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Aim: Intravesical Bacille Calmette-Guérin (BCG) is the mainstay adjuvant treatment of non-muscle-invasive bladder cancer. However, one third of the patients on BCG regimen relapse within the first year of treatment. This study aimed at identifying biomarkers to predict response to BCG treatment. Methods: Gene expression was analyzed in blood cells of 58 patients treated with BCG through six consecutive weekly instillations and then at month 3, 6, 9, and 12. Cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon (IFN)-γ, IL-1β, IL-2, IL-4, and IL-6; chemokines CCL2, CCL3, CCL8, CXCL9, and IP-10; and mediators of cytotoxicity CTLA4, Fas-L, Perf, GNLY, NOS2A, and HMOX-1 were analyzed before the 1st and the 6th week instillation and 24 h after to assess fast (within 24 h) and prolonged changes resulting from treatment. Results: BCG instillation led to fast-increased expression of IL-1β, TNF-α, and IL-10 genes. When compared to relapsing patients, patients with no relapses within one year showed significantly lower expression of IL-1β at 1st week and less IFN-γ, HMOX-1, and GNLY at week 6. HMOX-1 and GNLY were independent predictive biomarkers, and values above the cut-off ≥ 110 and ≥ 13.0 ‰ mRNA, respectively, were considered prejudicial factors. Patients with two HMOX-1 and GNLY factors had highest (66.7%) relapsing risk. Conclusion: Assessing immunomodulators' expression in blood allows the establishment of predictive cut-off values and identification of probabilities for patients' relapses after BCG treatment.
Key words: Bladder cancer, Bacille Calmette-Guérin, immunomodulatory molecules, multivariate analysis
Non-muscle-invasive bladder cancer (NMIBC) has an increasing incidence and a high relapse rate, even after transurethral resection of the bladder tumor (TURBT), the initial standard treatment. Due to the frequent need for follow-up procedures, NMIBC significantly reduces quality of life and is one of the most expensive malignancies to treat. Post-TURBT intravesical instillation of Bacille Calmette-Guérin (BCG), the attenuate strain of Mycobacterium bovis, is the recommended treatment for intermediate and high-risk NMIBC,[1] by preventing relapse and progression of NMIBC -- stages Ta, T1 and carcinoma in situ. While partially successful, 30% to 50% of the patients do not respond and experience relapse within the first year of BCG treatment. Of these patients, 15% develop tumor progression and form distant metastases.[2]
Despite many efforts,[3-5] there are currently no biomarkers that can predict patient's prognosis and that discriminate those who will respond to BCG treatment from those who would be best served by more aggressive therapy such as cystectomy or, alternatively, radio- and chemotherapy. BCG instillations can cause side effects ranging from incommodious cystitis to sepsis and even death of patients in rare cases. This fact reinforces the need for selecting and accompanying patients who enroll in BCG immunotherapy.
Treatment with BCG was first used empirically by Morales in 1976.[6] Today, it is well assumed that the efficacy of BCG is based on a massive, complex, and ongoing local immune activation. Hence, a healthy host immune system is a prerequisite to successful BCG therapy.[1,7,8] Within bladder tissue, the leukocyte distribution before and after BCG therapy is remarkably different, and the induction of complex inflammatory cascade events, reflecting activation of multiple types of immune cells, is well known.[9,10] The cascade of events results in secretion of an array of cytokines, chemokines, and cytotoxicity mediators that can be detected in tissue and in urine.[7,11] These are summarized in Table 1. Examples are (1) pro-inflammatory, T helper type 1 (Th1) cytokines such as interleukin (IL)-1β, IL-2, IL-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ; (2) Th2 cytokines IL-4 and IL-10; (3) chemokines, as CCL2, CCL8, CCL3, IFN-γ-inducible protein (IP-10), CXCL9; (4) cytotoxicity mediators, such as nitric oxide (NO) released by macrophages, and mediators of cytotoxic response such as perforin (Perf), granulysin (GNLY), and Fas ligand (Fas-L) pathway released by cytolytic lymphocytes [natural killer (NK) and T cytotoxic cells], and cytotoxic T lymphocyte antigen-4 (CTLA4) expressed by activated/exhausted T cell; and (5) molecules involved in stress homeostatic events such as heme oxygenase 1 (HMOX-1). The tight balance of such mediators is critical for the efficacy of BCG immunotherapy. Despite this knowledge, the precise immune mechanism involved in BCG therapy is still not completely clarified. Assessing immune response is thus fundamental to an understanding of BCG-induced antitumor mechanism and its prognostic value.
Table 1: List of molecules analyzed in this studyClick here to view
Interestingly, in many bacterial infections, analysis of immunomodulators detected in peripheral blood cells is extremely relevant to following a patient's immune response.[12] Blood is the predominant sample substrate for systemic analysis, and it allows depiction of the overall inflammation burden that accompanies infection.
Significant changes in the number and function of peripheral blood cells have been reported over the course of BCG therapy, such as the increase in BCG-activated killer (BAK) cells.[8] Few attempts have been made to assess the relevance of the systemic cytokine profile in peripheral blood cells.[13,14] However, the expression of cytokines and other BCG-induced mediators that are systemically detected over the course of BCG instillation has never been properly addressed. In this work, we sought to profile the expression of key molecules expressed by blood cells of NMIBC patients during BCG treatment. We analyzed the expression of cytokines TNF-α; IL-10; IFN-γ, IL-1β, IL-2, IL-4 and IL-6; chemokines CCL2, CCL3, CCL8, CXCL9 and IP-10; mediators of cytotoxic response CTLA4, Fas-L, Perf, GNLY and NOS2A; and HMOX-1, which is involved in homeostatic events. We established predictive cut-off values and developed a predictive grouping system that allows us to identify the most likely patients to relapse after BCG treatment.
From July 2005 until July 2007, 58 patients [mean age of 67.8 years (range 45 to 82)] were assisted at the Hospital São José, Lisbon, Portugal and diagnosed with NMIBC. Patients were BCG naïve and with high-risk tumors (T1 tumor, G3** [HG] tumor), CIS, multiple and recurrent and large (> 3 cm) Ta, G1G2 tumors, and they were treated with the same dose of BCG instillations (TICE® BCG) after TURBT. They entered this study after informed consent. BCG instillations were repeated once a week for 6 weeks followed by three weekly instillations at month 3, 6, 9, and 12. All the patients were followed for one year and the outcome variables were: tumor progression, relapse, and disease-specific survival. Patients who showed no relapses within a year after the beginning of treatment were named "BCG responders" [40 patients (3 women/37 men, mean age of 68, 3 years)]. Those patients who manifested relapses within that year were named "BCG-relapsing" [18 patients (1 woman/17 men, mean age of 67.5 years)]. In each case, four samples were collected before and after the first instillation and the week 6 instillation. The study has been approved by the ethical committee of the Hospital.
Isolation of RNA and real-time PCR
Blood specimens (2.5 mL) were collected in PAXgene™ tubes (Qiagen, Manchester, UK), incubated at room temperature for 4 h for RNA stabilization and then stored at -80 °C. RNA was extracted from whole blood using PAXgene™ Blood RNA System Kit (Qiagen), following manufacturer's instructions, and further purification of RNA was done with on-column DNase digestion. RNA concentrations and A260-to-A280 ratios were measured in a spectrophotometer, and only samples with A260/A280 ratios between 1.9 and 2.1 were further considered. 1 µg of total RNA was reverse transcribed with random primers, using High Capacity cDNA Archive Kit (Applied Biosystems, Foster City, CA).
Real time PCR gene quantification analysis was performed as described,[7,15] using Taqman assays from Applied Biosystems: Hs00234140_m1 (CCL2), Hs00234142_m1 (CCL3), Hs00271615_m1 (CCL8), Hs00171065_m1 (CXCL9), Hs00171042_m1 (IP-10), Hs00175480_m1 (CTLA4), Hs00181225_m1 (Fas-L), Hs01110250_m1 (HMOX-1), Hs00167257_m1 (NOS2A), Hs00169473_m1 (Perf), Hs00246266_m1 (GNLY), Hs00174128_m1(TNF-α); Hs00174086 _m1 (IL-10); Hs00174143_m1 (IFN-γ), Hs00174097_m1 (IL-1β), Hs00174114_m1 (IL-2), Hs00174122_m1 (IL-4), Hs00174131_m1 (IL-6), and 4352935E (β-actin). Each reaction was performed in duplicate. All genes, including endogenous controls, were always analyzed in the same run to exclude between-run variations. The number of PCR cycles needed to reach fluorescence threshold in each sample was defined as the cycle threshold (Ct). The mRNA expression was normalized using β-actin gene expression as a reference according to our previous observations.[15] Relative mRNA levels were calculated using formula 2-∆Ct × 1,000 which infers the number of mRNA molecules of the gene of interest per 1000 molecules of endogenous control. ∆Ct stands for the difference between cycle threshold (Ct) of the amplification curve of target gene and that of endogenous controls. Reactions with a Ct value higher than 35 cycles were considered negligible and were not considered further. Efficiency of the amplification reaction for each primer-probe was above 95% (as determined by manufacturer).
Statistical analysis
The Kruskal Wallis test was used to compare ratios in patients with and without recurrence. Fisher's exact test was used to identify the factors that were significant in the univariate analysis. Multivariate logistic regression was used to identify the two factors that were retained in the multivariate analysis. A significance level of P = 0.05 was used to identify possible factors for predicting response to BCG therapy in the univariate analyses. No correction was made for multiple endpoints or testing.
