text:
Hepatitis C: Current Standards of Care and Future Perspectives
Robert G. Gish , M.D.
(Download the pdf version)
Hepatitis C affects approximately 4-5 million people in the United States with nearly 75% having long-term hepatitis C virus (HCV).1 Even with advances in treatment, about one half of patients will not achieve an SVR.2;3 Pegylated interferon and ribavirin combination therapy is currently the standard of care for the treatment of chronic hepatitis C.4 Overall, sustained virologic responses (SVR) – defined as undetectable HCV RNA in the serum – greater than 50% have been reported from pivotal registration trials. However, pegylated interferon and ribavirin therapy is associated with a high incidence of side effects, including hematologic complications. Hematologic side effects are particularly common; bone marrow suppression caused by interferon may result in neutropenia and thrombocytopenia, and ribavirin is directly toxic to red blood cells and is associated with hemolysis, which is usually dose-related and generally self-limiting.4 The standard recommendation for management of hematologic side effects of interferon and ribavrin therapy has been dose reduction.4 More recently, there has been increasing emphasis on the use of growth factors such as filgastrim and erythropoietin to stimulate bone marrow production of leukocytes and erythrocytes to allow patients to receive the optimal doses of interferon and ribavirin rather than have the patient undergo dose reduction and risk a decrease in SVR.5 This practice is consistent with the available data suggesting that maintenance of optimal doses and adherence during therapy is associated with the best SVR rates.6;7 A study published in abstract form by Schiffman et al.8 examined the use of erythropoietin at the onset of therapy to maintain hemoglobin between 12-15 g during treatment; three groups were treated with weight based ribavirin (800 to 1600 g/day). A significant increase in SVR rates was observed in the group that received the high weight based ribavirin dose (1000-1600 mg/day).
Standard of Care
Recently the importance of adherence throughout therapy was studied with regards to its affect on SVR.8 Maintaining the optimal dose of both interferon and ribavirin is particularly critical in the first 12 to 20 weeks of therapy.9 One factor that determines adherence is the quality of life of patients during therapy. Another important determinant of adherence is the ability to manage the side effects of therapy including hematologic management.10
There is clear evidence that the response to interferon and ribavirin is greatest among patients who receive the optimal dose of interferon and ribavirin albeit this conclusion comes from retrospective studies. Much of the data has been compiled from post-hoc analyses of the pivotal trials with pegylated interferon alfa-2a and pegylated interferon alfa-2b.
The overall SVR among patients in the pegylated interferon (PEG-IFN) alfa-2b pivotal trial was approximately 54%. However, subgroup analysis among patients who were able to maintain at least 80% of each of the 2 medications for at least 80% of the time demonstrated an SVR of 63%. Among those who did not maintain at least 80% of the doses at least 80% of the time, the sustained response rate was 52%.
Among patients with HCV genotype 1, the patients that are the hardest to clear the virus in, only 34% of patients who did not maintain adherence to the "80-80-80" rule had an SVR. These data, albeit retrospectively derived, strongly suggest that adherence to optimal dosage regimens does in fact improve SVR.
Recent studies have shown that an early virologic response (EVR) is another important predictor of SVR; furthermore, adherence during the first 12 weeks appears to be a predictor of EVR. Davis et al.10 showed that patients who were able to maintain at least 80% of each of the drugs during those first 12 weeks had an 80% likelihood of achieving EVR. Shiffman et al. also showed that SVR was lower among patients who were unable to maintain optimal dosing for 20 weeks.10 Therefore, it is essential that treatment of hepatitis C should focus on the use of optimal dosage of therapy and attempts to minimize side effects to allow adherence.
Dosage and Duration
of Therapy
Identifying the correct PEG-IFN /ribavirin dosage and the correct duration for each of the HCV genotypes was the aim of a study led by Hadziyannis et al. There were 4 arms in this study: 2 groups received weight-based ribavirin for 24 and 48 weeks, while the other 2 groups received "flat-dose" ribavirin for 24 and 48 weeks, respectively.11 The study addressed 2 problems, namely the optimal duration of therapy and the optimal ribavirin dose.
Results showed that the responses among patients with HCV genotypes 2 and 3 were similar among groups regardless of ribavirin dose or duration of therapy (24 or 48 weeks). For patients with HCV genotypes 2 and 3, the National Institutes of Health recommended 24 weeks of therapy with PEG-IFN and ribavirin at a dose of 800 mg a day, regardless of a patient's weight.
A recent trial by Zeuzum et al. compared response rates between patients with genotypes 2 and 3.12;13 All patients were treated for 24 weeks of PEG-IFN and weight-based ribavirin. The SVR was higher among genotype 2 patients compared to those with genotype 3 (93% vs 79%, respectively). This difference was largely due to lower SVR among genotype 3 patients with high viral load. Treatment of genotype 3 with 48 weeks of medication has been proposed for high viral load patients but still needs to be confirmed in prospective studies. Among patients with genotype 1, there was a clear, almost linear response, with the best response rate among patients who received PEG-IFN and weight-based ribavirin for 48 weeks. There was an 11% lower rate of SVR among those who received flat-dose rather than a weight-based ribavirin dose.7 This study, among others, supports the use of PEG-IFN and weight-based ribavirin dosing for 48 weeks for patients with genotype 1 HCV. Short term therapy of 12, 14 or 16 weeks is now being considered by a variety of specialists.12;13
A preliminary study presented at the 2004 American Association for the Study of Liver Diseases meeting suggested that prolonged therapy may increase SVR among patients with a "slow" or "delayed" virologic response. Sanchez-Tapias et al. randomized patients with detectable virus after 4 weeks of therapy to 48 or 72 weeks of therapy. The SVR was superior among patients who had received the longer duration of therapy (46% vs 32%) due to a reduced relapse rate.31
A preliminary study presented at 2005 Digestive Disease Weekly meeting suggested that high dose retreatment with PEG-IFN may increase SVR. Gross et al. randomized 650 patients to receive PEG-IFN at 0.5 ug/kg, 1.5 ug/kg or 3.0 ug/kg. Incremental SVR increases were reported in the three groups (4%, 7% and 11% respectively).14
Hematologic Complications of Today's Treatments
Cytopenias are among the most common complications of interferon and ribavirin combination therapy. These include neutropenia, thrombocytopenia and anemia.
Neutropenia is generally defined in many trials as an absolute neutrophil count of less than 750. The cause is usually IFN-induced bone marrow suppression. PEG-IFN causes more neutropenia than standard IFN. The clinical significance of neutropenia associated with IFN therapy is unclear. A study from the NIH suggested that low neutrophil counts in patients being treated with interferon were not associated with an increased incidence of infections.15 A second study published in abstract form by Jacobsen et al. examined the data on more than 4,000 patients treated with PEG-IFN alfa-2b and ribavirin. This study, entitled the "WIN-R" trial, found that infections were reported in only 30 patients (0.7%). Serious infections were not associated with low absolute neutrophil counts. Based on these data, the investigators suggested relaxing the criteria for dose reduction of PEG-IFN.16 Instead consideration should be given to using the growth factor for white blood cells (GCSF) to treat the neutropenia, rather than lowering the dose. Although GCSF is not specifically indicated for treatment of neutropenia associated with PEG-IFN therapy, GCSF at a dose of 300 mcg subcutaneously 3 times weekly may be considered for maintenance of neutrophil counts during therapy. The use of this agent could occur when dose reductions with the package insert suggest changes, or at an ANC of 250 in patients without cirrhosis or 500 in patients with cirrhosis, to be more conservative with GCSF use.
Thrombocytopenia, defined as platelet count of less than 75,000 is another problem seen with PEG-IFN therapy and is also related to IFN-induced bone marrow suppression. Rustgi et al. authored a brief report addressing the role of oprelvekin (recombinant IL-11), the growth factor for platelets, to support thrombocytopenia associated with PEG-IFN therapy.13 The main side effect of oprelvekin is edema, which frequently requires diuretic therapy. However, it is the opinion of many experts that thrombocytopenia due to PEG-IFN therapy is rarely associated with any clinical manifestations. Even patients who have very low platelet counts appear to do well with PEG-IFN. An alarm level of platelets at 20,000 should prompt immediate therapy discontinuation in any patient, and dose reduction or very close laboratory monitoring at a platelet count of 30,000.
Hemolytic anemia related to ribavirin is the major hematologic complication associated with the treatment of HCV. The onset of anemia is observed very soon after initiating therapy; the greatest decrease in hemoglobin is noted approximately 4 to 6 weeks into the course of therapy. The decrease in hemoglobin level is generally in the range of 2.5g/dL to 3.0 g/dL; however, hemolytic anemia may be much more severe. The etiology of hemolysis related to ribavirin is caused by direct cytotoxicity to erythrocytes; hemolysis may therefore reverse with discontinuation of therapy.
Sulkowski and colleagues conducted a retrospective analysis of anemia associated with ribavirin therapy from 2 large studies of standard IFN and ribavirin combination therapy.17 A total of 595 patients were evaluated. The dose of ribavirin was 1,000 mg per day or greater; interferon dosage consisted of 4-weeks of therapy with 3 million units daily followed by three times per week with 3 million units three times per week. Anemia was found to be very common in this population; over 30% of patients had a decrease in hemoglobin of ≥25% or greater. Older age, renal function and hemoglobin level at baseline were factors associated with a significant decrease in hemoglobin. Men had a greater reduction in serum hemoglobin compared to women. A decrease in hemoglobin level of ≥3 g/dL was observed in 40% of men. Additionally, hemoglobin levels in the "critical" range (<10 gm/dL) were more often observed in women. Dose reduction of ribavirin occurred in women 4 times more often than in men.17
A number of possible mechanisms have been proposed to explain the hemolytic anemia caused by ribavirin. These include oxidative damage to erythrocyte membranes as well as damage to mitochondria, which may be mediated by depletion of adenosine triphosphate (ATP). Ribavirin is concentrated in red blood cells, where it is phosphorylated via adenosine kinase to its monophosphate, diphosphate and triphosphate forms, which are the pharmacologically active compounds. These ribavirin-phosphate conjugates are trapped within erythrocytes as a mixture and are gradually cleared slowly from red cells (half-life of 40 days). Ribavirin is much more rapidly cleared from plasma (half-life 24 hours). Steady-state concentrations of ribavirin are achieved after 2 to 4 weeks of treatment, at which time concentrations within red cells exceed plasma concentrations by a ratio of 60 to 1. De Franceschi and colleagues found that erythrocyte ATP levels were significantly decreased in the presence of RBV and basal hexosemonophosphate shunt (HMS) activity was increased, suggesting increased susceptibility of erythrocytes to oxidative stress.18 Ribavirin therapy in patients with chronic HCV demonstrated decreased activity of red cell Na+-K and increase in markers of oxidative stress such as malondialdehyde, reticulocytosis and evidence of increased sequestration of red cells by the reticuloendothelial system.
Another recent study examined markers of oxidative stress among patients with HCV before and after treatment with ribavirin and in normal controls. Some of the patients also had concomitant G6PD deficiency.17 Incubation of erythrocytes with dipyridamole (DPD), diethylmaleate (DEM) and glutathione ester (GSHE) showed that DEM augmented ribavirin-induced decrease in cellular glutathione, protein sulfhydrils, and osmotic resistance. Coadministration of GSHE and DPD prevented the ribavirin-induced decrease in osmotic resistance, ATP, and 2,3-diphosphoglycerate and reduced oxidative stress, as demonstrated by improved protein stability, increased glutathione levels and formation of thiobarbituric acid reactive substances (TBARs), commonly used markers of oxidative stress. The implications of this study are that erythrocyte antioxidant levels may influence ribavirin-induced cytotoxicity.
The Importance of QOL
The importance of adherence to treatment throughout therapy is probably the single-most important factor that may positively influence response. In particular, adherence during the first 12 weeks is critical, as well as the ability to deliver the optimal dose of ribavirin as demonstrated by Shiffman and colleagues.18 It is well recognized that an important factor influencing adherence is the quality of life during therapy. Management of side effects, in particular the neuropsychiatric sequelae is important; management of hematological complications is also critical because symptomatic anemia may result in significantly decreased quality of life during therapy and may lead to dose reduction or even discontinuation of therapy.
While it has generally been assumed that there is a direct relationship between the severity of side effects, quality of life, and, consequently, adherence, resulting in a lower SVR, detailed studies examining these associations have been carried out only recently.19
The incidence of dose modification due to anemia alone in the large multi-center trials was 22% in a study led by Fried et al., and 9% in Manns et al. However, it is important to remember that patients in the latter trial were given a lower dose of ribavirin than is currently used for genotype 1 disease. In a comparable large trial with PEG-IFN alfa-2b that compared viramidine to weight-based ribavirin, a comparable 25% of patients had a decrease in hemoglobin level to <10 g and would therefore have met criteria for dose reduction according to the package insert.19
