas at Austin Compensation Philosophy
To fulfill its mission, the university must attract and retain outstanding staff members. To meet institutional staffing needs and priorities, the compensation system has the following objectives:
- Establish compensation levels for positions on the basis of their relative internal worth and external competitiveness within relevant labor markets
- Reward employees on the basis of work performance
- Administer pay equitably and consistently
- Establish a compensation policy that is consistent with the judicious expenditure of funds entrusted to the university
- Ensure accountability for compliance with The University of Texas System Board of Regents' Rules and Regulations and statutory requirements
Glossary of Terms
Use the following glossary of terms to help you understand various aspects of the university's compensation system.
- Benchmarks: The standards used as a basis for comparison or measurement.
- Benefit Replacement Pay: A portion of salary that eligible individuals receive to replace the state-paid FICA, a benefit no longer provided.
- Classification: A group of positions sufficiently similar in content of duties and responsibilities that the same university title is assigned to each position.
- Classify: The assignment of a position to a classification.
- Compensation: All forms of financial returns and tangible services and benefits employees receive as part of an employment relationship.
- COLA: An annual cost-of-living adjustment in wages to offset a change in purchasing power, such as a change measured by the Consumer Price Index.
- Direct Compensation:
- Base salary
- Premium payments (overtime, longevity pay, hazardous duty, shift differential, on-call pay, benefit-replacement pay)
- Contingent programs (achievement awards, merit pay, incentive pay)
- Effective Date of a Reclassification: Normally no earlier than the first day of the month in which Human Resources receives the reclassification document. Retroactive actions may affect overtime exemption status (FLSA) and pay. Temporary reclassifications are normally effective the date an employee is temporarily assigned duties and responsibilities that support a different classification.
- Essential Functions: The primary job functions or tasks that an individual must be able to perform with or without a reasonable accommodation.
- Exempt Job: A job not subject to the minimum wage and overtime provisions of the Fair Labor Standard Act.
- Fair Labor Standards Act (FLSA): Federal legislation that sets the federal minimum wage, overtime pay, equal pay, record keeping and child labor standards for employees who are covered by the act and are not exempt from specific provisions.
- Indirect Compensation:
- Protection programs (social security, workers' compensation, unemployment compensation, pension plans, health, dental, vision, life, accidental death and long-term disability insurance)
- Paid leave, when employees are not at work (vacation, holidays, jury duty, sick leave, military leave, etc.)
- Intangible Compensation: Non-monetary rewards (work/life balance, alternative work schedules, on-the-job training, development opportunities, etc.).
- Job Analysis: Systematic study of jobs to identify the observable work activities, tasks and responsibilities associated with a particular job or group of jobs.
- Job Code: Identification numbers assigned to designated job titles.
- Job Description: An official, written description of a job, which includes information regarding the general nature of the work to be performed and specific responsibilities, duties and qualifications.
- Job Title: A specific name given to a particular job that is used to identify that position.
- Mean Wage: The average wage for a worker in a specific position or occupation, which is determined by adding together the total wages for all incumbents in a specific position or occupation and then dividing it by the total number of incumbents.
- Median: The middle value in a series of values arranged in rank order.
- Median Wage: The value between the highest paid 50% and the lowest paid 50% of workers in a specific position or occupation.
- Merit Pay: An adjustment to individual salary based on performance.
- Non-Exempt Job: A job subject to the minimum wage and overtime provisions of the Fair Labor Standard Act.
- Overtime: Under the Fair Labor Standards Act, working more than 40 hours in a workweek. Non-exempt employees must be paid at least one and a half times their normal wage rates or receive compensatory time for all hours worked in excess of 40 in any workweek.
- Pay Plan: A structure for classifying positions into occupational families, which provides a framework for the assignment of job codes, job titles, FLSA, EEO codes and salary ranges.
- Position: A group of duties and responsibilities requiring the services of one person for the hours per week specified.
- Reclassification: A change in the classification or evaluation of a job assignment as a result of a significant job duty change.