BCG treatment induces significant systemic fast changes
To assess whether BCG treatment induced significant changes in the expression of specific cytokines and molecular effectors in peripheral blood cells, we analyzed its expression in blood samples from patients during BCG therapy. The selected cytokines and molecular effectors depicted in Table 1 represent the reported complex events known to locally accompany BCG treatment, i.e. to occur in the bladder. Blood samples were collected before and 24 h after BCG treatment to assess fast changes. To assess prolonged changes, samples were collected at the first instillation (week 1) and at week 6 of BCG treatment. Significant levels of mRNA were obtained from all blood samples. Before BCG treatment (pre-BCG stage), the lowest expression levels were observed for IL-4 (0.024‰ mRNA) and maximum for GNLY (252.38‰ mRNA) [Figure 1]. During BCG treatment, we observed significant fast changes (24 h after the first treatment or after the instillation performed at 6th week) in IL-1β, TNF-α, IL-10, GNLY, and Perf [Figure 2]. No significant prolonged changes, i.e. during treatment, were observed [Figure 2]. In fact, 24 h after the first BCG instillation, significant expression changes were observed. IL-1β mRNA increased from 12.94‰ before treatment to 16.48‰ after treatment (P = 0.033), TNF-α mRNA increased from 3.70‰ to 4.23‰ (P = 0.002), and IL-10 mRNA increased from 0.17‰ to 0.24‰ (P = 0.026) [Figure 2]. At week 6, changes were still observed and were sometimes more pronounced [Figure 2]. In fact, IL-1β mRNA increased from 11.46‰ to 20.76‰ (P = 0.0001), TNF-α mRNA increased from 3.12‰ to 4.57‰ (P = 0.0045), and IL-10 increased from 0.13‰ to 0.23‰ (P = 0.0004). In addition, other significant changes were observed at week 6 of the treatment, such as decreased GNLY (159.2‰ to 111.9‰, P = 0.008) and Perf (49.74‰ to 43.26‰, P = 0.01) [Figure 2].
Figure 1: All the analyzed genes were significantly expressed at pre-BCG state, with the lowest mRNA levels observed for IL-4 and maximum for GNLY. Relative mRNA levels of IL-4, NOS2A, IL-2, IL-6, CCL8, CCL2, IL-10, CXCL9, IFN-γ, IP-10, CCL3, CTLA4, TNF-α, Fas-L, IL-1β, HMOX-1, Perf and GNLY were evaluated by real time PCR, as described in the Methods section. mRNA was obtained from blood samples of 58 patients, collected before any BCG treatment. Values were calculated, as referred to in the Methods section, by formula 2-∆Ct *1,000 and infers the number of mRNA molecules of a certain gene per 1,000 molecules of the endogenous control (β-actin). BCG: Bacille Calmette-Guérin; PCR: polymerase chain reactionClick here to view
Figure 2: Expression of IL-1β, TNF-α, IL-10, GNLY and Perf genes was significantly altered in the study population after BCG instillation. The relative mRNA levels of IL-1β, TNF-α, IL-10, GNLY and Perf were evaluated by real time PCR, as described in the Methods section. mRNA was obtained from blood samples of 58 patients, collected before (1WBT) and 24 h after (1WAT) the BCG treatment performed 1 week after TURBT and/or before (6WBT) and 24 h after (6WAT) the BCG treatment performed 6 weeks after TURBT. Values were calculated by formula 2-∆Ct *1,000 and infer the number of mRNA molecules of a certain gene per 1,000 molecules of the endogenous control (β-actin). Statistical significances (*P < 0.05, **P < 0.001 and ***P < 0.0001) refer to the differences between samples collected before (1WBT or 6WBT) and 24 h after (1WAT or 6WAT) BCG instillation. When not labelled, no significant differences were identified. BCG: Bacille Calmette-Guérin; PCR: polymerase chain reaction; TURBT: transurethral resection of the bladder tumorClick here to view
The observed fast changes in transcripts showed striking correlations [Table 2]. For example, there was positive correlation between pro-inflammatory cytokines: e.g. IL-1β correlated with TNF-α (Ρ = 0.85 or 0.74 at 1st or 6th week treatment). There was also correlation between cytotoxic mediators: e.g. Fas-L correlated with GNLY (Ρ = 0.92 or 0.84 at 1st or 6th week treatment). Finally, correlation between pro-inflammatory cytokines and cytotoxic mediators was also observed: e.g. IL-1β and IL-6 correlated with GNLY cytotoxic mediator (Ρ = 0.70 and Ρ = 0.85, respectively). Overall, data suggested the involvement of pro-inflammatory and cytotoxic mechanisms in patient's response to BCG therapy.
Table 2: Correlation values between fold changes in the transcripts observed within 24 h after Bacille Calmette-Guérin instillationClick here to view
Systemic molecular changes differ between BCG responders and relapsing patients
We then stratified our study population according to their response to BCG treatment. We considered two groups: patients who showed no relapses within a year after beginning treatment, i.e. "BCG responders" and patients who manifested relapses within that year, i.e. "BCG-relapsing." Stratification between BCG-responders and relapsing patients revealed interesting differences at week 6. After treatment, BCG responders showed significantly less expression of IL-1β (18.54‰) than relapsing patients (25.61‰, P = 0.018) [Figure 3]. At week 6, before BCG treatment, there was significantly less expression in BCG responders of the following transcripts: IFN-γ (0.22‰/0.66‰ in responders/relapsing, P = 0.04); HMOX-1 (10.80‰/15.81‰, P = 0.006), and GNLY (165.78‰/254.34‰, P = 0.01) [Figure 3]. Data suggest that the best response to BCG treatment involves the moderate contribution of specific immunomodulatory molecules.
Figure 3: Expression of IL-1β, IFN-γ, HMOX-1 and GNLY genes was significantly different between BCG responders and relapsing patients at week 6. Relative mRNA levels of IL-1β, IFN-γ, HMOX-1 and GNLY were evaluated by real time PCR, as described in the Methods section. mRNA was obtained from blood samples of BCG responder and relapsing (rel-) patients, collected before (6WBT) and 24 h after (6WAT) BCG treatment performed 6 weeks after TURBT. Values were calculated by formula 2-∆Ct *1,000 and infer the number of mRNA molecules of a certain gene per 1,000 molecules of the average of the endogenous control (β-actin). Statistical significances (*P < 0.05) refer to differences between samples from BCG responders and relapsing patients collected before (6WBT) or 24 h after (6WAT) BCG 6 weeks treatment. BCG: Bacille Calmette-Guérin; PCR: polymerase chain reaction; TURBT: transurethral resection of the bladder tumorClick here to view
Multivariate analysis revealed cut-off values for BCG response
To better discriminate BCG responders from relapsing patients, we used logistic regression analysis to establish cut-off values for each of the molecules identified above. We performed a univariate and a multivariate Cox analysis, whose results are represented in Table 3. In the univariate analysis, the variables that better distinguished responder vs. relapsing patients were IL-1β, IFN-γ, HMOX-1, and GNLY. Indeed, we could define a cut-off value for mRNA levels, below which it predicted a good BCG response (≤ 12.5‰ to IL-1β; ≤ 0.17‰ to IFN-γ, ≤ 110‰ to GNLY, and ≤ 13.0‰ to HMOX-1).
Table 3: Cut-off values of the relevant molecules with a predictive meaning for patients' response to BCG. Multivariate logistic regression was used to identify the two factors retained in the multivariate analysisClick here to view
In the multivariate analysis, only HMOX-1 and GNLY were shown to be independent predictive biomarkers. As shown in Table 3, we established a cut-off, above which these biomarkers are considered prejudicial factors. We then subdivided patients according to whether they show no prejudicial factors, one prejudicial factor, or two prejudicial factors (see supplementary data). One in twelve patients with no prejudicial factors relapsed (8.3%). Four in twenty-three patients showing one prejudicial factor relapsed (17.4%) and finally, ten of fifteen patients showing two prejudicial factors relapsed (66.7%). This allowed us to establish predictive cut-off values and a predictive grouping system, thus identifying the probability of relapse after BCG treatment.
Immunotherapies boost patient's immune response to improve its capacity to eliminate tumor. BCG is an immunotherapy, used as a standard of care to treat NMIBC patients to reduce cancer relapses. BCG instillations into the bladder attract antitumor effector immune cells to the tumor site,[8,9] and three months after the BCG treatment course, the cellular infiltrate of T and B cells is concentrated in the persisting granulomas, focused on elimination of cancer cells.[16] However, BCG treatment remains suboptimal because 30% to 50% of the patients show no response and/or relapse within the first year of treatment.[17]
Although the underlying mechanisms of BCG therapy are not fully elucidated, it is known that a Th1 response is required to stimulate cell-mediated tumoricidal activity.[18] The level of the Th1 cytokine, IL-2, expressed in situ can suggest patients at risk for bladder cancer relapses after a single course of BCG.[19] Yet, despite efforts to analyze the immune response in bladder tissue before and after BCG therapy,[4,7-9] there are currently no gold standard biomarkers to predict how effective or beneficial is the BCG-induced antitumor immune response. This knowledge is important to identify patients who may require more aggressive treatments such as cystectomy.[20]
A mode of predicting response to BCG therapy has been suggested through the analysis of IL-2 and IFN-γ mRNA in peripheral blood mononuclear cells during BCG treatment. IL-2 mRNA is increased in patients who responded with remission.[14]