In clinical practice, dose reduction is often performed even if the hemoglobin has not reached a nadir level of 10 g, since many patients become symptomatic with anemia with a 3 g to 4 g decrease from a baseline value of 16 g to 17 g. Addition of a growth factor to avoid dose reduction is becoming increasingly common, as the addition of epoetin alfa can reverse the anemia associated with ribavirin.19;20 Ribavirin induces hemolysis by direct cytotoxicty to erythrocytes in a dose-dependent manner that is reversible with discontinuation. The cause of anemia is the loss of a compensatory reticulocytosis due to ribavirin and bone marrow suppression by IFN or PEG-IFN. By promoting erythropoeisis, epoetin alfa therapy can overcome the effect of bone marrow suppression.
A recent controlled trial randomized patients with a decrease in hemoglobin to <12 g while on PEG-IFN/ribavirin therapy to receive epoetin alfa or placebo.21 After 8 weeks of double blind treatment, all patients previously given placebo were crossed over to receive open-label epoetin alfa. The initial dose of epoetin alfa used was 40,000 international units (IU) administered subcutaneously once a week. The dose was titrated up to 60,000 IU if the hemoglobin did not respond within 4 weeks. The objective of the study was to determine whether the use of epoetin alfa in comparison to placebo was superior in allowing maintenance of the desired ribavirin dose, alleviated anemia and its symptoms and, in turn, improved quality of life. The researchers reported that ribavirin dose was maintained in a higher proportion of patients who received received epoetin alfa (88% vs 60%) during the first 8-week period of treatment with PEG-IFN and ribavirin.
The subsequent data from this study were recently published. The latter study found that even with a relatively short duration of epoetin alfa therapy, ribavirin dose was maintained throughout the entire duration of therapy. There was a significant change in the hemoglobin level only during the period of epoetin alfa treatment. Hemoglobin levels in the placebo group increased to levels comparable to the group receiving epoetin alfa after crossover to active treatment – the ribavirin dose was maintained despite this. Although the SVR was 8% higher in the treated group, the study was not powered to show a difference in SVR between treatment and placebo groups.
Another important endpoint in this study by Pockros and colleagues was the effect of epoetin alfa on quality of life. Health-related quality of life scores were significantly higher in the epoetin alfa patients, in particular the vitality scores. Nausea was reported more commonly by patients treated with epoetin alfa at a slightly greater rate in the treatment group than the placebo group. Otherwise, there was no difference in the incidence of side effects between the 2 groups. Pockros and colleagues emphasize caution to avoid high hemoglobin values with epoetin alfa because of the risk of cerebral or other thrombosis.22
The other concern regarding the use of epoetin alfa is the development of pure red cell aplasia (PRCA). Two such cases have been reported in the United States associated with erythropoietin treatment in hepatitis C patients. The clinical signs included lack of response to epoetin alfa and progressive anemia. There was resolution of PRCA in both cases with discontinuation of epoetin alfa therapy.32 Pockros et al. recommended that ribavirin and erythropoietin therapy, as well as IFN should be discontinued in the setting of PRCA, in addition to follow up of reticulocyte count and testing for antibodies against red blood cells along with transfusions if necessary and consultation with a hematologist. The package inserts for epoetin alfa include a safety note to this effect.33 Pockros et al. found that, compared to placebo, epoetin alfa therapy resulted in a significantly greater proportion of patients maintaining their desired ribavirin dose. Treatment was associated with a higher hemoglobin and better quality of life. Although epoetin alfa was well-tolerated in this study, the authors recommend that patients be monitored for the development of pure red cell aplasia and possible CNS effects during therapy and urge caution to avoid "overshooting" hemoglobin levels to higher than normal.
Current Treatment Challenges
The SVR with PEG-IFN/ribavirin therapy has increased greatly from the initial reports of 10% in 1990 to approximately 50% in the current era. However, this leaves nearly one-half of the HCV population in the category of relapsers and non-responders.
A major challenge in the management of HCV is overcoming treatment barriers among individual patients. One major factor influencing response is the frequent presence of insulin resistance and hepatic steatosis among patients with HCV. Studies have suggested that it occurs in nearly one half of CHC patients.23 A large proportion of patients with hepatic steatosis are obese or have a body mass index >30. It is thought that non-alcoholic fatty liver disease (NAFLD) associated with obesity may be the major cause of liver disease in the United States and may become an important cause of morbidity and mortality from liver disease in the coming decades. NAFLD may interact negatively with HCV, results in faster progression of fibrosis and lowers response rates to treatment, although the exact mechanisms have not been fully elucidated.24
There is also evidence that HCV, particularly in patients with genotype 3, may independently lead to hepatic steatosis even in the absence of other risk factors for steatosis, such as obesity or type 2 diabetes mellitus.25;26 Successful treatment in this setting may lead to resolution of steatosis. However, the presence of visceral obesity, as observed in patients with metabolic syndrome and with a BMI >30 is associated with more advanced liver disease and lower response rates to therapy. Therefore, possible intervention for obesity and hepatic steatosis should be considered prior to initiating therapy.
Special Populations
In addition, certain groups have substantially lower response rates to the current treatment regimens including African-American patients and HIV/HCV-coinfected patients.27-29 HIV coinfection with HCV presents treatment challenges and is characterized by more aggressive liver disease. Furthermore, SVR is generally lower among coinfected patients than among HCV mono-infected patients. The best current results are from the AIDS Pegasys Ribavirin International Coinfection (APRICOT) trial, which reported a 40% SVR with PEG-IFN, compared to 20% in the control group, (usually a standard IFN and ribavirin treatment).30
African-American populations represent another challenging group with regard to PEG-IFN/ribavirin therapy. Two prospective trials so far have demonstrated that using the same regimens, African-Americans respond only half as well to therapy as Caucasian patients treated with the same drug therapy. Factors associated with SVR include genotype, RNA levels, histology, race, co-infection, and adherence. The response rates to re-treatment with PEG-IFN/ribavirin are highly variable ranging from 4% to 13% of patients previously treated to 0% to 3% among African-American patients who previously did not respond to a course of therapy.
In summary, current therapies have provided unprecedented success in our ability to cure chronic hepatitis C viral disease, but therapy is not always a success. Therefore, there remains an unmet need for other therapies for such patients.
Standard of Care?
Currently, there are new therapeutic approaches being investigated in an effort to augment SVR rates in all patient groups, especially those who currently have a poor response to therapy. Several novel IFNs, interferon delivery systems, IRES inhibitors, ribavirin-like molecules, protease and polymerase inhibitors, newer immunomodulators, and other hepatitis C replication enzyme inhibitors are currently being studied in clinical trials. In addition, antifibrotic agents, caspase inhibitors and antibody therapies and vaccines are also under development.
The treatment of chronic HCV has advanced greatly over the last 15 years. SVR rates have increased almost 5-fold over the past decade such that overall, 50% to 60% of patients with chronic HCV can expect an SVR with therapy. The current standard of care is PEG-IFN and ribavirin therapy, administered weekly for 48 weeks to patients with genotype 1 infection and for 6 months to patients with genotypes 2 and 3 infection. The importance of maintaining optimal doses of interferon and ribavirin for the defined duration of therapy has placed greater emphasis on adherence. Therefore, management of neuropsychiatric and hematologic complications during therapy with antidepressants and growth factors has taken precedence to dose reduction. Epoetin alfa is effective in helping to maintain ribavirin dosage among patients with chronic HCV and has been shown to improve quality of life. There are now data to support that this strategy may be associated with improved SVR rates, although very large licensing trials that would provide more definitive data are awaited to clearly demonstrate that the use of epoetin alfa improves SVR among patients being treated with PEG-IFN and ribavirin, and lead to more expanded use and easier reimbursement.
Please visit the HCV Advocate Web site's The Medical Writers' Circle article "Future Therapies for Hepatitis C" by Robert Gish, MD for more information on new therapeutic approaches.
Reference List
1 Gish RG, Afdhal NH, Dieterich DT, Reddy KR. Management of hepatitis C virus in special populations: patient and treatment considerations. Clin Gastroenterol Hepatol 2005; 3(4):311-318.
2 Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358(9286):958-965.
3 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr. et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347(13):975-982.
4 National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C 2002 (June 10-12, 2002). Gastroenterology 2002; 123(6):2082-2099.
5 Tien PC. Management and treatment of hepatitis C virus infection in HIV-infected adults: recommendations from the veterans affairs hepatitis c resource center program and national hepatitis C program office. Am J Gastroenterol 2005; 100(10):2338-2354.
6 Sterling RK, Hofmann CM, Luketic VA, Sanyal AJ, Contos MJ, Mills AS et al. Treatment of chronic hepatitis C virus in the virginia department of corrections: can compliance overcome racial differences to response? Am J Gastroenterol 2004; 99(5):866-872.
7 Kraus MR, Schafer A, Csef H, Faller H, Mork H, Scheurlen M. Compliance with therapy in patients with chronic hepatitis C: associations with psychiatric symptoms, interpersonal problems, and mode of acquisition. Dig Dis Sci 2001; 46(10):2060-2065.
8 McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123(4):1061-1069.
9 Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology 2003; 38(3):645-652.
10 Shiffman ML, Di Bisceglie AM, Lindsay KL, Morishima C, Wright EC, Everson GT et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology 2004; 126(4):1015-1023.
11 Hadziyannis SJ, Sette H, Jr., Morgan TR, Balan V, Diago M, Marcellin P et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140(5):346-355.
12 von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 2005; 129(2):522-527.
13 Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, Sanchez-Tapias J et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40(6):993-999.
14 Shiffman ML, Hubbard S, Wilson M, Salvatori JJ, Sterling RK, Stravitz RT et al. Treatment of chronic Hepatitis C virus (HCV) genotype 1 with peginterferon alfa-2b(PEGIFN), high weight based dose ribavirin (RVN) and Epoetin alfa (EPO) enhances sustained virologic response (SVR). Hepatology [Nov], abstract. 2005.
15 Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K et al. Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002; 36(5):1273-1279.
16 Ong JP, Younossi ZM. Managing the hematologic side effects of antiviral therapy for chronic hepatitis C: anemia, neutropenia, and thrombocytopenia. Cleve Clin J Med 2004; 71 Suppl 3:S17-S21.
17 Sulkowski MS. Anemia in the treatment of hepatitis C virus infection. Clin Infect Dis 2003; 37 Suppl 4:S315-S322.
18 De Franceschi L, Fattovich G, Turrini F, Ayi K, Brugnara C, Manzato F et al. Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 2000; 31(4):997-1004.
19 Gish RG. Treating HCV with ribavirin analogues and ribavirin-like molecules. J Antimicrob Chemother 2006; 57(1):8-13.
20 Gish RG. Maximizing the benefits of antiviral therapy for HCV: the advantages of treating side effects. Gastroenterol Clin North Am 2004; 33(1 Suppl):xxiii-xxxiv.
21 Afdhal NH, Dieterich DT, Pockros PJ, Schiff ER, Shiffman ML, Sulkowski MS et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study. Gastroenterology 2004; 126(5):1302-1311.
22 Pockros PJ, Shiffman ML, Schiff ER, Sulkowski MS, Younossi Z, Dieterich DT et al. Epoetin alfa improves quality of life in anemic HCV-infected patients receiving combination therapy. Hepatology 2004; 40(6):1450-1458.
23 Choudhury J, Sanyal AJ. Clinical aspects of fatty liver disease. Semin Liver Dis 2004; 24(4):349-362.
24 Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004; 126(2):586-597.
25 Cholet F, Nousbaum JB, Richecoeur M, Oger E, Cauvin JM, Lagarde N et al. Factors associated with liver steatosis and fibrosis in chronic hepatitis C patients. Gastroenterol Clin Biol 2004; 28(3):272-278.
26 Gordon FD, Pomfret EA, Pomposelli JJ, Lewis WD, Jenkins RL, Khettry U. Severe steatosis as the initial histologic manifestation of recurrent hepatitis C genotype 3. Hum Pathol 2004; 35(5):636-638.
27 Alvarez DF, Latorre JS. Hepatitis C virus and HIV coinfection: clinical management and new strategies. AIDS Read 2004; 14(10 Suppl):S16-S21.
28 Daniel S. Chronic hepatitis C treatment patterns in African American patients: an update. Am J Gastroenterol 2005; 100(3):716-722.
29 Fleckenstein J. Chronic hepatitis C in African Americans and other minority groups. Curr Gastroenterol Rep 2004; 6(1):66-70.
30 Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E, Gonzalez-Garcia J, Lazzarin A et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351(5):438-450.
31 M Diago, Manuel Romero-Gomez, J Crespo, A Olveira, R Perez, R Barcena, Jose M. Sanchez-Tapias, M Munoz-Sanchez. Peginterferon Alfa-2a (40kd) (Pegasys®) and Ribavirin (Copegus®) in Patients Infected with HCV Genotype 1 Who Failed to Respond to Interferon and Ribavirin: Final Results of the Spanish High-Dose Induction Pilot Trial. American Association for the Study of Liver Diseases, 2004, Poster #522.
32 Stravitz RT, Chung H, Sterling RK, Luketic VA, Sanyal AJ, Price AS et al. Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C. Am J Gastroenterol. 2005;100:1415-19.
33 The Package Insert for PROCRIT® (Epoetin alfa) can be found here
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Element is one of the biggest brands in the game. With a whole range of skateboards, footwear and clothing, they pretty much have it covered. The brand logo is recognisable globally and is available around the world. Their clothing collection contains a huge range of apparel including hoods, jackets, jeans, t-shirts.