- Salary Range: The span from minimum to maximum that constitutes a pay or salary range established for a particular job.


text:
" Type: Other Desserts "
PRICE: £1.49 per pack, each containing 2 x 90g pots
NUTRITIONAL INFORMATION (per pot):
Calories: 370
Kj: 1530
Protein: 3.0g
Carbohydrates: 19.0g
(of which sugars): 15.0g
Fat: 31.8g
(of which saturates): 19.8g
Fibre: 1.0g
Sodium: Trace
Equivalent as salt: Trace
Double cream (60%), Belgian dark chocolate (20%), buttermilk, Demerara sugar (Belgian dark chocolate contains cocoa mass, sugar, fat reduced cocoa powder, soya lecithin, vanilla)
Suitable for vegetarians
No artificial colours, flavourings or preservatives
Contains cow's milk, soya
Not suitable for nut allergy sufferers
Marks & Spencer Pot au Chocolat desserts come in packs of two. The outer cardboard wrapper and bears an image on the front of one of the pots with a spoonful of the dessert suspended over it. The nutritional information, ingredients list, dietary/allergy advice, storage instructions, M&S's contact details and recycling information is shown on one of the sides.
Firstly, one has to go through an elaborate unpacking process to actually get to the pots containing the desserts. The cardboard outer sleeve is difficult to tear, but once that has been managed and each dessert pot is released, there is a lot of grappling which has to be performed in order to remove the cellophane seal on top of the pots. There is a small marked area with a tear-open point, but it's not immediately visible - I had to turn the first pot around a couple of times before I could work out how to break and remove the outer seal. Once that task has been performed, the second seal has to be removed. This second seal is made of foil, and has a pulling tab - the tab is a little difficult to grasp, but once you've got hold of it, this foil seal is easier to remove than the outer cellophane one.
The pots containing the dessert are made of fairly thick ridged glass, and can be quite heavy to carry if you're doing a lot of other shopping.
The most important part of these desserts for me though, is the eating.
Each glass pot contains what looks like a very small serving of dessert. The dessert is a rich coloured muddy chocolate brown and looks rather bland, as there are no decorations such as piping, chocolate curls or cream. There isn't a noticeable smell of chocolate or anything else....nothing really to get the taste buds drooling in anticipation, as the dessert also has a rather boring appearance - but, appearances aren't everything.
For eating purposes and due to the smallness of the glass pots, the best size spoon to use is a teaspoon.
On digging the teaspoon into the dessert, it slides in nicely, and the consistency was a lot stiffer than I expected it to be - I'd say it's the same consistency as slightly softened ice cream. Moving the spoon to my mouth, I noticed no marked chocolate smell and hoped that the eating experience would be more exciting than the anticipation.
Once inside my mouth, this was when the fireworks truly began to explode....I'd even go as far as to say the earth almost moved! I gobbled down a whole 2 pots in no time, and was left begging on my knees for more, more, MORE!
These desserts have a beautifully rich dark Belgian chocolate flavour which is cocoa-ish more than creamy (that's OK though because I prefer my chocolate like that). The velvety smoothness feels divine inside your mouth, and the whole lot just melts and slides down your throat, leaving a beautiful chocolate sensation after-taste. There is a very definite real cream flavour present too, which comes from the presence of double cream rather than the chocolate being creamy, and the whole blend of chocolate and cream is a combination that transported me instantly into epicurean paradise.
I did try to eat the first pot slowly, so as to savour this new-found food sensation, but it was so delicious that I was unable to control myself, and the serving just vanished down my throat at the speed of light. My antidote to that was to begin scoffing the next one. Because of the pure unadulterated luxurious richness of this dessert, I was able to use a modicum of restraint on the second pot and thus could concentrate on savouring the dreamy creamy melty chocolate sensation for a bit longer.