In this study, we have extended this methodology and analyzed the profile of several key molecules expressed by blood cells in NMIBC patients treated with BCG. Expression was analyzed before and after (24 h interval) the 1st and the 6th week instillation, to assess fast (within 24 h) and prolonged changes during treatment.
During BCG treatment, significant fast changes were the expression of IL-1β, TNF-α and IL-10, which increased at the 1st and 6th week, while the expression of GNLY and Perf decreased fast at 6th week. Correlations found between the fast changes of transcripts coding several pro-inflammatory cytokines and cytotoxic mediators further demonstrated that BCG promptly affects the systemic profile of mediators involved in both inflammatory and cytotoxic mechanisms. This coincides with previous studies demonstrating that BCG instillation influenced local immunological activity and a systemic immune response through both sorts of factors.[21] For instance, a higher cytotoxic activity in the PBMCs after BCG instillation has been correlated to the appearance of IL-2 and IFN-γ in the serum.[21]
Interestingly, our data showed that although the expression of IL-1β was higher after BCG instillation, there was a significantly lower expression of this potent pro-inflammatory cytokine in BCG-responders than in relapsing patients [Figure 3]. The increase in IL-1β is an expected, normal physiological inflammatory response to BCG treatment that boosts immune response in bladder tissue. However, it is well known that prolonged exposure to inflammatory cytokines has also the potential to stimulate tumor growth through the promotion of proliferation, angiogenesis, DNA damage (due to their capacity to generate reactive oxygen and nitrogen species), and other events favorable to metastasis.[22] In fact, high levels of cytokines induce reactive oxygen and nitrogen species.[23] This may explain why patients with an excessive elevation of systemic expression of IL-1β are more likely to relapse than patients who moderately express this cytokine.
In addition, it was observed that the basal expression profile of the immunomodulators also influences the response to BCG treatment. Indeed, patients who were considered BCG-responders, when compared with relapsing patients, exhibited significantly less expression of IFN-γ, HMOX-1 and GNLY immediately before the treatment at week 6 [Figure 3]. These data agree with the idea that specific immunomodulatory molecules are involved in the success of BCG-treatment, but in moderate levels. Patients with relapsing tumors may be genetically prone to develop exacerbated chronic inflammation or cytotoxic responses during BCG treatment or during the disease itself.[24] This exacerbated inflammation may add to the burden of the disease. For instance, IFN-γ is an essential component of cell-mediated immunity, and in BCG therapy it has an inhibitory effect on bladder cancer cells.[25] However, depending on signalling intensity and microenvironmental factors, this cytokine can drive novel cellular and molecular inflammatory mechanisms that may underlie tumor initiation, immunoevasion, and progression.[26] Likewise, HMOX-1 catalyzes the degradation of heme and is considered a key enzyme to protect cells from stress and to regulate cell growth and proliferation. However, increased levels of HMOX-1 expression and activity were observed in various tumor tissues. The knockdown of HMOX-1 suppresses the growth of bladder cancer cells, and HMOX-1 expression was even proposed as an independent predictor of NMIBC recurrence and progression.[27] This agrees with our data, showing that patients with lower levels of HMOX-1 before treatment are likely to respond better to BCG. On the other hand, granulysin is a cytolytic and pro-inflammatory molecule expressed by activated cytotoxic T cells and NK cells,[28] necessary to kill target cancer cells. However, it has been described that granulysin kills bacteria[29] and therefore it may lessen the efficacy of BCG therapy.
Our results point to the fact that the systemic expression of molecules that promote inflammation is involved in BCG host response. However, since inflammatory response shares various molecular targets and signaling pathways with the carcinogenic process, a good BCG response occurs only within limited levels of these molecules. Taking this into consideration, we define cut-off values for mRNA levels of IL-1β, IFN-γ, HMOX-1, and GNLY, beneath which a good response to BCG is predicted. This allowed us to discriminate BCG responders from relapsing patients.
Univariate and multivariate analysis showed that IL-1β, IFN-γ, HMOX-1, and GNLY expression levels could reliably predict responder vs. relapsing patients. Based on our data, we established cut-off values above which these biomarkers are considered a prejudicial factor. We subdivided patients into whether they showed no prejudicial factors, one prejudicial factor, or two prejudicial factors (see supplementary data). We also established a predictive grouping system to identify the probability that patients would experience relapse after BCG treatment and to help design more personalized immune-based strategies. For instance, a promising avenue of clinical research in bladder cancer is the use of immune checkpoint inhibitors that target molecules involved in the balance and regulation of immune response, hence inducing proper T-cell anti-cancer response.[30]
In conclusion, the analysis of mRNA expression of PBMCs by real-time PCR was a relatively simple, accurate technique for assessing the expression profile of several key immunomodulators in patients with NMIBC, as compared with classical histopathological evaluations and even with urine detection because not all patients have urine detectable levels.
Our results revealed that molecules with immunomodulatory roles, such as IL-1β, IFN-γ, HMOX-1, and GNLY, have a role in BCG therapy but only at certain amounts, above which they appear to contribute to poor response to treatment. Thus, we established a cut-off value for mRNA levels of each molecule and propose the use of this information to predict which patients with NMIBC will be good BCG-responders, which patients will relapse when undergoing BCG treatment, and who therefore would benefit from alternative treatment strategies.
Authors' contributions
Conceived and designed the study: H. Trindade, D. Ligeiro, F.M. Calais da Silva, F.E. Calais da Silva
Performed literature search and prepared manuscript: P.A. Videira, M.G. Cabral
Acquired clinical data: F.M. Calais da Silva, F.E. Calais da Silva
Performed the experimental study and data acquisition: D. Ligeiro
Analyzed data and prepared presentation of manuscript: P.A. Videira
Performed statistical analysis: R. Sylvester
Revised the manuscript: F.M. Calais da Silva, P.A. Videira, D. Ligeiro, M.G. Cabral, R. Sylvester, F.E. Calais da Silva, H. Trindade
We thank João Sobral, Helena Gouveia, and Sofia Mendes for help in preparing patients' samples and data.
Financial support and sponsorship
This work was supported by a grant of Astellas Pharma, obtained after application.
Conflicts of interest
There are no conflicts of interest.
Patient consent
Patients entered this study after written informed consent and were analyzed anonymously.
Ethics approval
The study has been approved by the ethical committee of the Hospital. All procedures followed the universal bioethical principles (Universal Declaration on Bioethics and Human Rights of UNESCO, 19 October 2005; The Charter of Fundamental rights of the EU, 2000; Ethical principles for medical research involving human subjects - Declaration of Helsinki (2008) with 2013 amendments.
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- 29. Ernst WA, Thoma-Uszynski S, Teitelbaum R, Ko C, Hanson DA, Clayberger C, Krensky AM, Leippe M, Bloom BR, Ganz T, Modlin RL. Granulysin, a T cell product, kills bacteria by altering membrane permeability. J Immunol 2000;165:7102-8.
- DOI PubMed
- 30. Bidnur S, Savdie R, Black PC. Inhibiting immune checkpoints for the treatment of bladder cancer. Bladder Cancer 2016;2:15-25.
- DOI PubMed PMC
- 31. Sander B, Damm O, Gustafsson B, Andersson U, Håkansson L. Localization of IL-1, IL-2, IL-4, IL-8 and TNF in superficial bladder tumors treated with intravesical bacillus Calmette-Guerin. J Urol 1996;156:536-41.
- 32. De Boer EC, De Jong WH, Steerenberg PA, Aarden LA, Tetteroo E, De Groot ER, Van der Meijden AP, Vegt PD, Debruyne FM, Ruitenberg EJ. Induction of urinary interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guérin in superficial bladder cancer. Cancer Immunol Immunother 1992;34:306-12.
- DOI PubMed
- 33. Conticello C, Pedini F, Zeuner A, Patti M, Zerilli M, Stassi G, Messina A, Peschle C, De Maria R. IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins. J Immunol 2004;172:5467-77.
- DOI PubMed
- 34. Bevers RF, Kurth KH, Schamhart DH. Role of urothelial cells in BCG immunotherapy for superficial bladder cancer. Br J Cancer 2004;91:607-12.
- DOI PubMed PMC
- 35. Bevers RF, de Boer EC, Kurth KH, Schamhart DH. BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines. Eur Cytokine Netw 1998;9:181-6.
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- 36. Luo Y, Han R, Evanoff DP, Chen X. Interleukin-10 inhibits Mycobacterium bovis bacillus Calmette-Guerin (BCG)-induced macrophage cytotoxicity against bladder cancer cells. Clin Exp Immunol 2010;160:359-68.
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- 37. Yamada H, Odonnell MA, Matsumoto T, Luo Y. Interferon-gamma up-regulates toll-like receptor 4 and cooperates with lipopolysaccharide to produce macrophage-derived chemokine and interferon-gamma inducible protein-10 in human bladder cancer cell line RT4. J Urol 2005;174:1119-23.
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- DOI PubMed