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Comic Book Convinces Kenyans to Dye Their Chickens Pink
March 07, 2014
It also has good advice about chickens.
Trigger Happy
March 03, 2014
It has moved from blogs and into college classes. Can it be stopped?
Some Cities Are Promising Free College to High School Students. Does It Work?
February 21, 2014
If a college degree is the new high school diploma, why not make higher education free? These cities did.
How Much Is Too Much to Spend on College? One Study Has an Answer.
February 16, 2014
Two new studies show college is still a great investment.
Let's Stop Pretending That French Is an Important Language
February 02, 2014
The idea that American-born children need to learn French has become more reflex than action, like classical music played at the wedding of people who live to modern pop.
How Taxpayer-Funded Schools Teach Creationism—and Get Away With It
January 30, 2014
It's National School Choice Week, and among the latest controversies is whether and to what extent publicly funded alternatives to traditional public schools should be held to the same test-based accountability standards.
David Brooks Forgot to Do His Research Before Writing About Poverty and Pre-K
January 24, 2014
He says we've "made two mistakes" in helping underprivileged children. His column has more mistakes than that.
What Obama's New Task Force Should Do to Fight College Rape
January 23, 2014
Experts suggest the administration's way forward on campus sexual assault.
A Crash Course in California Politics
January 19, 2014
Corinthian Colleges is one of the worst-performing higher education companies in the country. So why did the California government let it off the hook?
Would You Send Your Kids to a School Where Students Make the Rules?
January 05, 2014
This school claims to take the angst out of education. The results make it look that way—among other things.