I'm very glad that I bought two packs of these desserts, and am also glad that I don't live within easy reach of an M&S shop, otherwise I'd be living on them and very soon the lbs would pile on my already ample body frame to the point where I'd probably have difficulty passing through an average-sized doorway.
The down-side of these desserts are that they quite possibly are one of the most horrifically high in fat and calories things I've ever eaten, but on the other hand we can't expect food of this nature to be squeaky-clean and healthy.
Initially the price of £1.49 for two pots can seem a bit on the high side, but when all's said and done it is quite reasonable, because one pot would be more than ample for most people, due to the quite extreme richness of the dessert. Therefore, £1.49 as a dessert which would easily serve two people, I consider reasonable.
This is the kind of dessert that I think would be very suitable to serve after a special meal - for instance, if you are having dinner guests or are cooking something like a romantic anniversary meal for a partner. It wouldn't be easy to pass them off as your own creation though, because the desserts couldn't be transferred from the pots in which they are bought onto a plate, but you could maybe add a squirt of swirly cream to the top if you want something with a more decorative appearance; taste-wise though, it really doesn't need anything extra.
My only little gripe would be that the ridges on the inside of the glass pots do make it a bit difficult to scoop up every vestige of the dessert with a spoon, and it is awkward to get into the nooks and crannies.
I'd strongly recommend M&S Pot au Chocolat Desserts though, because they are luxurious, rich, delicious, chocolatey, creamy and utterly, utterly divine!
Thanks for reading!
~~ Also published on Ciao under my CelticSoulSister user name ~~
Type: Desserts / Brand: Marks & Spencer


text: Hi group, I feel really silly asking this, but I can't figure out how to install programs correctly. I copied the file from the "Downloads" folder into the "Applications" folder. Then I ran the installer file. It put an icon on my desktop but it contains an installer package. What am I missing here? Thanks in advance for the help. Blessings, Nicole> > Click on the link below to go to our homepage. > http://www.icanworkthisthing.com > > Manage your subscription by using the web interface on the link below. > http://www.freelists.org/list/macvoiceover > > Users can subscribe to this list by sending email to > macvoiceover-request@xxxxxxxxxxxxx > with 'subscribe' in the Subject field OR by logging into the Web > interface at http://www.freelists.org/list/macvoiceover >


text:
I have a rather large web site I maintain that runs PHP and connects to an IMAP server. The client wants to get quota information. Quota info can be retrieved from Cyrus but the PHP IMAP libraries only support quota info using the c-client libraries.
No problem I thought, Mail::Cclient is built on the c-client libs and I've used it to connect to our Cyrus server. PHP can just do the same, right? Wrong. imap_connect() is hanging indefinitley.
What am I left to? PHP source hacking. I'll have to hack the imap_get_quota() function to work with Cyrus. Sad thing is, it's probably a trivial fix, if any is needed at all.


text:
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text:
PRZOOM - /newswire/ -
New York, NY, United States, 2010/11/10 - Hoojobs is a new niche job board for the public relations, communications, and social media community, featuring an innovative design and user-friendly functionality.
Lindsay Olson and Jolie Downs, managing partners of the public relations and marketing staffing firm Paradigm Staffing, today unveiled Hoojobs.com. Hoojobs is a new niche job board for the public relations, communications, and social media community, featuring an innovative design and user-friendly functionality.
Having served the public relations and communications industry for over 10 years, Hoojobs founders, Lindsay Olson and Jolie Downs, had become used to hearing complaints from both job-seekers and hiring managers. Many job-seekers were overwhelmed with the complicated process of applying for jobs online. Signing up with several different job sites, each with lengthy, complex sign-up processes only makes finding a job more frustrating, says Olson. With this in mind, Hoojobs was designed to allow job-seekers to apply for jobs without having to create an account or re-create their resume. The candidates simply enter their contact information, attach their resume, and submit directly to the employer.