text:
HACKENSACK, N.J. — Bergen County residents will soon be able to have booze delivered to their door, thanks to Hackensack High School graduate Bryan Vargas.
The app — LiqCures — that allows users to connect to the nearest liquor stores for delivery or pick up.
"I'm just an avid wine drinker and I wanted something better," Vargas, 24 of Teaneck, told Daily Voice.
He thought of the concept in July, when he and his girlfriend both wanted a bottle, but were too lazy to go get it themselves.
After some research, he found that his concept had already been out there in larger cities, but Vargas said he wants to bring it to the suburbs of New Jersey.
LiqCure users will be able to order delivery items (from stores that offer delivery service) and can place orders from their phones for the store to set aside for pick-up immediately or at a later time, Vargas explained.
Customers can also search specific types of alcohol and the app will connect them to the stores that carry it.
Vargas is hoping for a December or January rollout.
Click here to sign up for Daily Voice's free daily emails and news alerts.

subset: commoncrawl


text:
Friday, January 22, 2010
Mr. Darcy Broke my Heart
Title: Mr. Darcy Broke my Heart
Author: Beth Pattillo
From the back cover:
Claire Prescott doesn't understand Mr. Darcy's appeal. She's been comfortably dating Neil, a nice- if a bit negligent- sports fanatic. But when she agrees to stand in for her sister at a Jane Austen seminar in Oxford, England, she finds herself holding a lost version of Pride and Prejudice. Scholars thought Austen's original manuscript was destroyed centuries ago, but as Claire reads the beloved author's first draft, she discovers that Austen didn't always have Darcy in mind for Lizzie Bennet.
And when a tall, dark, and dashing stranger crosses Claire's path, will she suddenly discover her inner Lizzie Bennet? Neil's unexpected arrival in Oxford complicates Claire's journey to finding her true romantic lead, and she discovers that finding the right hero can be more difficult that she ever imagined.
My take:
First of all, don't you just love this cover? I read another book this author wrote called Jane Austen Ruined My Life. It is related to this one, but both books stand alone and both are fabulous ~ if you like Jane Austen.
There is a current popularity for all things Austen. I don't mind at all ~ but it can lead to a certain amount of been there-read-that syndrome. The basic concept of these books is not brand new. I don't know how many fans have dreamed of discovering letters or manuscripts tucked away somewhere that escaped a fiery death. What makes this interesting is the way she goes about telling the story and the characters she uses to tell it.
This is a packed novel. If you are just a casual fan of Jane Austen, you can learn a lot about her just from reading this story. There are also mysteries to be solved. Some of them are simple and resolve themselves quickly and some seem dangerous. People are not always who or what they seem to be and many of them change over the course of the novel.
Then we come to the love story. The back cover really told you just about as much as I can without giving too much away. Let me just add that the romantic scenes are wonderfully written. Claire has a time where she isn't sure which end is up as far as her heart is concerned. At one point, I didn't know who she was going to end up with, and I can usually guess these things in advance.
Claire was such a complex person. I liked that she wasn't perfect. She was someone I could relate to in at least a few situations. All the characters, with one possible exception, were people I felt I could meet on any street. Claire's struggles felt authentic, and the fact that she didn't overcome them right away was real as well.
There are incredible secondary characters like Harriet, an old woman who lives near the college and loves to talk to Claire over tea ~ when she remembers who Claire is. Then there's Martin. He's an older gentleman who adopted Claire during the seminar and looks after her. He's an expert on all things Austen but came anyway, just to spend time with people who love Jane Austen.
And that's what this book is really about ~ love. What we do for it, how it changes us and why, who we love... what real love is. It doesn't just examine romantic love, but looks at it in all its glorious facets. What the love of parents, friends, and siblings looks like.
What's your favorite love story so far this year? How about of all time?
4 comments:
I have Jane Austen Ruined My Life on my wish list and now I'm going to have to add this one too! Great review, btw. :)ReplyDelete
Hmmm, good question...I love "You've Got Mail" and one book that I remember because of the love story is Roses for Mama by Janette Oke, that was a very sweet love story. Last year I have say that A Passion Most Pure was my favorite love story and I need to get the other books in that series.
This sounds so good!! I agree with you that there are almost too many Austen spinoffs nowadays but I just can't resist them! This one really does look especially good, I'm adding it to my to read list!ReplyDelete
I gotta read this book Lee!!! Thank you for the review! :-)ReplyDelete
As for the question, geez Lee that's so hard but this year my favorite read so far is LFYI Hershey, PA by Cerella Sechrist! It's such a cute romance plus it made me LOL which is important! As for the all time favorite that's hard too but it would probably be Pride and Prejudice (secular fiction) with my Christian Fiction pick being A Paassion Denied by Julie Lessman!
xoxo~ Renee
Not a Jane Austen fan *ducking and running*, but this cover is fabulous. Thanks for the great review, Lee.ReplyDelete
Favorite Romance so far this year: I gotta agree with Renee ~ LFYI Hershey Pennsylvania. I laughed thru the first 3/4 of the book, and cried the last 1/4. It's an excellent debut novel for Cerella!
All-time Favorite Romance: I gotta choose a series here...Susan May Warren's Noble Legacy series. I could read this series over and over! Though Julie Lessman's Daughters of Boston series is a VERY close 2nd. *sorry Julie!*


text:
Idaho entrepreneur wins award and capital backing for inventing a device device that connects spliced electrical wires and heavy-duty cables
|June 9, 2010
|View for printing
It's called the Melni http://www.melni.org/ "Quick Grip" Connector http://melni.org/melni_press_releases.pdf , a small device that connects spliced electrical wires and heavy-duty cables, and it's something that Melni says will revolutionize the way electricians and utility workers connect wires.
"I got the idea after watching an elderly friend of mine splicing wires," Melni said. "By the time he was done, his hands and wrists were sore from having to crimp the wires together."
On May 19, Melni won the prestigious Idaho TechLaunch competition http://www.idahotechconnect.com/rais ... techlaunch/ , which is judged by the state's leading investors and innovators, and includes $10,000 in capital to expedite the invention's entrance into the market place.
Joshua Palmer
Full Story: http://www.magicvalley.com/business/ ... c002e0.html
No reader comments so far. Be the first to comment by clicking the button below.
Reprinted under the Fair Use doctrine of international copyright law. Full copyright retained by the original publication. In accordance with Title 17 U.S.C. Section 107, this material is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.


text:
Inspired by Catholic Social Teaching, the Office of Community Engagement at the University of St. Thomas focuses on course-based community engagement. Our Office supports the design, implementation, and evaluation of courses that use collaborative strategies of engagement to advance the common good.
Faculty design their courses after developing partnerships with non-profit organizations, schools, or government agencies in order to provide a learning experience for the students grounded in the real world. St. Thomas students undertake a project for the partnering organization related to their discipline of study. Community partners become co-educators with our faculty—all with the goal of advancing the common good through the education of St. Thomas students.
Our vision is to create partnerships to respond to the region's most pressing needs. These include ensuring equitable access to education, dismantling racism, promoting women's equality, improving public health, alleviating poverty and hunger, establishing food security, securing environmental sustainability, advancing justice and peace, fostering interreligious understanding, and caring for elders and people with disabilities.
Course-based engagement is a key way St. Thomas demonstrates it is "all for the common good."


text:
Chrissy and Nathan, December 2013. The first Wish
Christina Franklin, 26 of Cotton Tree and her fiancé Nathan Moon were gifted the 2013 My Wedding Wish $24,000 white wedding. The ceremony and reception was held in December 2013, in the Sunshine Coast Hinterland.
Ms Franklin suffers from Adenocarcinoma of the bowel and metastasis in the liver. She was diagnosed when she was 21 weeks pregnant with the couple's second child, and advised that she would not survive the pregnancy without starting chemotherapy immediately. A caesarean section was booked for 36 weeks, but tragically their son died in utero at 35 weeks.
The couple's other son, 14 month old Blair has feeding, respiratory and development problems which require ongoing medical intervention.
Ms Franklin has chemotherapy on a fortnightly basis, and her condition is terminal with doctors saying she has 2-3 years to live. When told they were being offered the prize, Ms Franklin and Mr Moon were ecstatic. "I can't believe it," Ms Franklin said, "I never win anything." Mr Moon added that, "Now she'll have something positive to direct her energies to."
Bridesmaid Hayley Brooke said that winning the wedding had been such a positive change to Christina's life and that "she has something positive to focus on for a change".
Check out the absolutely brilliant work of Norman Benecke from Divine Studios who put together this beautiful short video of Chrissy and Nathan ! Get your tissues ready!
Our suppliers on the day:
– Accommodation – Secrets on the Lake
– Bonbonnieres – The Chocolate Petal
– Bridal hair – River Terrace Hair Studio
– Bridal headpieces- A Veiled Affair, North Brisbane
– Bridal makeup – Photofinish Makeup and The Beauty Case
– Bridal nails – On Trend Beauty
– Cake – Sweet Creations, Buderim
– Celebrant – Lynette Maguire
– Ceremony styling – Decorating Divas
– Ceremony venue- Maleny Manor
– DJ/Music – Elite Sounds Entertainment
– Flowers – Willow Bud
– Invitations – Invitation Designs by Eliza, Brisbane
– Keepsake bouquets – Crystal Wedding Boutique
– Photo booth – Noosa Photo Booths
– Photography – Andrea Sproxton Photography
– Proprietor / organiser – Lynette Maguire
– Reception styling – Coast to Country Weddings and Events
– Suits – Suits Direct, Mooloolaba
– Reception Venue – The Badgers Firkin English Pub, Flaxton (business closed)
– Sweet Table – Sweet Tables by Marie (business closed)
– Videography – Divine Studios, Brisbane
– Wedding bands – Sunstate Jewellers, Caloundra
– Wedding cars – A Chevy Experience
– Wedding gown and bridesmaids dresses – Exquisite Gowns by Yvonne, Morayfield
– Wellness Coaching – The Body Whisperer


text:
You're free to contact me by mail: Simon Hoerder, firstname.lastname@example.com (Friendly mails preferred.)
Some people think it's fun to write lengthy pieces of legalese on everything. I don't. Some lawyers think it's their god given right to make an income generating expensive lawsuites about nothing. I disagree. (There are much more worthy causes than correct spelling of disclaimers a lawyer could fight for. Human rights for example.) Therefore I'm not going to publish more or less useful legal disclaimers for each reader's country.
But since you've continued reading to this point, I'm going to give you a few guidelines which should make everyone happy:


text:
There are over 100 applications in Myo Market. Here are just 15 ways people around the world are exploring gesture control with the Myo armband:
1. Myo Mouse and Keyboard
Control your computer from a distance. Point, click, and type using your Myo armband.
Myo Mouse and Keyboard is built into Myo Connect. Learn more.
2. Myo for Presentations
Put down your presentation remote and engage with your audience in real time. Use Myo for Presentations to control your slides, a digital pointer, and zoom in on your presentation using gestures and motion.
Find out more about using Myo for Presentations. Built into Myo Connect.
3. Myo Music
Stay in control on the go! Download Myo Music for iPhone or Android.
4. Keyboard Mapper
With Keyboard Mapper, making a connector for your favorite application is easy. Simply map gestures to keyboard presses and mouse clicks and you'll be controlling a new application with the Myo armband in seconds.
Learn more about using Keyboard Mapper in Myo Connect.
5. Race the Sun
Ready. Set. Race! Control Flippfly's Race the Sun using the motion of your arm.
6. Counterstrike
Use your Myo armband to replace your mouse. Shoot bad guys from your couch and play with your friends.
7. Fruit Ninja
Use gestures to slice fruit and play Fruit Ninja for Windows!
8. Play Audiosurf
Load your favorite song into Audiosurf and play on a course dynamically generated by your music.
9. Use Myo as a puppet
A virtual talking puppet show! Just another way to bring your computer to life with Myo.
10. Play with a friend
With connectors like Drunk Painting Simulator, compete with a friend to cover up as much as the blank portrait as possible.
11. Quickly launch websites
Use the quick launch menu built into Myo Connect to launch Twitter, Facebook and more. Find out more about using the Quick Launch Menu.
12. Use Myo as a remote for Roku, Kodi, Netflix
If entertainment is what you're looking for then you've come to the right place. Check out the Multimedia category in Myo Market for connectors for Roku, Kodi, Netflix, Spotify, YouTube and take control with a wave of your hand.
13. Take control of Sphero
An intuitive and easy way to take control of Sphero. Master high speed rolls with your Sphero, Ollie, or BB-8.
14. Fly drones like a superhero
Get a bird's eye view fully controlled by your hands. With apps like Parrot 3.0, we've made it easy for you to take flight.
15. Create an interactive experience on stage with Leviathan
Control your favorite music software and analog synthesizers using custom gestures and movements with Myo.
Take a deep look at the data your Myo armband can give you by taking a look at the Myo Diagnostics page.