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text: Islamic Law and Human Rights Return to Course Catalog Professor Kristen Stilt Spring 2015 Reading Group Meets: W 5:00pm - 7:00pm in WCC Room 4057 1 classroom credit This reading group will address difficult questions in the contemporary world at the intersection of human rights law and some interpretations of Islamic law. Topics to be examined include religious freedom, free expression, sexual relations and sexuality, gender equality, the rights of children, and public dress and behavior. The reading group will focus on how human rights organizations—international, regional, and local—have worked on cases in these areas of concern, and will consider how such organizations can most effectively address issues that involve religious belief. Students will be evaluated on the basis of class participation and short papers on the assigned readings. Students who enroll in the reading group should have some familiarity with international law and human rights law in particular, but there are no specific pre-requisites. Note: This reading group will meet on the following dates: 1/28, 2/4, 2/11, 2/18, 2/25, and 3/4. Subject Areas: Human Rights , International, Comparative & Foreign Law .


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Slow Cooker Moroccan Lamb Tangine
The slow cooker replicates the moist, gentle cooking of an actual Moraccan tangine; a ceramic vessel traditionally used to make the stew.
1 1/2 pounds boneless lamb shoulder or lamb stew meat
1/2 teaspoon salt
1/2 teaspoon ground ginger
1/2 teaspoon ground cumin
1/4 teaspoon ground turmeric
1/4 teaspoon ground cinnamon
1 1/2 cups coarsely chopped, peeled sweet potato
2 medium carrots, cut into 1-inch pieces
1/2 cup chopped onion (1 medium)
1/3 cup chopped roma tomato (1 medium)
1/3 cup pitted whole dates, quartered
1/4 cup pitted green olives, halved
2 tablespoons quick-cooking tapioca
1/2 teaspoon finely shredded lemon peel
1 tablespoon lemon juice
1 tablespoon honey
2 cloves garlic, minced
1 14 1/2 ounce can chicken broth
1 teaspoon orange-flower water
3 cups hot cooked couscous
Sliced almonds, toasted
1. Trim fat from meat. Cut meat into 1-inch pieces. Place meat in a large bowl. In a small bowl combine salt, ginger, cumin, turmeric, and cinnamon. Sprinkle over meat; toss gently to coat.
2. Transfer meat to a 3-1/2- or 4-quart slow cooker. Stir in sweet potato, carrots, onion, tomato, dates, olives, tapioca, lemon peel, lemon juice, honey, and garlic. Pour broth over mixture in cooker.
3. Cover and cook on low-heat setting for 8 to 10 hours or on high-heat setting for 4 to 5 hours. Stir in orange-flower water. 4. Serve in shallow bowls over hot cooked couscous. Sprinkle with almonds.
Source: BHG.com


text: Description Suggest an Edit The Algonquin Road Trail and Paul Douglas Forest Preserve Trail combine to completely encircle the large forest preserve in northwestern Cook County. The paved trail provides access to many of the preserve's facilities, as well as the communities northwest of the park. In the north, the trail parallels Algonquin Road, occupying the north side of the busy street between S. Roselle Road and S. Ela Road and the south side for the remaining length. The southern portion of the loop within the Paul Douglas Forest Preserve features gentle, rolling hills and is generally quiet—a nice respite from much of the rest of densely populated Cook County. In the west, the trail continues from the intersection of Algonquin Road and Huntington Boulevard to the entrance for the Crabtree Nature Center. The preserved landscape is popular with birdwatchers and also offers an extensive network of hiking trails. At S. Roselle Road, the pathway meets the Palatine Trail, offering cyclists and pedestrians direct off-road access to Harper College, the Deer Grove East Forest Preserve and a variety of parks and other amenities in the Village of Palatine. Click to read more Parking and Trail Access Parking for the Algonquin Road Trail/Paul Douglas Forest Preserve Trail can be found at the entrance to the Crabtree Nature Center on the south side of W. Palatine Road. Parking is also available at the entrance to the Paul Douglas Forest Preserve off W. Central Road (east of Huntington Boulevard). Click to read more Reviews Paul Douglas Trail July, 2014 by dseyller We have now been to this forest Preserve twice and really enjoyed the trail. It is pretty well kept and very beautiful along the way. The only thing not so good is not much restroom facilities. We also did the Palatine trail through town and will never ...read more Good exercise loop for windy days. April, 2014 by dfdalton The surface is in good condition, only it needs to be swept clean. Luckily I did not encounter glass, but there was a lot of loose asphalt gravel especially in those sections closest to the roads. This path runs along busy roads for most of its length ...read more A+++ September, 2013 by akelkar I had been here once before but was immediately put off by the fact that there is a huge section of the trail that is along Algonquin Road. And so I never returned here. Preffered to go to Busse Woods. But since this trail is so close to where I live, ...read more


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Chasing anything that moves swell wise in the water in Tasmania is what i froth on, mainly cause i have nothing else to do. When not surfing/photoing/filming i can be found travelling our amazing state or working as a deckhand for a ab diver.
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Bio & Incident Details
Age: 50
Tour: 19 years
Badge # Not available
Military veteran
Cause: Heart attack
Weapon: Person
Offender: In custody
· Leave a Reflection
· Add to My Heroes
· Update this memorial
Sergeant Daryl Giles suffered a fatal heart attack shortly after breaking up a large fight at George Washington High School, on Bustleton Avenue, in Northeast Philadelphia.
He struggled with two students as he broke up the fight. Following the fight he informed other officers that he was suffering chest pains, and a short time later he was found unresponsive in a bathroom. The school nurse initiated CPR until medics could transport him to a local hospital, where he was pronounced dead.
Three students were charged with disorderly conduct as a result of the fight.
Sergeant Giles was a U.S. Air Force veteran and had served with the Philadelphia School Police Department for 19 years.


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March 25, 2012
Box Score
NATCHITOCHES, La. - Northwestern State designated hitter Matt Farmer picked up three hits and drove in five runs Sunday afternoon at Brown-Stroud Field, helping the Demons to a three-game Southland Conference sweep of Lamar with the 10-5 victory.
The Cardinals are now just 8-15 on the year, but more importantly, fell to 1-8 in Southland play. Lamar will host No. 7 ranked Rice University on Tuesday evening at 6:30 p.m. from Vincent-Beck Stadium. The Cardinals claimed a 5-4 win at Rice on Wednesday.
Sophomore right fielder Jude Vidrine got the Cardinals off to a good start as he drilled Andrew Adams' fifth pitch of the game over the center field wall to put Lamar ahead 1-0. The next three Cardinals would go down in order as Adams settled down to pick up his first win of the year.
Farmer got the Demons (10-12 overall, 7-2 in the SLC) on the board in the second inning as he hit a two-run home run off Lamar starter Collin Chapman. Will Watson, who scored on the blast, had reached on an error by Chapman. It was one of four Lamar errors on the day which resulted in four unearned runs for NSU.
The Demons extended their lead to 6-1 with a four-run third inning. Catcher Nick Purdy hit a sacrifice fly to score Drew Helenihi for the first run of the inning. NSU then rallied for three more runs with two outs in the inning to chase Chapman from the game.
Vernon Maxwell relieved Chapman with two runners on and promptly gave up a two-run single to Farmer. All six runs were charged to Chapman who allowed four hits and six runs (four earned) over 2.2 innings of work in taking the loss and falling to 0-2 on the season.
The Demons added two more runs in the fifth and a pair in the sixth to build a 10-1 lead. Nick Hinojos singled off Maxell with one out, prompting Lamar to bring Chase Angelle into the game. Angelle got the first batter he faced out, but Hinojos would score on a Jeff Abt error.
Purdy and Watson added RBI singles in the sixth inning for NSU.
Lamar would not go quietly, though, scoring twice in the eighth and twice in the ninth. Aaron Olivas walked to start the eighth, and moved to third two batters later as Seth Dornak reached on an error by NSU shortstop Matt Burns.
Darian Johnson then stepped up and drove in the Cardinals second run with a double to left field. Thomas Henk was then hit by a pitch to load the bases with one out, and Dornak would score to make it 10-3 as Abt drove in the run on a fielder's choice.
Pinch hitter Brad Picha led off the top of the ninth with a double for the Cardinals. Joe Arechiga then singled to put a pair of Cardinals on with no outs. Olivas hit a sacrifice fly to left field that scored Picha and made it a 10-4 game. Dornak then doubled to right to score Arechiga with two outs, but NSU's Joe Scanio ended the game by inducing Johnson to ground out.
Adams (1-2) worked 6.1 innings for NSU, allowing just four hits and one earned run with five strikeouts.
Lamar's Ben Coram and Andrew Beasley pitched solid in relief as the duo combined to work the final 2.1 innings, allowing no hits or runs while striking out three.
Dornak finished the day with two hits, a run and a run batted in, and now leads the Cardinals with a .385 batting average against Southland competition. Arechiga added two hits on the day for Lamar, while Vidrine and Abt had the other two Lamar RBI.