Employers in the PR and communications field also expressed interest in an online job board dedicated specifically to the community. Have you seen the crazy responses you get when you post on some of the larger, well-known job boards? Its not pretty. Hoojobs reduces the noise, saves time, and delivers candidates who better match the positions posted. We want to give employers a simple site to post their open positions and connect with their next hire, says Olson.
Hoojobs (hoojobs.com) was also designed to make navigating the site a truly user-friendly experience. The site features a live search tool that lets the user quickly find relevant results. The candidate can also sign up for job alerts based on search keywords and subscribe to an RSS feed of jobs relevant to their search. By offering integrated social media tools, Hoojobs also offers candidates to ability to easily e-mail a job listing to a friend or share it on Twitter, Facebook, and LinkedIn.
Its niche, its social, and its simple to use. Hoojobs is about making it easy for both employers and job-seekers in the industry.
Agency / Source: Hoojobs
Availability: All Regions (Including Int'l)
Traffic Booster: [/] Quick PRZOOM - Press & Newswire Visibility Checker
Distribution / Indexing: [+]


text:
Richard Le Gallienne
Richard Le Gallienne (1866-1947 / England)
» Click to list general statistics » OR, select a date :
My Books
What are my books?--My friends, my loves,
My church, my tavern, and my only wealth;
My garden: yea, my flowers, my bees, my doves;
read more >>
- Hits: Number of visitors who read the poem on the given date.
- Posts: Number of visitors who posted the poem to a friend (via e-mail) on the given date.
- Dates that have "0" hits may not be shown on the list.
- Dates, poems and poets that have "0" hits may not be shown on the list. Statistics are generated daily.


text:
Aloha-seyo, Koreans!
Two years ago, about 600,000 South Koreans visited the U.S. and many of them had to wait in line for hours outside the U.S. embassy in Seoul to get a visa. But last year, the U.S. started its visa-waiver program for South Koreans, cutting out much of the hassle.
U.S. officials say the number of visitors from South Korea will pass 1 million this year as a result of relatively strong economic conditions in Korea and the visa-waiver policies.
The big winner has been the state of Hawaii, where the number of South Korean visitors has more than doubled to over 100,000 this year.
"Since Hawaii is in such close proximity, Koreans are choosing Hawaii as their first U.S. destination to visit for leisure purposes," says Irene Lee, Seoul representative for Hawaii Tourism Authority, the state's tourism promotion agency.


text:
VBS offering leads to new home
WASHINGTON—For years, boys and girls attending Vacation Bible School at Washington, First have challenged each other to see which group can bring the largest offering during the week. Most of the time, the offering has gone to benefit the Oklahoma Baptist Homes for Children.
Last year, however, the children's gifts to the Lord stayed closer to home in this McClain County town of about 550 just northwest of Purcell, thanks to the vision of church secretary and VBS director Charlotte Singletary.
Singletary knew a young lady in the community—then 16-year-old Leah Hays—was facing brain surgery in August to help alleviate the debilitating effects of grand mal seizures she suffers as a result of a fetal stroke.
"We always have a huge VBS offering where the boys and girls have a little contest with coins," said pastor Davies Vanpool. "Generally, there are hundreds of dollars in pennies brought in, which we have the privilege of counting.
"This year, we decided we wanted to do something local and God just laid Leah on Charlotte's heart. She talked to me about it, and I saw it was an awesome deal and the boys and girls at VBS jumped on it. Then, when we had our big family day at the end of VBS, the moms and dads added to it and it just took off from there."
The children collected an amazing $1,100 on their own that week, and their parents gave another $1,600.
"The church added some more, so we were able to give Betty a check for $3,200 to help pay for the surgery," Charlotte said. Then, the local Methodist church gave $2,500, and money kept coming in and we were able to give Betty another check for $3,700.
Meanwhile, donations for Leah continued to come in. That's when Charlotte's vision grew into more than just helping with her surgery, and a plan for an "extreme home makeover, Washington-style" was born.
"People kept sending money, and that's when I decided we needed to try to fix their little house up," Charlotte recalled.