text:
By Vicki Barclay
Approaching a big race like the Trans-Sylvania Epic, people always ask, "How you are feeling?" and "Are you ready?" I always find it a funny question to answer! The same way as when someone asks how a job interview went, men tend to answer with confidence, I have noticed, whereas females tend to be more coy and careful. I prefer the coy and careful approach.
The truth is, mountain bike stage racing is like no other racing. As Heidi Klum from Project Runway would say (yes, I know, I love crap TV!): "One day your in, the next you're out" (with a very abrupt tone for out). You can be having the ride of your life, only to be taken out by a mechanical, illness, etc. In other words, hope for the best and prepare for the worst.
This spring, with the incredible support from the Stan's NoTubes Women's Elite Team, I have been able to participate in a whole range of races on my journey towards TSE, including the Maryland State Champs at Greenbriar; the Whiskey Off-Road; the Wildcat 100; Mike Kuhn's universal relay race; a 4 hour endurance race; and a cross country race in the Mid-Atlantic super series. It has been the most enjoyable spring racing to date, mostly because I have loved racing my Cannondale Scalpel 29er! The bike climbs like a cross-country hard tail, but floats over the rocks like an amazing full suspension bike.
But do all those races mean I am ready for TSE? Thoughts start creeping across my mind, like "Should I have done more back-to-back hard days of training instead of racing?" "Why didn't I make the effort to pre-ride some of the stages that I don't ride too often?" "Should I be more anal about my bike set-up, positioning etc?"
What I am learning more and more with stage racing, and indeed all other types of racing however, is that you have to quietly accept and be at peace with your preparations, turn up to the start line rested, and not get caught up in what other people are doing in training, eating, drinking, etc. At least that's how it works for me.
The prologue starts Sunday and I am excited about what the week will bring. Are you ready?
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text:
from Wiktionary, Creative Commons Attribution/Share-Alike License
- adj. Turned away; averse.
- adv. Forth; forward.
- prep. From; away from.
from the GNU version of the Collaborative International Dictionary of English
- prep. A way from; -- the contrary of toward.
from The Century Dictionary and Cyclopedia
- Turned away; averse.
- Forth; forward.
- From; away from: opposed to toward.
from Wiktionary, Creative Commons Attribution/Share-Alike License
And from thence-fromward they be all obeissant to him.
And fro thens fromward, thei ben alle obeyssant to him.
The Principal Navigations, Voyages, Traffiques and Discoveries of the English Nation
For several years, I have found it useful to employ the coined adjectives hormetic and aphormeticto characterize the tendencies fromward or toward, as exhibited in the association of ideas.
And when the endeavour is fromward something, it is generally called AVERSTON.
And, when the endeavour is fromward something, it is generally called aversion.
Chapter VI. Of the Interior Beginnings of Voluntary Motions, Commonly Called the Passions; and the Speeches by Which They Are Expressed
And when the Endeavour is fromward something, it is generally called AVERSION.
*** The flowers shee had wrought caried such life in them, that the cunningest painter might have learned of her needle: which, with so pretty a manner, made his careers to & fro through the cloth, as if the needle it selfe would haue been loth to haue gone fromward such a mistresse, but that it hoped to returne thitherward very quickly againe; the cloth looking with many eyes vpon her, and louingly embracing the wounds she gaue it: the sheares also were at hand to behead the silke that was growne too short.
The microscope is accordingly reproduced naively with an "endeavor fromward" attached to it, and likewise the reflex, with an "endeavor toward" it. 39 Thus is the expression completed of a wish which had been partially outspoken in the conversation with Dr.X. While the external physical stimulus (scratching) must be thought of as being represented dynamically somewhere in the arrival platforms of the brain, it is necessary to think of the internal psychic stimulus (or wish) as existing in the form of facilitations, or ready-made connections of ideas and motives, as it were awaiting, in a state of mobilization, the proper signal to discharge into consciousness.


text:
Posts Tagged 'bioshock infinite first gameplay'
Bioshock Infinite Preview: First Gameplay!Posted by Giancarlo Marciano on November 18, 2010 under News, TrailersBioShock Infinite's teaser is one of the best we've seen here at GameGuideDog. There's a great sense of theatre: a slow pan through a fishtank, and a familiar theme apes the first BioShock teaser, before Booker is literally thrown into Columbia. It's July 4, the Grand Old Flag (one of America's more tubthumping national anthems) is playing from a gramophone as a conductor mimes in front of it, tel... more.


text:
When using either createSound or createStream I continually get the ERR_INVALID_PARAM result back and it isn't obvious to me what the issue is.
RESULT result = fmodSys.createSound("sound.wav", MODE.DEFAULT, ref sound);
Both variables 'sound' and 'fmodSys' are instance variables.
The application is being written with XNA Game Studio Express 1.0
Any help would be appreciated as I feel as if I'm missing something obscenely obvious.[/code]
- 331Rage asked 12 years ago
Perhaps the wav has a strange encoding not supported by FMOD — it might be worth trying to load one of the sample sounds delivered with the API package.
Also, you should maybe check that your sys.init call succeeded.
Thank you. You were correct about the sys.init call. I failed to write this line before it:
FMOD.Factory.System_Create(ref sys);
You should probably supply a complete path to sound.wav since it's hard to predict what the current directory will be at runtime (remember to prefix the string with an at symbol ("@") before the first double-quote if you're using C# so that you don't have to double the backslashes in the path. In Microsoft Visual Studio, the current directory will probably be the debug or release folder where your application is compiled and not the folder where all your source files are.
I tried both relative and absolute paths to the audio file and still receive the invalid param error. Also, if the audio path was the issue, shouldn't it return a file not found error, not invalid param?
I threw all my code into a single class to test things out and I'm still running into the same issue.
static void Main(string[] args)
FMOD.System sys = new FMOD.System();
sys.init(100, FMOD.INITFLAG.NORMAL, System.IntPtr.Zero);
FMOD.Sound sound = null;
FMOD.RESULT result = sys.createSound(@"F:\Programming\Visual Studio Projects\fmodtest\ConsoleApplication1\ConsoleApplication1\bin\Debug\gamesound.wav", FMOD.MODE.DEFAULT, ref sound);
if (result != FMOD.RESULT.OK)
throw new ApplicationException("Error when loading sound:" + result + "-" + FMOD.Error.String(result));
Console.WriteLine("Sound Loaded");
FMOD.Channel channel = null;
result = sys.playSound(FMOD.CHANNELINDEX.FREE, sound, false, ref channel);
if (result != FMOD.RESULT.OK)
throw new ApplicationException("Error when playing sound: " + result + "-" + FMOD.Error.String(result));
Console.WriteLine("Sound Playing");
The exception is still being thrown after calling createSound()[/code]
Please login first to submit.


text: I have found tons of threads/posts discussing people's cheating girlfriends, cheating wifes, cheating joint venture partners, cheating with poker, and just cheating in general... However, I am wondering if there are any ebooks or products anyone has which are related to adultery, infidelity, catching a cheater etc.... I have looked, maybe I am not looking hard enough, however due to the nature of the issue at hand, there are so many discussions containing such keywords, but like I said they are only discussions... I've also found some online using various techniques, but I am talking about more extensive ebooks/products, like those on amazon or clickbank. Could someone help me in this area, please? It would be much appreciated