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Hotels in 05478 - Saint Albans VT
Only hotels in 05478 zip code are listed below. Search for cheap and discount hotel rates in Saint Albans, VT for your upcoming leisure or conference / group travel. We list the best 05478 hotels and motels so you can review the Saint Albans hotel list below to find the perfect lodging. Hotels in Franklin county and area code 802 are also listed.
05478 Hotels & Accommodations
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Related Topics
Krugman on Millionaires' Money
From Paul Krugman's New York Times op-ed column: "Isn't keeping taxes for the affluent low also a form of stimulus? Not so you'd notice. When we save a schoolteacher's job, that unambiguously aids employment; when we give millionaires more money instead, there's a good chance that most of that money will just sit idle."
Two points in response. First, the claim that the money of millionaire just sits "idle." That's ridiculous. Most millionaires don't keep money in their mattresses. They spend it on cars and houses and private jets and yachts. They invest it in corporate stocks and bonds or in venture capital funds or in private equity funds or real estate partnerships that build businesses that create employment and growth. They deposit the money in banks that make loans to businesses and homeowners. They buy government bonds that fund government spending. The money isn't going to sit idle whether taxes are high or taxes or low; the only question is whether the money will be allocated by private individuals or by politicians.
Second, the formulation, "we give millionaires more money." This assumes that the money belongs to the government, or society, in the first place, rather than belonging to the person who earned it. And it assumes that allowing a person to keep the money he earned constitutes a "gift" from the government. What a peculiar notion of property rights.
by Ira Stoll | Aug 9, 2010 at 11:07 am Related Topics: Paul Krugman, Press, Taxes receive the latest by email: subscribe to the free futureofcapitalism.com mailing list
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Yes, this is a really whack move indeed. Especially because of Jennine's fierce presence as a fashion blogger. She's not only a top blogger but she created the IFB which is a site that transitioning professional bloggers like myself use everyday. Like you stated in the article, it was probably a weak attempt at getting some of her site's traffic but you can't seem that desperate. Why couldn't they use the "if you build it they will come mantra" instead of trying to steal her shine? No bueno.
Can you believe that. I personally am not okay with this. I am lucky to married to a lawyer, when this happened to me. I went straight to my general counsel and took serious action. The site was down in seven days.
Jacob has no grounds for a lawsuit. "Thecoveted.com" domain was free for the taking and Jacob must know that. Not to mention that Jacob's site is a fashion blog, and the other strictly showcases closets… 2 different ideas
I know she has no grounds, I luckily did when I had a similar issue. There is different content with both Coveteds and different brand identities. But you can't tell me that there aren't striking similarities; anyone can see the parallels to Jennine's personal brand. It's a disgrace that brands and bigger sites are now graying the lines in this way. Feels like Forever 21 copying original designs – nothing you can do, but you know it was done.
Actually she does. She can apply for a trademark for 'the coveted' and since she has established a vast presence for 'the coveted' over the years she will likely get it. Then the fake 'the coveted' will have to give up the domain.
Actually she Jennine's THE COVETED is Trademarked! Great point! We've referred Jennine to several attorneys to help her with this matter.
That's great news!
Steve, sorry, that strikes me as a very lame argument. One is a fashion blog, and the other is a website about closets, full of fashionable clothes? And certainly no one would ever have started such a site without years and years of fashion bloggers creating unique and interesting content about fashion, including documenting what they and others wear – just like documenting what very fashionable people have in their closets.
I agree. Something seems a little shady to take a name of an already VERY established blogger.
This is what's referred to as "passing off" and it's bullshit. Team Jennine! Good luck brandishing your trademark iron, I've been through it and know all too well.
Its TACKY TACKY TACKY of them to use this name!
It's SO lame really.. what's funny is I did a search for Jennine the other day – typed THE COVETED in google – and ended up at the new "thecoveted.com" and IMMEDIATELY wondered if Jennine knew about it. I'll admit, I was outraged for her. At the time I had no idea that it was a creation of the Refinery 29 crew ….which now makes me dislike them even more actually.
It's funny when you become part of the blogging world, you get to see first hand who is loyal & helpful & friendly ….and who is not. I've met Jennine in person, she IS one of the few that is all those things I listed above. Refinery 29, among MANY others are not. Not even close. But I guess in the end, it's all business as usual, or high school as usual.
I hope Jennine comes out on top of this one.
just to clarify, if I confused the creators of the new "coveted" with Refinery, I retract my statement, lol. Obviously confusion ensued
I really feel for Jennine, to have someone copy your site and use your name is really awful. We've had that a few times with wikifashion, albeit very minor issues have arisen that no one really would have noticed. Hopefully this gets sorted out soon!
I just read her post and the strange thing is, the company said they had no previous knowledge of her blog, however she was on their mailing list? Another thing that strikes me as strange is that with all of their connections and press that they have garnered, surely they could have chosen another name and built success around that. To name themselves thecoveted was destined to confuse many people in the online fashion world. Obviously they didn't really think that through well enough.
Some people have no ethics.
I'm team Jennine all the way. I feel like there is no way that this could have been unintentional. The Original The Coveted is popular that you would have to be living under a rock to not know about it. Such a disappointment that some people think that they can just take your ideas and ride on your coat-tails.
It;s a dirty business to infringe on the good will and intellectual property of a fashion blogger with a large following. The claim that they were unaware of Jennine's site is insulting in its duplicity and expectation that anyone with an interest in being a new member of the fashion community wouldn't check all name combinations. Strangely, the new site could capitalize on good will were it to swiftly change its name. Playing a game with high priced lawyers is an ugly thing and few bloggers have access to the kind of money to let this go to fruition. Such a dirty thing to do.


text:
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What is an Area Sales Analysis?
An area sales analysis is a listing of property sales in a given area or neighborhood that have occurred during a specified time. In Maryland, all sales are recorded with the local assessment office as deeds transferring the property are recorded with the Clerk of the Court. These sales are reviewed and the sales that are considered to be valid, arms-length transactions are included on the area sales analysis report.
For each property the following characteristics are identified:
1. Address
2. Property Type-Split Level, Split-Foyer, Detached Dwelling, Townhouse End, Townhouse Center, etc.
3. Stories - Split Foyer, 1 Story with Basement, 1 Story No Basement, 2 Story with Basement, etc.
4. Year Built
5. Enclosed Area - The total of the foundation square footage (both finished and unfinished) times the story height of each section of the dwelling.
6. Land Area - Total land area expressed in square feet, number of acres or simply as the number of building sites.
7. Sales Date
8. Sales Price
9. Estimated Market Value - An estimate of the market value of the property based on the analysis of market data as of the indicated date.
10. Account Number
How Is It Used by the Department?
The Area Sales Analysis is used as a part of our valuation process. Residential property is valued using both a cost model and a sales comparison model. The basic concept of the sales comparison model is that the estimated market value of a property equals the sale price of a comparable property after adjustments for differences are made. For example, if Property X has a garage but the comparable has none, the value of the garage would be added to the comparable=s sale price. The result would be evidence of what Property X=s selling price might be. Assessors use more than one comparable to determine values using the sales approach. They also use more complex models that incorporate many more factors. Rather than considering properties one at a time, assessors use mass appraisal techniques and computer software to appraise many properties of the same general type. This listing represents one part of the total process to determine market value.
The Department also uses the sales analysis as a quality control measure. For assessments, one measurement of quality is the ratio of the assessed value to the sales price. Simply stated, a ratio is the relationship of two numbers-in this case the assessed value (the Department=s estimated market value) divided by the sale price. It allows us to measure how closely our assessed values compare to the actual sale prices.
How Is It of Use to the Property Owner?
The property owner can use it as a tool to compare their property to similar properties that have recently sold in their neighborhood or surrounding area. The best indicator of fair market value is market activity. Buyers and sellers create market values by their transactions. In an appeal, the best evidence of market value is sale price - the sale price of the subject property or of similar properties.
Go through the area sales analysis (you've requested from your local Assessment Office) to find properties that are most similar to the property in question. Compare the market values or the prices at which the properties have sold. Remember, however, dates are important when comparing values. Assessed values are as of January 1, of the year indicated on the report, sale prices are as of the date of sale. The real estate market is constantly changing. Therefore, the most recent sales of comparable properties typically offer the best evidence of market value.
Need More Information?
Contact your local Assessment Office.


text: I don't have that on my sd, but I do on my usb hdd. It's been years since I worked with wii. so i'm sorry for all the trouble. I changed it on my hdd and I see it's good in settings. but now how do I put my isos to my hdd. I have a fat32 hdd format. anyway to install my gamecube isos with my wii games? I tried one but I don't see it at all?