A short time later, church member Larry Mobley was asked to install a new water heater at the Hays home. He did so, but came away from the job with the uneasy feeling that the structure really needed to be replaced.
"I thought it really needed to be torn down," Mobley confessed.
"It was a piecemeal, wood frame house that had been brought in in three sections and put together, and honestly, you could see the ground through the floor in some areas," said Charlotte's husband, Larry Singletary.
So, on Sept. 18, 2008 Betty and Leah watched as their house was demolished to begin the process of building them a new one. It was an act of faith beyond measure.
"You have to remember, Betty stood out here and watched her house being torn down on faith," Larry Singletary said. "We didn't have any financial backers. We didn't have a money man saying OK, if this doesn't happen, I'll write a check. This was all God and all faith, and a lot of the faith came from Betty, believing God was tugging at Charlotte's heartstrings, saying you're going to do this. And God provided."
Now, whenever she gets the opportunity, Charlotte shares the story of her little group of about 100 children in VBS who stepped out in faith and changed the lives of a mother and daughter.
"I want people to see this is what can happen through VBS," she stressed. "It started there, and we should never doubt what God can do. It can start with the littlest ones among us who sometimes have the most faith of any of us."
On March 9, Betty and Leah, who had been living with Betty's mother for six months in Norman while the construction was completed, got to see their new brick, two bedroom, two bath, 1,056-square-foot home for the first time. KWTV reporter Doug Warner was on hand to broadcast the big "reveal" at 6:45 a.m.
As a crowd numbering around 50 applauded, they took possession of their home with tears of joy.
"I think this is the way God intended for us to treat one another when you look at the church model in the book of Acts," Vanpool said, "helping those, who through no fault of their own, find them in a circumstance in which they cannot help themselves.
"The church has bent over backwards and has done things that we don't see a whole lot of in today's world, and it just blesses your heart to know that when Christ gets ahold of someone's heart and gets ahold of everything in them, it is awesome."
It was especially gratifying to see the huge smile on Leah's face, the pastor said.
"Leah suffers from really severe grand mal seizures. Since VBS last year, she has had two brain surgeries, both of which worked for a time, but even as late as last week, she was still struggling with her seizures pretty severely," he said.
"As for Betty, over the course of years, taking care of a sick child like that, she has worked several jobs at a time. She has never been willing to just take what people give her; she has always wanted to work, and she is still doing that now.
"But, when you have a sick child like that, she has to be the caregiver and that's hard on employment, but she's a trooper."
Leah, who is home schooled, turned 17 in January.
"I can't believe this," Betty said as her daughter hugged friends and volunteers who had shown up for the occasion. "I'm so glad there are still people who follow Christ and want to be so humble. It's amazing. I never thought it would be like this. It's so wonderful. They're angels on Earth.
"I know Jesus puts a lot of humility and love and caring in our hearts, but to take it from your heart and give it to someone else is amazing. We are definitely surprised. I can't wait for all of my family to see it. They've done a great job with it.
Watching the delight on her daughter's face, Betty smiled and said, "Leah is doing OK. God has blessed her; He's kept her with us. We've had some stressful moments lately, and it has been hard at times. It's great to see her smiling so big. But she's really always done that.
"Sometimes she gets discouraged, but then she'll call her brother and sister-in law, and they'll pray with her and, of course, we pray, too."
After taking a tour of the furnished house and filling it with laughter, Leah took a moment to sit in a new recliner and reflect about what had just happened.
Asked what her favorite part of the new house was, she said, "Favorite part? I don't have a favorite part. I think it's the whole house; just to have the house. And knowing the people who did it did it out of love. That's my favorite part."


text:
A Phase 2 Trial of Antisense Nucleotide to PKC-Alpha (LY900003, ISIS 3521) Plus Gemcitabine and Carboplatin in Patients With Advanced, Previously Untreated Non-Small Cell Lung Cancer.
This study has been completed.