text:
H2O+ Beauty Eye Oasis
45 reviews
22% would repurchase
Package Quality: 3.8
Price: $$$
Package Quality: 3.8
Price: $$$
Where to Buy
- When you make a purchase through these links, we may receive a commission from the eBay Partner Network or other affiliates.
Start your review
on 7/3/2015 3:54:00 AM
Age: 19-24
Skin: Very Dry, Fair, Not Sure
Hair: Black, Other, Other
Eyes: Green
Luckily, I got a trial size instead of buying a full size of this. I didn't really find that it did anything. It smelled nice, but wasn't moisturizing or any kind of effective.
on 4/4/2014 6:28:00 AM
Age: 18 & Under
Skin: Combination, Fair-Medium, Not Sure
Hair: Black, Other, Other
Eyes: Brown
I have now used this eye gel for about 10 months. Throughout this time, I have also tried other types of eye creams and I find myself still returning to this one. This eye gel instantly makes my eyes look awake and it is very hydrating and lightweight. I hate putting anything oily around my eyes, because it makes my eyeliner crease. This gel minimizes that, and its oil-free formula feels fresh and comfortable. Although the ingredients list does say it contains alcohol, I have never experienced any irritation with this product. And as I've said, I've used this for almost a year on a daily basis. One 15ml tube can last for 3-4 months, so it's pretty worth it for its price. I especially recommend this eye gel to those living in humid areas, because it is water based and refreshing. I have no clue if this helps with fine lines since I don't have any at the moment. However, I think the best age group for this product would be 16-25 years. For older individuals, something richer with more benefits would be better. The main purpose of this eye gel is simply to lock in moisture. It doesn't promise much other than that. Nonetheless, I am loving this currently!
on 4/24/2012 5:55:00 PM
Age: 19-24
Skin: Normal, Olive, Not Sure
Hair: Brown, Other, Other
Eyes: Brown
My mother gave me this after getting it in an h20 gift set... Doesn't really moisturize that intensely and I tend to have reallyyyy dry skin around my eyes that gets irritated super quick. When I work out, the sweat irritates it so I have to go the extra mile to keep it moisturized regularly. Anyway, long story short, I put this on at night after washing my face and it burned like hell! Left a nasty tacky feeling too. Don't waste your money.
on 7/27/2010 8:18:00 PM
Age: 30-35
Skin: Combination, Fair, Cool
Hair: Blond, Wavy, Medium
Eyes: Grey
I have been using this product for about a month. It does moisturize very well and absorbs quickly. I am ready to apply eyeshadow primer within minutes after application. I do not have lines or darkness on my eyes but I do tend to get dry patches under my eyes because my eyes water a lot. Since I have used this, the dry patches are gone.
on 4/14/2010 2:46:00 AM
Age: 25-29
Skin: Acne-prone, Olive, Warm
Hair: Black, Straight, Medium
Eyes: Brown
It keeps my eyes moisturized. It doesn't do much else. I got plenty of this product because I used to buy a set that came with it but one tube goes a long way.
on 2/23/2010 7:21:00 PM
Age: 19-24
Skin: Acne-prone, Fair-Medium, Warm
Hair: Black, Straight, Medium
Eyes: Brown
This eye gel does moisturize my eyes, but I don't think it does anything for dark circles or anything like that. I started using eye creams this summer (2009) and none of them made a difference :\. Well I don't really need eye creams because I don't have puffyness or wrinkles, but the area under my eyes are dark and I was hoping to lighten that. And after I wash my face, even though I don't wash my eyes, that area gets really dry anf uncomfortable.
So this eye cream moisturizes it... but it does nothing else. I can just put some of my regular face cream under my eyes. So no repurchase, unless it was on major sale.
on 7/20/2009 6:25:00 PM
Age: 19-24
Skin: Acne-prone, Fair-Medium, Not Sure
Hair: Black, Other, Other
Eyes: Brown
I used this product and it did not work very well for me. It smells alright though.
on 6/28/2009 2:00:00 AM
Age: 19-24
Skin: Very Oily, Medium, Not Sure
Hair: Black, Other, Other
Eyes: Brown
I got this with a set of other Oasis products, so I cannot comment on pricing.
When I first started using this product, I got strange little bumps around my eye lids, one of which turned into a whitehead that took forever to remove since it was literally on the part of the lid right above the eye and thus was sensitive. But now it doesn't do it. I've never used eye products before and it may have been a getting used to/mini purge process. I just thought I'd mention this for anyone experiencing it.
As for other results...I haven't seen any. Admittedly, I don't really have problems with my eyes other than circles and sometimes puffiness (I wish laugh lines could count) so I don't use eye products at all, but I was hoping it would have made the area around the eye at least a bit brighter. As a light little moisterizer, sure...why not? But there's no need for me to own one.
EDIT: So recently I have finally gotten my first set of fine lines due to increased stress and dare I say it...age? (I hope not, I'm not old!) This has not helped said fine lines...and I've found out that it rolls off when I try to brush on my mineral makeup to cover my undereye circle...annoying. I've tried to wait even up to 15 min for it to sink in...no luck. Also, I don't know if this is due to increased usage of the gel or other reactions but I've started occasionall developing small white bumps under my eyes. Arguably they can be allergic reactions to something or other...but they only really appeared after more regular use of the eye gel. But in conclusion, I am taking one more lippy off.
on 3/5/2009 11:54:00 AM
Age: 36-43
Skin: Oily, Dark, Warm
Hair: Black, Kinky, Other
Eyes: Brown
Although I am over 40, I do not have issues with wrinkles, bags or circles. Every eye product that I find that works for me gets discontinued :-(. So I'm on the hunt for something new. I need a simple yet effective eye moisturizer. I also have oily skin so I have to use something that will not make me breakout where the eye cream touches my upper cheekbone and I wear contacts so it must not migrate. I got this as part of an H2O Oasis set. I used it one morning . The texture is exactly what I am looking for, a light creamy gel, really hydrating, felt great going and in a hygenic tube too! However, for the first time ever in my life, someone at work asked me if I just woke up . . . uuuhhh nooooo???? . . . it takes me an hour to get to work . . . so NO, i did not just wake up! I looked in the mirror and OMG!! I looked like I'd been down with the flu or a bad case of allergies. I actually don't look THAT bad when I have just awaken. The puffiness and bags were shocking!! Not sure what's in it to make me look "swollen" but I will not use or purchase again. Sigh.
on 2/23/2009 8:44:00 AM
Age: 19-24
Skin: Combination, Fair, Not Sure
Hair: Black, Other, Other
Eyes: Black
I think a lot of people don't realize that this eye cream is not for older audience. It is made, like a lot of other H2O plus products, for a younger audience like around 18~early to mid 20s. This eye cream will really work if your skin is very dry. But for me, it does get rid of puffiness and little fine lines when I apply it during the night. I wake up to non-puffy eyes in the morning. It is also important don't drink water before going to bed because that will contribute to puffy eyes. Although I don't feel the hydration as much, I still find that this is a nice light eye cream, that gets rid of little fine lines and puffiness. And also, one of these tubes lasts forever. Definetly will repurchase. But I usually just get it in a set along with my other H2O plus products.
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Intro: Light Through the Bottle.
This is a picture of a PET bottle, filled with water and bleach: 15 Fl Oz of water and 1.5 Fl Oz of bleach.
1/3 of bottle outside. The bottle then will omit light through the bottle which then makes the bottom 2/3 of the bottle shine a light like a light bulb. I attached a few pictures for you to see an example of the light going through the bottle.


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Saddle pressure
Pressure mapping at the saddle enables the exact analysis and optimization of the point of contact saddle in a professional bike fitting. more..
Foot pressure
Flexible pressure sensor mats in the cycling shoe deliver previously immeasurable information concerning the exact load during the pedalling cycle. more..
Motion Analysis
Our high-speed video-analysis enables the exact capturing of motion quality, joint angles and pedalling motions. more ..
Force Analysis
The gebioMized force measurement makes it possible to analyse the force applied to the crank at every point of the pedalling cycle. more..
Add-on Aero-Pad
For the first time ever, our pressure sensor mats allow the exact and quick analysis of the stability in the aero-position. more…
Add-on MTB grips
With our pressure mapping mat for the mtb-handlebar we address previously unsolved questions regarding the force distribution between saddle and handlebar. more..


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Obama rallies Democratic base with Obamacare remarks
President Barack Obama Tuesday tried to rally Democratic leaders and base voters behind his Obamacare network, and slashed at his critics for supposedly trying to block people from getting health care.
"The debate over repealing this law is over, the Affordable Care Act is here to stay," Obama insisted during a late-afternoon April 1 press event in the Rose Garden, that was attended by Democratic legislators who cheered his announcement that the network had reached 7.1 million signups.
Obama coupled those reassurances for worried Democratic legislators with campaign-style compliments for the Democratic supporters that he needs to help elect Democrats in November.
He also smeared GOP legislators and voters who want a decentralized, free-market health-care system — rather than his centralized, government-managed Obamacare system — as opposed to health care for Americans.
"I've got to admit, I don't get it," he said. "Why are folks working so hard for people not to have health insurance? Why are they so mad about the idea of folks having health insurance?" he said as he offered anecdotes about three people in a country of 310 million who have gained from his reorganization of the nation's health sector.
In fact, nearly all Republicans want people to be able to buy their own health insurance, usually with government aid.
But Obama needs to energize his base voters enough to overcome their sour mood about the stalled economy, especially because many Democrat-leaning swing-voters are expected to stay home.
"Many of the tall tales that have been told about this law have been debunked. There are still no death panels. Armageddon has not arrived," Obama said from his Rose Garden podium.
Obama also suggested to his supporters that people oppose the law because they don't like him personally. "Regardless of your politics or your feelings about me, or your feelings about this law, [increasing health-care coverage is] something that's good for our economy, and it's good for our country," he said.
The mood in the Rose Garden was good among the Democrats because a late rush of signups had boosted the Obamacare network's subscribers up to 7.1 million by March 31.
Many Democrats are worried that the law will allow the GOP to win a Senate majority in November.
But Obama and his fellow Democrats made sure not to highlight the problems.
The law is more unpopular among likely GOP voters than it is popular among likely Democratic voters.
Many of the claimed 7.1 million subscribers are expected to drop out before making their first payment.
Several million of the subscribers are likely people whose 2013 insurance plans were canceled by Obama's stringent 2010 regulations, which violated his much-repeated promise that Americans could keep their health-care plans.
Obama also did not mention that most of the law's most unpopular features have been delayed past the November election, often with out any legal authority.
Those unpopular features include new regulations on company-provided health care, cancellation of plans offered by small companies to millions of Americans, and the public announcement of price spikes for 2015.


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At age 79, Stephen Covey, the best-selling author of The Seven Habits of Highly Effective People, passed away following injuries he sustained in a bicycle accident. The in-demand speaker, writer and entrepreneur had spent years teaching people the foundations of effective leadership in life and business.
Covey was a guest on The Christophers' TV program in 2006. Producer Tony Rossi remembers him well.
He says, "Covey was not only friendly; he burst into song. When I took him to meet our make-up artist, Janet, he spontaneously started singing Bless Your Beautiful Hide from Seven Brides for Seven Brothers! Janet appreciated the compliment, and the whole crew was left smiling. In that impromptu moment, Covey put everyone at ease and demonstrated an important leadership principle. If you connect with people on an individual level, inspire respect in them, and even make them smile, they'll want to do a good job for you. You won't just be a boss; you'll be a leader. Covey obviously practiced what he preached."
Support your faith with goodness. (2 Peter 1:5)
Enable to inspire respect and joy, Lord.