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text:
Hi vis clothing is important safety clothing. Our high viz range includes high vis vests, singlets, polos, fleeces and jackets. Hi visibility clothing is available in day and night colours. Need help with hi vis products? Call 0800 228 723
Hi Vis Vest - Hot Pink with tape
Product Code: FUN208
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Right now were out of stock for this product but we will have more soon.
Hi Vis Vest in Hot Pink
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Does not meet the AS/NZ Standards


text:
According to Boxofficemojo, only eight "action heroine" movies have crossed the $100 million line at the box office—seven if you acknowledge more people saw Terminator 2: Judgement Day for Arnold Schwarzenegger than Linda Hamilton. But replace that classic with the missing blockbuster Wanted—which more people saw for Angelina Jolie than James McAvoy—and that means half of the eight female-led nine-figure actionfests starred Jolie. Unsurprisingly, another might be on its way. According to Deadline, Kurt Wimmer has begun work on a sequel to Salt, the 2010 film that featured Jolie as basically the female Jason Bourne.
Jolie has said she's interested in returning to the character, though only Wimmer is officially signed to the project. The choice to bring back Wimmer is a little ironic, considering there are three different cuts of the film found on the DVD—one reason director Philip Noyce definitely will not be returning to the potential franchise. But it's possible the second film would be comparably streamlined, able to focus on kick-ass set piece instead of the complicated backstory that burdened the original. And if Angelina's Cleopatra is even half the headache every other Cleo film has been, she might enjoy tumbling over some car hoods with a gun.
[Photo: Getty Images]


text:
The Buchanan's get shocking news from Asa's lawyer, Marty tries to get Todd back, and Dorian is confronted by Viki and Charlie...
When Beaver Calhoun, Asa's lawyer, shows up at the Buchanan mansion, with a message from Asa, Clint, Bo, Nora, Renee and Nigel are shocked to hear that it involves Asa's long lost son! Beaver puts in a DVD where Asa rants at his family for allowing Buchanan Enterprises to sink since his death. After Asa declares, "You knew the stakes… stock up, you're rich, stocks down, you're broke. You blew it," he informs that the gravy train is over - Nora is kicked out of the mansion, Clint is instructed to try to get Viki back and Bo to get a better job! Asa then says it's time to give someone else a chance - the son he never acknowledged… Asa leaves his entire empire to David Vickers! Asa knows that David is a con, says that he'll probably spend his money as fast as he can then challenges his family to, "Stop him!" Before Beaver leaves, he instructs everyone to get their stuff together then says he has a detective looking for David, who will have everything turned over to him the minute he finds him!
Later, after Bo, Clint and Nora decide to stay quiet about this, until they can outsmart David, they are thankful that no one else knows that David is Asa's son - but Nigel tells him that he confided in Max Holden and Alex Olanov was listening! Nigel assures Clint that Max won't say a word - and Alex is in St. Blazes, where no one will be in contact with her!
In the diner, Charlie, Viki, Moe and Noelle are shocked to see David - dressed as a monk! They listen as David talks about being transformed… how he was on a plane that almost crashed and how a calm man who was sitting next to him helped him. David remembers being brought back home with the man - to a monastery, where he learned everything about becoming a monk! "I gave up everything I had, and now I have everything I want," David says. When Viki wants to know what he's doing back in Llanview, David claims he needs to atone to all of his sins - then confesses that he knew about Dorian drugging Charlie! As David calmly apologizes, Viki and Charlie storm out, leaving David feeling unburdened - and asking Noelle for a Vegan menu!
Todd thinks he's dreaming when he finds Marty in his house, but Marty replies, "It's no dream." Though Todd thinks Marty came to kill him, she makes him believe otherwise. Todd quickly gets dressed then returns, to which Marty says, "I came to retrieve something I left behind." Marty lifts the mattress, takes out her journal and starts to read from it… about how they were going to run away together and how they loved each other. Though Marty hates Todd for keeping her from her son, she can't deny that what's in the journal is real, leaving Todd to ask, "Is there a chance for us?" Marty snaps, asking Todd how he could dare to think that she would be with him again! Though Todd asks for one night to prove his love, Marty screams, "No! I'm leaving," then rushes out!
Once Marty gets home, she calls Todd, reminds him that he asked for one night then makes plans to meet him for New Year's Eve!
Rex is shocked to see people lined up outside Ultra Violet. When Gigi brings him inside, she shows him a Puddle of Mudd poster, leaving Rex excited that she was able to get the band to play at his club! Rex realizes that now he won't lose his business then takes Gigi in his arms with thanks!
Outside, Cole and Markko stand in line for tickets to see Puddle of Mudd on New Year's Eve, as Markko gives Cole advice about him and Starr.
Over at the mansion, Dorian gives Langston another gift - a framed certificate of adoption - then announces they'll be going to the Big Apple for New Year's Eve! When Markko calls to tell her about the concert tickets, Langston says, "I can't go," then heads upstairs to pack for New York. Having overheard her phone conversation, Dorian cancels the trip - and tells Langston to find Markko and tell him she's going to the concert!
In the kitchen, John arrives back from his trip and takes Blair into a passionate kiss. Blair gives John his Christmas gifts: a Hawaiian shirt and one of his favorite records. Next, John hands over Blair's gift: plane tickets to a new beach resort. However, when Blair says, "I can't accept this," John understands why she can't leave the kids right now and informs her that the tickets are open-ended. John and Blair make plans to spend New Year's Eve together.
When Langston finds Markko in Angels Square, he's happy to hear that she can go to the concert!
Viki and Charlie arrive at the mansion, accusing Dorian of drugging Charlie and getting him to drink! Though Dorian denies it, Viki and Charlie continue lashing out at her - then threaten her with legal action! Viki and Charlie leave to find Bo!
Dorian quickly rushes into the kitchen and rants to Blair that she doesn't plan to spend the new year in prison! After Blair leaves, refusing to get sucked into Dorian's problems, Dorian makes a plane reservation - then packs for St. Blazes!
Next on One Life to Live:
Puddle of Mudd performs!
John talks to Blair about the future.
Todd prays Marty gives him one more chance!
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Hi MiceChatters.
It's that time of year that Delaware Saengerbund has there German Christmas Bazaar. (also known as there German Christmas Festival)
A fun place to sit and eat great german food and watch german dancing.
As always. Santa is here to greet us in.
A part of Delaware Saengerbund's ceiling.
The prices of the food.
I got a Weisswurst, Macaroni Salad, German Potato Salad, & Sauerkraut
Also I got this cupcake. Hard to tell you, what kind of cupcake it was. Some kind of spice tasting cupcake. It was really good.
And of course, the always a must. The Black Forest Cake.
This year me and my mother ate in this Delaware Saengerbund German Library. All german books with german only literature.
A note that was in this German Library. (sorry for be so blurry. Hopefully you can still read it) it's pretty much what I just told you. It's a german library w/ only german literature in the books.
Just showing one of the books.
Just a ladies room sign.
The Deutsche Halle
I bought this chocolate Lady Bug, that I thought was really cute.
I also bought these German cookies.
Some German knick knacks in Delaware Saengerbund.
Lastly some german dancing. The first picture shown, is some of them about to be ready.
Also two YouTube videos I made of random german dancings.
2011 Delaware Saengerbund's German Christmas Bazaar (German Dancing 1 w/brooms) - YouTube
2011 Delaware Saengerbund's German Christmas Bazaar (German Dancing 2) - YouTube
This is all I have to show for this year's German Christmas Bazaar at Delaware Saengerbund. I hope you have enjoyed looking at my trip report and I thank you for stopping by.
-Hayley B.