Eli Lilly and Company
Information provided by:
Eli Lilly and Company
ClinicalTrials.gov Identifier:
First received: August 2, 2002
Last updated: July 18, 2006
Last verified: July 2006
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
Detailed Description:
The purposes of this study are to determine the following:
Whether LY900003 plus gemcitabine and carboplatin can make your tumor smaller or disappear, and for how long.
If treatment with LY900003 plus gemcitabine and carboplatin can help you live longer.
The safety of LY900003 plus gemcitabine and carboplatin and any side effects that might be associated with the combination of these three drugs.
How LY900003 is distributed and broken down by your body when it is given with carboplatin and gemcitabine.
Whether LY900003 affects the way gemcitabine and carboplatin are distributed and broken down by your body.
|Carcinoma, Non-Small-Cell Lung Pulmonary Neoplasms Neoplasms, Lung
|Drug: Gemcitabine Drug: Carboplatin Drug: LY900003
|Phase 2
|Study Type:
|Study Design:
|Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:
|A Phase 2 Trial of Antisense Nucleotide to PKC-Alpha (LY900003, ISIS 3521) Plus Gemcitabine and Carboplatin in Patients With Advanced, Previously Untreated Non-Small Cell Lung Cancer.
Resource links provided by NLM:
Genetics Home Reference related topics: lung cancer
MedlinePlus related topics: Lung Cancer
Drug Information available for: Carboplatin Gemcitabine Gemcitabine hydrochlorideU.S. FDA Resources
Further study details as provided by Eli Lilly and Company:
|Study Start Date:
|June 2002
Definition: The phase 2 study will provide important information regarding effects of LY900003 on safety and efficacy of patients treated with gemcitabine and carboplatin. LY900003 will be given at approximately 2 mg/kg/day for the first 14 days of a 21-day cycle. The dose and schedule for LY900003 administration are based on results of prior studies of LY900003 and are currently being used in other studies of LY900003. Gemcitabine will be administered on Days 1 and 8 at 1250 mg/m2 and carboplatin will be given on Day 1 at AUC 5.
|Ages Eligible for Study:
|18 Years and older (Adult, Senior)
|Sexes Eligible for Study:
|Accepts Healthy Volunteers:
Inclusion Criteria:
- Diagnosis of Non-Small-Cell Lung Cancer.
- Stage IV or Stage IIIB disease.
- ECOG Performance Status of 0 or 1.
- Adequate organ function
- One unidimensionally measurable lesion.
Exclusion Criteria:
- Prior therapy for NSCLC.
- Serious concomitant disorders.
- Untreated CNS metastases.
- Uncontrolled, active infection.
- Previous LY900003/ISIS trial participation.
Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00042679
Please refer to this study by its ClinicalTrials.gov identifier: NCT00042679
|United States, California
|Bakersfield, California, United States
|Berkeley, California, United States
|Torrance, California, United States
|United States, Florida
|Miami Beach, Florida, United States
|United States, Illinois
|Chicago, Illinois, United States
|Park Ridge, Illinois, United States
|United States, Maryland
|Baltimore, Maryland, United States
|United States, Tennessee
|Chattanooga, Tennessee, United States
|United States, Texas
|Lubbock, Texas, United States
|United States, Virginia
|Charlottesville, Virginia, United States
|United States, Wisconsin
|Milwaukee, Wisconsin, United States
Sponsors and Collaborators
Eli Lilly and Company
More Information
Keywords provided by Eli Lilly and Company:
Additional relevant MeSH terms:
ClinicalTrials.gov processed this record on September 20, 2017
|ClinicalTrials.gov Identifier:
|NCT00042679 History of Changes
|Other Study ID Numbers:
|Study First Received:
|August 2, 2002
|Last Updated:
|July 18, 2006
Keywords provided by Eli Lilly and Company:
Non-Small-Cell Lung Cancer
Carcinoma Squamous
Adult Lung Cancer
Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
ClinicalTrials.gov processed this record on September 20, 2017