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As reported in the Albanian press: A wolf was caught in the mountains and was put in a cage in the village of Patok in Lezhe, about 4 months ago.
They put a donkey in the cage, for the wolf to eat. Apparently, the lonely wolf, was more hungry for friendship. Since then they got attached to each-other, cohabitating the cage and teaching the people some humanity. If only our politicians, would ever learn to co-habit with each-other!And here's how humans project their own feelings, on these animals:
A donkey grazing in a small meadow saw a wolf creep up on him, and at once pretended to be lame. The wolf, coming nearer, asked why he was limping. The donkey said that he had passed through a hedge where he had trod with his foot on a sharp thorn. He advised that the wolf pull it out, so that it would not harm his throat when he ate him. The wolf agreed and lifted up the foot, and concentrated on the hoof. Then the donkey kicked his teeth into his mouth and galloped away. Fearfully mauled, the wolf said: "I deserved what I got. Why did I attempt the art of healing, when my father only taught me the trade of a butcher?"
Filed under: wolves in the news | Tagged: Canis lupus, news, wolves | Leave a comment »


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Last updated on February 18th, 2017 at 09:00 pm
This crockpot chicken noodle soup is a classic and hearty soup, requiring minimal effort giving you tender chicken, loads of noodles and a delicious broth.
Today we had a very quiet day at home since we celebrated Easter yesterday at my sister's house. I was not in the mood to really cook anything but with it being Easter and all I decided to make a pork roast but what I was really craving is some chicken noodle soup. Growing up, chicken noodle soup was very common to have with our Sunday night dinner, so I think that just stuck with me.
Usually when I make chicken noodle soup I use a whole chicken with skin and bones and all, but I just didn't have one this time so this is why I used boneless skinless chicken breasts. If you like dark meat you could also use thighs instead. Basically making chicken in the crockpot is the same as making it in a regular soup pot on the stove top just easier and less babysitting. I just threw the carrots, onion and chicken in the crockpot, you could also use celery but I for one am not a fan of celery in soup so I skipped it in mine.
So I have to tell you about a secret ingredient I use in all my soups. Coming from Eastern Europe we always use Vegeta in soups. Vegeta is a Mediterranean seasoning made from dry vegetables and other spices. I've always used this, it gives the soup a beautiful yellow colour and an amazing taste. Many times I'll use this whenever a recipe calls for chicken broth because I really love the flavour. Now if you don't have Vegeta you can use chicken broth instead, maybe a low sodium version.
I also put the onion in whole and removed it when I shredded the chicken because I'm fussy again about my chicken noodle soup, I like a nice clear broth with just carrots, chicken and noodles. It's just how my mom always made chicken noodle soup so this is how I like it. You must also use wide egg noodles just so you have the entire chicken noodle soup experience.
I remember when I was a kid I used to hate the soup and carrots and just wanted to eat the noodles, so I'd always eat the soup and the carrots first so I was left with the noodles and chicken. Then I could take my sweet old time eating noodles and enjoying them. I've grown up since then and now I eat chicken noodle soup the normal way. It's funny the things we remember.
If you guys love this recipe, and most importantly make it yourselves, please let us know. Take a picture and tag it #jocooks on Instagram so we can see it. I always love to see what you guys come up with!
This crockpot chicken noodle soup is a classic and hearty soup, requiring minimal effort giving you tender chicken, loads of noodles and a delicious broth.
- 1 large onion peeled
- 2 large carrots peeled and sliced or chopped
- 2 stalks celery optional, chopped
- 3 chicken breasts boneless and skinless
- 2 tbsp extra virgin olive oil optional
- 2 tbsp Vegeta or 6 cups low sodium chicken broth
- 7 cups of water if using Vegeta otherwise 1 cup water
- salt and pepper to taste
- 1/2 tsp dried rosemary optional
- 1 bay leaf
- 2 cups wide dry egg noodles about 4 oz
- parsley for garnish
- Add the onion, carrots, chicken, celery, olive oil, vegeta or chicken broth, salt, pepper, water, bay leave and rosemary to your crockpot. Cook on low for 7 hours or 4 hours on high.
- Remove the onion and take out the chicken to either cut into pieces or shred with two forks. Add chicken back to crockpot and add egg noodles. Cook for another 1 hour on high or until noodles are cooked.
- Garnish with parsley.
You can buy Vegeta on Amazon here.
Please keep in mind that nutritional information is a rough estimate and can vary greatly based on products used.
Check out this recipe for Homemade Chicken Noodle Soup from scratch!
Flu Fighter Chicken Noodle Soup


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at first i just thought it might be due to the fact that i hadn't installed it yet but when i inserted the provided MSI disk and tried to install the driver it got to 55% then told me that it hadn't been verified by microsoft and i clicked "continue anyway" then the computer restarts itselfand it happens all over ive tried installing other drivers eg. nvidia etc. but nothing works please help me.
Edited by DistuRbed?, 18 August 2006 - 02:36 AM.


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Citing a need to be more competitive and meet changing needs in the marketplace, Atlantique City will hold its annual spring show and drop the fall edition starting in 2009.
The change was announced in a letter from show management to dealers during the recent fall show Oct. 18-19 at the Atlantic City Convention Center.
"Just as you have studied your business this year to become more competitive, we have evaluated Atlantique City and its role in the market in 2009," the letter stated. "As a result we have decided to return Atlantique City to its original once-a-year schedule. Our next show will be March 28-29, 2009 and we look forward to March-dated shows going forward."
It continued, "We believe holding Atlantique City once a year will renew interest in the show from collectors and dealers over the long term. It will solidify Atlantique City as the destination show it is and help dealers maximize their investment in exhibiting here. This decision does not tarnish the gains we made and the customers we brought you this fall. Our marketing plan is bringing thousands of new customers, and new dealers are trying the show."
The show, produced by F+W Media, was founded in 1986 and began as an annual event held in March.
"The announcement that we were returning to the one big show a year format was met by exhibitors with understanding and optimism," says Atlantique City Show Producer Eric Bradley. "Presenting a single show allows us to focus energy and resources on creating one, very dynamic show per year – a not-to-miss event. Our exhibitors showed that they agreed by getting their contracts to us before they left the show. And, my phone has been ringing off the hook with folks who want to come back."
For more information about Atlantique City, visit www.atlantiquecity.com.
Click here to discuss this story and more in the AntiqueTrader.com message boards.


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Here are some random shots of Frontierland from the 80's and 90's. First up is The River Belle Terrace, brought to you by Hormel - Makers of Fine Meat. Next up is Big Thunder Ranch (remember Big Thunder BBQ?), brought to you by those fine people at Central Soya.
Friday, September 26, 2008
Thursday, September 18, 2008
Main Street and Construction
Here is a lovely little view of the Guided Tour Gardens , circa 1990. Note how much more open it is and there were restrooms back there too.
Posted by Bearride - Raymond at 11:38 PM 3 comments:
Tuesday, September 16, 2008
Backstage Goodies
This shot is from 1997, during the Tomorrowland remodel. This is from the backstage area behind the Country Bear Theater. There, laying on the ground is the entrance sculpture to Space Mountain (the original 1977 one). It currently is the one next to the Star Trader. But if you look further in the pic, you'll see the Mouserail. Sitting in storage for years after the 35th anniversary, it will soon be chopped up and painted grey, outlined in orange tape and put into the que for Rocket Rods.
Posted by Bearride - Raymond at 1:49 PM 4 comments:
Thursday, September 11, 2008
Souvenier Friday
Here is a ticket to a private party that I went to in 1995, the year of Indy. This was I believe the last year for this particular private party. If you have never been to a private party at Disneyland, it is a surreal experience. Low crowd numbers, dancers everywhere but as I remember 3 food facilities for 30,000 people! Oy!
Posted by Bearride - Raymond at 11:30 PM 2 comments:
Wednesday, September 10, 2008
Souvenir Stand at Alpine Gardens
Long before Tinkerbell and Ariel, but after the House of the Future was a little out of the way place called Alpine Gardens. In the photo below is a shot of the souvenir stand that is in the place that Ariel used to spin out. The souvenir stand was originally the four seasons porch from the House of the Future. Look at all them postcards.
Posted by Bearride - Raymond at 3:09 PM 1 comment:
Wednesday, September 03, 2008
Odds and ends
To go with the post over at Vintage Disneyland Tickets, here is the postcard from that same time. Image is copyright Disney. :)
I have been very busy lately here in Phoenix. I was the chair of this city's first Red Dress Party called "Red Hot Salvation". It was a fundraiser for the Bill Holt Clinic for Pediatric AIDS. We raised somewhere in the neighborhood of $2000. And I have had a guest all the way from Paris. So I've been showing him the beautiful Southwest! Anyway, I'll be back on a more regular schedule next week after I get back from Disneyland.
Till then!
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I love it, can you take a look at my blog and maybe follow me? i follow back everyone.
and here's my page on facebook (about fashion and more): https://www.facebook.com/ModelsontheRunway
Would mean a lot if you like it!!
thank you, and it won't let me view your blog for some reason :(Delete


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Companies increasingly understand they must take into account competition laws in their business planning or face potentially significant risks. Some may have a higher awareness of competition law issues because of past investigations, successful prosecutions and/or onerous settlements in other jurisdictions that involve their industry. Hong Kong might have a brand new competition law system but firms should be very mindful of the Competition Commission's clear enforcement focus on cartels, global enforcement trends and topical issues in the local business environment.
Directors, management and in-house lawyers alike should take note of the lessons from other jurisdictions to ensure competition law compliance is (and stays) high on the business agenda:
In-house counsel are primarily responsible for controlling legal risks, as well as building the business case for compliance. Ultimately however it is up to the drivers of commercial strategy – the board and other senior management – to implement this advice.
Internal lawyers can help push the competition compliance message by advising not only on the costs of efficient and effective compliance but also the opportunities to implement (or protect) highly profitable commercial strategies.
Directors should have plenty of incentives to take competition law risks seriously and keep it on the board agenda. After all, they bear the responsibility for the actions of their companies, including personal liability for fines under the Competition Ordinance. Overseas studies have shown that director disqualification is seen by businesses as a very effective deterrent – after even the criminal penalties.
Both executive and independent directors can influence the direction of commercial activities as well as embed values for a compliant corporate culture.
- Management (and some employees) can get caught up in competition investigations as potential witnesses – even if they leave the business.
Staff working in higher risk areas of the business can work closely with legal advisers to help optimise practices and create a competitive advantage, rather than focusing only on compliance.
Protecting your business from enforcement actions under competition laws takes more than a once-off legal risk assessment and some compliance training. Every company should have a tailored strategy but risk awareness is always the starting point.


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What is STEVIA?
The extract from the leaves of the amazing little stevia plant is naturally sweet — up to 200 times sweeter than sugar! Stevia leaf extract has zero calories and is used to make Zing™ Baking Blend and Zing™ Zero Calorie Stevia Sweetener with only real ingredients for perfect sweet taste.