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Gear Review
Solid Glove
Ordered this as well as the Forge. This one has more dexterity than the Forge, but doesn't feel like it'd be as warm. Fits true to size guide provided. As Finley stated in his Cons of the glove, it does seem like the lining should be a little longer to allow for more movement when the palm is open but it's not something that I considered a deal breaker.
View More Details on Stoic The Duke Glove


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You have made a wonderful app that you are sure users will love. But after building it, how do you get it to the users? Appboy is a resource that can help you to expand, engage and understand your user base so that your wonderful app can be appreciated and used by thousands of people.
Understanding your users is the first step of marketing and promotion. If you know what and how your targeted market works, half of the job is done. Appboy is a window into how, when and why people use your app, so that you know exactly what they demand of you.
Appboy allows a user to get an overview of your app in an interesting way. It includes news, alerts and a feedback form. Through Appboy, you can cross-promote and recommend your app to others. Your users also get a good-looking user profiles with badges and recent app usage.
Appboy allows game app to grand badges and give rewards for in app achievements.
With Appboy, you can get accurate stats and data to help you with decision-making. The interactive dashboard of Appboy allows you access to Appboy analytics (track sharing, investigate usage), CRM (targeted outreach, feedback, bug reports and questions, see rich user profiles) and the ability to manage the features that come with their SDK. Appboy comes complete with an excellent backend.
Appboy integrates with your app easily. After you have setup your app with Appboy, you and your users can interact in a new way.
All in all, Appboy is a great resource for developers where they can easily manage their users, get insights on user behaviour, interact with them, make their app look cool, cross-promote and get customized reports!
Appboy has been supported by investors namely Blumberg Capital, Accelerator Ventures, Metamorphic Ventures, T5 Capital and Bullpen Capital.


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A Brazilian wax sounds like the most potentially scary style of bikini wax, but it's not so bad if you know what to expect going in. Here are some details about what happens during a Brazilian wax.See Transcript
Transcript:What Happens During a Brazilian WaxHi, I'm Jenn Pesce for About.com, and today, I'm going to tell you what happens during a Brazilian bikini wax.
Arriving for Your Brazilian WaxUpon arrival, if you have never visited the salon or spa for any type of waxing, you might be asked to fill out a questionnaire. This will make sure the staff is aware of any personal conditions or allergies you might have. Get ready, you will be lead to a private treatment room by your specialist and then she will ask you to remove your pants and possibly your underwear. Then, she'll ask you to recline on a treatment bed.
The Consult and the Brazilian WaxNow, for the consult: your specialist will ask you if you'd like to leave any hair behind or take it all off. The prep: your specialist will cleanse the area to be waxed. If hard wax is used, oil will be applied, or if strip wax is used, powder will coat the skin to protect it before applying wax. The process: wearing gloves, your specialist will apply warm wax on the hair with an applicator. Hard wax doesn't require a strip, so it will dry a bit before it's removed. With liquid wax, a strip of cloth or muslin will be put over the wax. The technician will hold your skin taut before removing the wax in a quick pull to effectively remove the hair and reduce the pain factor. Then she will work in sections until all of the desired hair is removed.
Brazilian Wax AftercareThe clean up: because wax shouldn't be applied over skin more than once, any stray hairs missed by the wax will be cleaned up with tweezers or by threading. A lotion, oil or gel may be applied to remove any wax residue and to help calm the skin. Then, your treatment is finished and all you'll need to do is get dressed! Maintain your aftercare at-home: waxing, like any type of hair removal, may cause redness, irritation and possibly bumps and ingrown hairs, so it is important for self-care after treatments. 48 hours of rest is best! This time period is when your skin is most sensitive and susceptible to outside germs.
Thanks for watching. To learn more about what happens during a Brazilian bikini wax, visit About.com.
About videos are made available on an "as is" basis, subject to the User Agreement.


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Recent Posts
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Monthly Archives: January 2010
Followup: "YouTube is my Homework?!"
Post by Matthew Ragan – – As I mentioned in the "YouTube is my Homework?!" presentation on 1/14/10, there are tremendous resources available on the net for video. These have great potential both in and out of the classroom, but … Continue reading
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Measuring Fair Trade
What makes a fair trade athletic shoe company better for the environment? What is certification in fair trade and when does it matter? How can a company regain control of its inventory? Students in Tamara Stenn's Integrated Quantitative Literacy class, … Continue reading
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Increasing transparency of international climate finance
As international climate finance flows increase to reach $100 billion a year by 2020, it is crucial that transparency is provided on the fulfilment of Parties' commitments and the outcomes on the ground. Transparency is an important tool for building trust between developed and developing country partners. It will also help to improve the effectiveness of climate finance.
EU MRV regime includes annual reporting on climate finance
In the UN climate change negotiations, Parties have agreed to strengthen the international framework for the measurement, reporting and verification (MRV) of international climate finance.
The EU Member States and the European Commission see transparency in climate finance as key to building trust. In 2013 the EU adopted an enhanced reporting framework on climate finance as part of its broader MRV policy.
The EU Monitoring Mechanism Regulation provides for annual reporting of information on financial support and technology transfer activities to developing countries based on the best data available.
In January 2014 the EU submitted its first biennial report(76 kB) to the UNFCCC, including information on financial resources and transfer of technology.
MRV of developing country actions needed as well
The EU and its Member States are also committed to working with developing country partners to advance discussions on the implementation of a suitable MRV framework for them.
For the international climate regime to function, it is important to provide full transparency both on climate finance flows and on action on the ground. MRV of finance from developed countries needs to be matched by MRV of emissions mitigation actions by developing countries.


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This is where you will find Brittany Stover on most days – inside the Tribe Gymnastics practice gym. She runs, flips, flies, and balances – all in the hopes of bringing home a national title.
The William and Mary sophomore was named the E.C.A.C. gymnast of the year, and with it, she has qualified for the NCAA gymnastics regionals next week where the best of the best will compete.
"I will focus on cleaning up the little things," she says before practice on Wednesday. "I will be going against the top girls in the nation and a tenth here or there could be a difference."
Is she nervous?
"Maybe a little, I tend to keep my nerves under control. I know I have nothing to lose. I will go out and do my best."
Brittany will compete in the all-around competition where the top two scores will advance to the national championship. What is her best or favorite event?
"My best is the vault, but my favorite tends to be the bars. Whatever happens [next week] is based on what I do. If it happens, great, if not, I'll just try harder next year."
"I want to be a national champion on the rings," says William and Mary senior Landon Funicello – he has also qualified for the NCAA regionals. His score of 16.4 on the rings is the second highest score ever recorded in the nation.
NewsChannel 3 asked him if he can improve his score.
"There's always room for improvement."
This weekend, he and his William and Mary Tribe teammates go for an E.C.A.C. title and an automatic bid to the NCAAs.


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Hold down Control (PC) or Command (Mac) key + mouseclick to select more than one option
|Avg. Dinner Entrée
|Greater than $25
|$18.01 - $25
|$12.01 - $18
|$7.01 - $12
|Less than $7
Posted by Stella K. on 02/15/2014
I absolutley adore this place. There's not enough good words I can say. I would recomend this for anyone.
Posted by Piper M on 04/03/2013
We had read the excellent reviews and were really looking forward to a new Italian dining experience in Cambridge. But, starting with the fake Christmas flowers in the front windows in the week after Easter (!!) and having to sit at a tiny high-top table for dining (way too small and uncomfortable)-and paper napkins!!, I was put off and the food never made up for it. My dinner (the interesting and rich 2-cheese and prosciutto appetizer drizzled with great balsamic and the veal scallopini entree) were okay but not especially pleasing. The scallopini was too much, too many ingredients (mozzarella, prosciutto, puddles of olive oil and something else, brown like gravy--??), and too much in taste and texture like the appetizer. I could only eat half the scallopini and my friend and I had shared the appetizer. We had also ordered a side dish to share of their homemade pasta to try it--it was rigatoni with garlic but it was, sadly, quite tough, and not very good. A big disappointment because we had been looking forward to trying their homemade pastas. My friend liked her eggplant entree but also couldn't finish it. My red wine (Nero D'avola) was good but I agree with an earlier reviewer that the Italian wine list could be a tad longer (I realize it is a very small restaurant and wine storage is probably not easy in that space, but. . .). The artisan breads were wonderful--the best ever!! Fantastic!! We did not have dessert. Service was great--pleasant and helpful, and Ali (the young owner who is Moroccan Italian) was enthusiastic and eager to please. Sadly, I'm not sure I'll return, though I should probably give it another try, especially since it is true that Cambridge is low on good Italian restaurants. (I like Gran Gusto best, on Sherman St., and also Pulcinella mostly because it is right around the corner from where I live, so it's convenient for walking.)
Posted by Sabrina Hamilton on 01/07/2013
Some of the best Italian food I've had in a very long time - at great prices. And bread to die for!
Posted by Russell on 12/02/2012
Hot, hearty and really good Italian food! My only complaint is the wine list: It would be pretty easy to add 4 or 5 bottles of good red Italian to the list and dont be shy charging for the good stuff!
Posted by Arlingtonian on 07/20/2012
Yummy bread basket, great arugula salad, loved our meals of pasta in zucchini sauce with shrimp and little gnocchi-like pasta with broccoli rabe and clams. everything was different than i've ever had before. Also the chianti was perfectly smooth and delightful. i might have preferred the restaurant to be slightly lighter inside but that could just be my aging eyes.
Posted by Wendy Rodwin on 12/11/2011
This is Italian food like I eat in Italy at friends' houses--well-presented, healthy, in reasonable proportions. A delight.
Posted by Mrs. T. on 09/15/2011
BEST, BEST, BEST Italian food I've had in a long, long time! As I am an Italian American who loves to cook, I don't usually frequent Italian restaurants and when I do go, I get bored with the "Italian Restaurant Row" in the North End of Boston; Franchese, Marsala or Parmigiana gets old after a while! This place, however... is a breath of fresh air to say the least. I'm not sure what the name of our appetizer special was but it was a large, fresh bundle of mozzarella cheese on a bed of baby arugula with a sweet drizzle of a balsamic reduction and some freshly sliced proscuitto. The catch? When you bit into the fresh mozzarella, there was a creamy marscarpone center... it was "to die for"! My husband had the special risotto which was the best I've ever tasted and I had the homemade papparadelle pasta with baby shrimp in a zucchini based sauce. First of all, the pasta was light & airy; not dense & heavy like some homemade pasta can be and I would really like to know how they managed to cook baby shrimp without it getting well done! Every bite was even better than the last! We shared a Tiramasu for dessert and even though we were both full beforehand, we ate every last morsel of it! As if the rest of my review wasn't enough for you... the assortment of home baked breads actually made me dizzy with delight; they even sell them by the loaf! I simply cannot say enough about this place... Great food, reasonalbly priced, charming servers... what more could I have asked for? Once the liquor license or beer & wine license comes through, I just may rent an apartment upstairs! Ciao bella!


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Which kind of mouse am I? Some days, I just don't know. We recently moved into a much more rural area of Central PA with visions of a huge garden, wind power, and a simpler lifestyle. But there once was a time when my favorite way to spend a day was roaming the streets of… [read more]
City Mouse, Country Mouse
October 19, 2011 by Leave a Comment


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What is Unitarian Universalism
Month of Sundays
Monthly Calendar
Life Span Religious Education
Small Group Ministry
Congregational Governance
Mission and Vision
UU Links
Contact Us
Book Marks
RRUU Green Team
Organizes Texoma Earth Day Festival
Elbert Hill Wins 2015 NTUUC Marty Robinson Volunteer Award
As the only Unitarian Universalist congregation between Plano, TX and Norman,
OK, Red River Unitarian Universalist Church aspires to meet the needs of
religious liberals living in a large area of north Texas and southern Oklahoma.
RRUU members and friends come from Sherman, Denison, Pottsboro, Van Alstyne,
Howe, Savoy, Sadler, Southmayd, Gunter, Whitesboro, Whitewright, Princeton, and
Bonham in Texas and from Durant, Colbert, Cartwright in Oklahoma to attend
Sunday services and other church activities.
We are a diverse group of people from all over Grayson
County and Fannin County, Texas and Bryan County, Oklahoma who meet on Sundays and other
times in our building in Denison, Texas because we
share common values and common goals. We don't all believe the same things
about God, Jesus, the afterlife, or other theological matters, but we all
share pretty much the same views about religion.
Then you might be a Unitarian Universalist! Go to
www.beliefnet.com to find out.
Red River Unitarian Universalist Church |
Meeting at Red River Unitarian Universalist Church, 515 N. Burnett Ave.,
Denison, Texas


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Harvey Washbangers is undeniably one of my favorite places to go when it is time to wind down. The staff is friendly, the atmosphere is relaxed, the conversation is good, and I can even convince myself I am being productive by doing my laundry in the back.
I started going to Harvey's at the beginning of last fall, after transferring to Aggieland from San Antonio. I quickly established myself as a regular customer, coming in almost too much. Guzzling down their patty-melts, tasting every new piece of pie, every new seasonal special, and every new burger- I always made sure to wash it down with a glass of Big Red.
So what is their special this season? Its their Chorizo Burger, and it's a darn good eat. I have always been a patty-melt kind of guy, and boy do they have a killer patty-melt; but there is something about the Chorizo Burger that is extraordinary.
This handmade half-beef, half-chorizo cheeseburger is covered in pico avocado with tortilla chips stacked on top. Every order comes with fresh-cut French Fries that are salted just enough, still sparkling from just having come out of the kitchen.
Harvey Washbangers has definitely got this burger right, as it is a very popular special that is so good, it is being permanently added to the menu. One of my good buddies in the Corps came with me once and tried the chorizo burger while we did some laundry. He liked it so much, he went there again not two days later – and didn't bring me. Granted, I was out of town when he went, but he admitted he just couldn't resist the craving. When Superbowl Sunday came around, guess where my buddies wanted to go?
The Chorizo Burger is far from being the only hit burger at this joint. Another popular burger they serve is their Jalapeño Cream Cheese Burger, along with my repeated personal weakness; their patty-melt.
If you are looking for the perfect burger, there is no better place to begin your journey. Located just off Texas and Holleman between H-E-B and Yogurtland, you can't pick a better place to start.
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Sam Clucas leaves Mansfield Town for Chesterfield
Posted: September 01, 2014|
WINGER Sam Clucas has left Mansfield Town to join local rivals Chesterfield for an undisclosed fee.
The Spireites first registered their interest in the 23-year-old last week, but no fee could be agreed between the two clubs and the Stags said 'a line had been drawn under' the saga.
However, Chesterfield have today come back with an improved bid for the player, who is out of contract in the summer.
"The Spireites improved their initial bid for the player, who made it clear during discussions that he wasn't going to sign a new contract when his current deal expired at the end of the season and wished to further his career," said a statement from the club.
"The transfer will allow manager Paul Cox to further strengthen his squad."
Only last Thursday, Mansfield boss Cox had said: "With the club in question, we couldn't agree a valuation, so we agreed we would just move on.
Clucas was left out of the starting line-up while his future was in doubt, but he returned to the first XI for Saturday's 2-1 defeat to Burton Albion.
The former Hereford United man made the switch to One Call Stadium last summer and finished as the club's top scorer last term with 13 goals.
His lively performances though, caught the eye of a number of other clubs and there was speculation surrounding a move during the January transfer window.
Hereford will be due a 15 per cent sell-on fee, following a clause inserted into Clucas' contract.


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Ben Affleck's gambling thriller Runner, Runner failed to impress critics or moviegoers over the weekend. With a $7.6 million gross, the film landed in third place on the weekend box office list–a hefty $48 million behind top spot holder, Gravity. Waking up to disappointing returns is not something the two-time Oscar winner hasn't experienced before. Despite praise for his acting, screenwriting, and directing, Affleck has been partial to more than one bad decision over the years–more or less any time his character is required to get a spray tan. (Does a little gem called Gigli ring a bell?)
To further explore Affleck's lowest of lows, we dug up his most disappointing box office performances that were also panned by critics, all of which seem like even more quizzical choices if you've watched Argo, Good Will Hunting, or The Town over the last few months. Check out the list below, which proves moviegoers have a short memory when it comes to Oscar winners.
5. Jersey Girl (2004)
Opening Weekend Box Office Gross/Worldwide Box Office Gross: $8.3 million/$37 million
Rotten Tomatoes Rating: 41%
Affleck teamed up with frequent collaborator Kevin Smith to play a successful, career-driven New York publicist whose life is suddenly transformed by unexpected single parenthood. Smith later said his film "wasn't for critics," but with such modest box office numbers, it apparently wasn't for moviegoers either.


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This weeks interview is with Personal Branding expert Colette Mason In this fascinating interview we discuss , why you should brand yourself and how you actually go about it and much more. I really enjoyed this interview and learned a lot during the course of it. I hope you enjoy it as much as I did! During the podcast we mentioned HARO which is "Help a Reporter Out " you can find them at http://helpareporter.com/ If you have any questions for Colette or comments leave them below or in the thread about the interview in the WPgoldmine Forum Podcast Powered By … [Read more...]
You are here: Home / Archives for colette mason


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Forgot the name of great breakfast place near Crocs on S. State
A bellman at the Palmer House told us about this place three years ago. We are going to Chicago but staying somewhere else this time, but we want to eat at this place. We don't know the name and so don't know how to find out whether it is still there. We're thinking of going there for a late breakfast and then walking to the Art Institute. I'm not sure, but I think there was a fancier part of the restaurant that is open at night but is downstairs or next door. I just remember there were 9 of us without a reservation and they had no problem. The people who owned it weren't Greek, but it is the kind of restaurant Mike Royko used to write about and called "Greek".
Talk is closed, but that doesn't mean the conversations have to stop!
Check out this post for a more thorough explanation, and jump onto our Facebook page or our Twitter feed to keep the conversations going!