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Now This trick will increase your productivity work, now you can create notes in the chrome browser and save directly into the google docs spreadsheets automatically with the help of "Citable" therefore is a Instant web clipper which reduces the effort of the user and provide easy way to copy the respective titles or even URLs along with many more resource information with other important notes can then be copied in this clipper. Possibly the individual can then be able to add the important notes including summaries with tags and much more additional information are then to be saved in this clipper in the form of spreadsheet that is Google Docs, associated application for the individual. Hence, the individual made their task ease manner by the help of this web based clipper which keeps the tracks of all the respective references along with the collaboration with other individuals who are online available. Citable which turns out to be the simple clipper for the individual offers the user to save the complete website details along with a feature to add each note to a separate and with numbered rows are then provided in the spreadsheet format along with that individual may then be able to ensure the easiest managed and retrieval of all the respective stored research sources. Moreover the individual can then be able to create as well as manage those respected notes and the individual can even organize those notes with just a click and the individual can even get those notes printed as well as export those notes whenever the individual needs them.
Furthermore when the individual is done with installation of this clipper extension of the Google Chrome and then the individual happen to come across the most happening contents which seems to be very fruitful for the research of writing then the very next step the individual need to take is to click the icon button which is available at the toolbar and then this extension which carries out the task automatically by saving those required details which include URL,date along with author's name for the current task and additionally the individual can then be able to add the respective summaries along with the required tags and other details as well by manually process from the individual.
Perhaps when the individual is done there user can store those notes with the help of the Save button which, therefore, stored in a spreadsheet in the individual's Google Docs account. Moreover the user can even hit the button which is made avail at the bottom left of the pop-up so as to export those notes or even to get printed them onto Post-it's for the individual's easy offline collaboration.
Citable is a handy extension for the Chrome which therefore a web clipper for the user in which the individual can then be able to collect as well as simplifies the respective quotes and notes or even the important notes along with that the individual can even get the reference information for further needed so as to make the web citation. Therefore, the individual then be able to save those important notes in spreadsheet in the individual's Google Docs account along with that user will get the collaboration feature so as to analysis the required collected information content in a simple way. Therefore, this extension that also provides the individual with a secure way of accessing along with privacy feature as well.Citable which seems to be secure and best suited for the individual who loves to secure all the required notes from the others.
Download Citable Chrome Extension


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4:13:02 PMOur View: Less secrecy, more accountability needed in bombing investigations
BOSTON — More than four months after the Boston Marathon bombings, many questions linger about warnings that were missed before the explosions, actions taken during the search for the bombers and the mysterious death of a potential witness during questioning by the FBI. What's most disturbing is that there appears to be no comprehensive effort to answer questions of public interest.
But several recent incidents indicate the search for answers continues:
— GateHouse Media, parent company of The Herald News and Taunton Daily Gazette, has continued to raise questions about documents missing from the official docket of the case against accused bomber Dzhokhar Tsarnaev. Last week, Michael J. Grygiel, an Albany, N.Y., attorney hired by GateHouse and other media outlets, wrote to U.S. District Court Judge George A. O'Toole in Boston, noting the missing files and saying that federal prosecutors have also not publicly identified any compelling law enforcement or government interests to justify it.
On Aug. 19, O'Toole ordered that 13 previously sealed court filings be released, and that all other sealed documents would remain impounded until further order of the court. But Grygiel wrote that the fact that there are still missing documents prevents the press — as the eyes and ears of the public — from determining whether a constitutional challenge is warranted.
Unnecessary secrecy only fuels speculation and conspiracy theories. There are well-established procedures for sealing court documents critical to an investigation or trial. Violating those procedures not only keeps journalists from doing their jobs, but also raises questions about what the government might be trying to hide.
— U.S. Rep. William Keating, D-Mass., has written a letter to the new director of the FBI seeking answers to questions he has raised before as a member of the Homeland Security Committee. He wants to know how Tamerlan Tsarnaev fell off the radar of federal counter-terrorism teams despite warnings from Russian intelligence services, why some information about the bombing suspects wasn't shared with local law enforcement and about loopholes in terrorism "watch lists."
The University of Massachusetts Dartmouth, where Tsarnaev attended school and lived on campus — including immediately after the bombings — has completed an internal investigation showing that university officials handled the situation about as well as they could have under the circumstances. The unprecedented shutdown of the campus in the days following Tsarnaev's capture so law enforcement could search for evidence was difficult for all involved.
— The state prosecutor in Orlando, Fla., has announced he will investigate the death of Ibragim Todashev during FBI questioning. Todashev, a friend of Tamerlan Tsarnaev, was reportedly unarmed and alone with a single FBI agent at the time of the shooting, but the FBI has refused to answer questions about the incident. The state probe will rely heavily on the FBI's investigation of its own agent, making it less than fully independent, but at least State Attorney Jeff Ashton promises to make his findings public.
There are other pressing questions, particularly about the searches in Watertown and two firefights that left one suspect dead and the other wounded. Some answers will likely come from Dzhokhar Tsarnaev's trial.
Meanwhile, a trial won't answer important public policy questions: What went right that week? What went wrong? How well did dozens of federal, state and local public safety agencies coordinate operations? How can we be better prepared the next time terrorists' strike?
Answering those questions will take a comprehensive inter-agency review, with its conclusions open to public scrutiny. Unfortunately, we've seen no signs of such a review under way, and heard no calls for one from public officials. Until then, many of the most important questions about the marathon bombings will remain unanswered.
Taunton Daily Gazette Editorial Board
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Last time I taught my Edit Like a Pro: Elements of Fiction seminar, one of the students questioned the absence of The Elements of Style from my recommended reading list.
"It's a primer," I said. "If you're writing novels, you're beyond Strunk and White."
That little book is such a milestone for most of us that we often forget that the text on which it is based was written almost a hundred years ago by a college professor whose freshmen students couldn't write. Prof. Strunk was so irked by the inability of his incoming students to write a coherent paper that he put together a little pamphlet with some basic writing advice for them. Continue reading


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Recent Posts
All content is copyright 2012-2018 Jaime Zanocco Fagan. Please do not use the photographs and/or content from this site without written permission. Thank you!
- Jaime Fagan is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to amazon.com.
makingofahomehomestead on InstgramLast night I had the pleasure of hosting an event honoring and celebrating Rockford-area senior artists. This journey of coordinating Aroha Philanthropy's Artful Aging Program through the YMCA has been truly magical. The conversations I have had over the course of the last year with our participants tell me that art is truly transformational. These programs not only enabled men and women to venture out of their homes and learn (or rediscover) a new skill set, but gave them a safe space in which to share stories with one another of life's trials and triumphs.💚 #artcantransformlives #artcantransformtheworld #rockriverymca #rockfordillinois #rockfordrocksDinner prep 🌿 #rootvegetables #rootveggies #homegrown #urbanhomestead #homestead #homegrown #growityourselfMy youngest decided to experiment with homemade gluten free pasta, so she busted out my Nona's old school ravioli maker 😍👩🏼🍳 #urbanhomestead #homeschool #makeityourself #homeschoolkids #oldworlditalianwithatwistGuys, we are having so much fun down at the @rockriverymca 🙌🏻 Come down and join us! We will be here until 8 PM #saturdaynightfun #rockriverymca #lovemyjob #rockfordrocksBring your kids and come hang out with me tomorrow night!!! 🙌🏻😘 This event is going to be beyond amazing, so you don't want to miss it! (The festivities have been moved inside to the main basketball courts because of the cold weather forecasted for tomorrow.) @kam_b_killn_em #rockriverymca #rockfordrocks #saturdayvibes #lovemyjobThis year for homeschool, my father-in-law is working on woodworking skills with the girls. This is their first completed project! So awesome! #toobeautifultobeoutside #homeschooling #homeschoollife #homeschoolingmomKind of can't wait for this event 🙌🏻🧘🏼♀🙌🏻#rockriverymca #yogakombuchaandbreakfast #rockfordrocks @taunia_mayWhen your pumpkin vines reach all the way to the garden gate 🍂🧡🍂 #firstdayofautumn #firstdayoffall #urbanhomestead #homestead #growityourself#homeschoollife #homeschooling #homeschoolingmom #upnorth #wisconsinlove 🍂🍄🍁
Tag Archives: string art
I have been thinking deeply lately about the notion of creating. In a world of increasing destruction and devastation, the simple act of creating something, creating anything really, is cathartic. At our homeschool co-op I teach a writing and an … Continue reading
Posted in Holistic Living Tagged art, artistic, artistic movement, arts and crafts, craft, crafting, create, creation, DIY, holistic, holistic living, homeschooling, homeschooling mom, make, making, making of a home, mindfulness, mom, mother, rough cut wood, string art, string art project, string art project idea, woodworking 2 Comments


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Life is pictures. I choose the beautiful ones.I capture nice objects, outfits, faces, just by taking their picture. In the street, other blogs, shop windows, at my journeys, in my place and closet, anything that makes me happy, you can find it in this handmade blog.
you don't know what you do to me.Now all I see ,is new to me
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A vulnerability have been discovered in Mandriva bash package, which
could allow a malicious user to hide files from the ls command,
or garble its output by crafting files or directories which contain
special characters or escape sequences (CVE-2010-0002). This update
fixes the issue by disabling the display of control characters
by default.
Additionally, this update fixes the unsafe file creation in bash-doc
sample scripts (CVE-2008-5374).
Packages for 2008.0 are provided for Corporate Desktop 2008.0


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DOWNEY - Rancho Los Amigos National Rehabilitation Center is hosting its annual Spinal Injury Games this Saturday.
The event begins with a welcome ceremony at 8:45 a.m. Admission is free and the public is invited.
The full schedule of events is below:
10 a.m. - noon: bowling, golf, football accuracy throw and hockey shot
10-11 a.m.: quad rugby
11 a.m. - noon: power soccer and baseball
11-11:30 a.m.: Rancho Re-Walk exoskeleton demo and paragolfer demo
12-1 p.m.: kids sports demo and lunch
1-2 p.m.: obstacle course
2-3 p.m.: football and tennis
Members of the Los Angeles Dodgers organization will be in attendance singing autographs, and the L.A. Kings Ice Crew and Galaxy Star Squad will be giving out prizes and chances to win autographed merchandise.
The Spinal Injury Games are an annual event where Rancho patients are introduced to innovative adaptive sports equipment.
It also allows beginning wheelchair users to get active.
"It is always so encouraging to see our patients demonstrating that they can participate in a variety of sports in their wheelchairs and be competitive with others, something that many did not think they would be ever able to do," said Rancho CEO Jorge Orozco. "Thanks to the Rancho medical and therapy staff, the Spinal Injury Games allows them to exceed their expectations and experiences."
********** Published: Oct. 10, 2013 - Volume 12 - Issue 26