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Home Gastroenterology Targeting Disease Progression in Crohn's Disease: Fighting an Unrelenting…
Targeting Disease Progression in Crohn's Disease: Fighting an Unrelenting Enemy
This satellite symposium took place on 17th February 2017 as part of the European Crohn's and Colitis Organisation (ECCO) Congress in Barcelona, Spain
Iris Dotan1
Remo Panaccione,2 Iris Dotan1
1. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
2. University of Calgary, Calgary, Alberta, Canada
Prof Remo Panaccione has received research/educational support from AbbVie, Abbott, Ferring, Janssen, Schering-Plough, Centocor, Millennium, Elan, Procter & Gamble, and Bristol-Myers Squibb and has served as a consultant for AbbVie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Eisai, Ferring, Janssen, Merck, Schering-Plough, Shire, Centocor, Elan, Glaxo-Smith Kline, UCB, Pfizer, Bristol-Myers Squibb, Warner Chilcott, Cubist, Celgene, Gilead Sciences, and Takeda Pharmaceuticals. He has participated on speaker's bureaus for AbbVie, AstraZeneca, Janssen, Schering-Plough, Shire, Ferring, Centocor, Elan, Prometheus, Warner Chilcott, and Takeda Pharmaceuticals International GmbH and served on the advisory board for AbbVie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Eisai, Ferring, Genentech, Janssen, Merck, Schering-Plough, Shire, Centocor, Elan, Glaxo-Smith Kline, UCB, Pfizer, Bristol-Myers Squibb, Warner Chilcott, Takeda Pharmaceuticals International GmbH, Cubist, Celgene, and Salix. Dr Iris Dotan has received consultancy fees from Takeda Pharmaceuticals International GmbH, Janssen, AbbVie, Pfizer, Genentech, Rafa Laboratories, Ferring, Falk Pharma, MSD, Protalix, Given Imaging.
Writing assistance was provided by Janet Fricker.
The publication of this article was funded by Takeda Pharmaceuticals International GmbH. The views and opinions expressed are those of the speakers and not necessarily of Takeda.
EMJ Gastroenterol. 2017;6[Suppl 8]:11-18. DOI/10.33590/emjgastroenterol/10311106. https://doi.org/10.33590/emjgastroenterol/10311106.
In the first presentation, Prof Panaccione considered how early treatment of Crohn's disease (CD) is key for achieving the therapeutic goals, which include symptomatic remission and mucosal healing. The latest STRIDE guidelines,1 published in 2015, endorse endoscopic remission defined as "resolution of ulceration at ileocolonoscopy", and emphasised the need for tight monitoring of inflammation. He explored data highlighting how the ability to achieve mucosal healing decreases with increased disease duration, that benefits from mucosal healing may not be realised until the second year of treatment, and how patients who experience mucosal healing are less likely to be hospitalised and require surgery. Studies show patients do better with the 'top-down' approach, receiving anti-tumour necrosis factor (TNF) drugs early in the disease course, which has led to the introduction of a treatment algorithm suggesting patients with high-risk factors for poor prognosis should receive early 'top-down' therapy and lower-risk patients traditional 'step-up' therapy. The need for decisive early treatment to slow progression emphasises the importance of facilitating early diagnosis, and identifying patients for early biologic therapy. In the second presentation, Dr Iris Dotan explored data suggesting that optimal positioning for vedolizumab appears to be early in the course of disease. Furthermore, vedolizumab's effect on clinical remission improves over time, clinical remissions have been shown to be maintained long-term, and vedolizumab reduces rates of hospitalisation. A favourable risk-benefit profile for vedolizumab has been shown for long-term use with no increase in the incidence of adverse events in the 5-year analysis. There are now 77,382 patient-years of post-marketing exposure to vedolizumab worldwide.2 The latest European Crohn's and Colitis Organisation (ECCO) guidelines recommend the use of vedolizumab in patients with moderate to severe localised ileocaecal and colonic CD refractory to steroids and/or anti-TNF-αs.
Slowing Progression of Crohn's Disease: Decisive Treatment for Early and Long-Term Remission
Professor Remo Panaccione
Since 1995 there has been an evolution in the management of CD, starting first with 5-aminosalacylic acid (5-ASA), steroids, and azathioprine,3,4 then moving around the year 2000 to anti-TNF-α biologics,5-7 in 2013 to biosimilars8,9 and vedolizumab,10 and finally in 2016 to ustekinumab.11 Throughout this time surgery has remained an option in CD. With so many possible treatments, clinicians need to consider the 'patient journey' and identify patients early enough to receive the right drug at the right time.
The biologic revolution began almost 20 years ago with the approval of infliximab for moderate-to-severe CD.6 Despite the subsequent development and approval of newer anti-TNF-αs, overall induction of remission in randomised controlled trials has remained between 30% and 50%5,12-14 and maintenance of remission between 20% and 40%.14-17 Such data, explained Prof Panaccione, demonstrates that therapeutic gaps still exist in treatment of inflammatory bowel disease (IBD), underlining the need for new agents.
Many important lessons have been learnt from anti- TNF-αs. These agents are generally safe (although some issues remain); antibodies are detrimental for efficacy, adequate drug levels are good, and data suggest the benefit of combination therapy (anti-TNF-α plus immunomodulators). Furthermore, paradigms have changed in the anti-TNF-α era with the recognition that treating early is beneficial, and treating beyond symptoms decreases rates of surgery.1
CD is a chronic progressive disease inducing cumulative structural damage. A 2011 study by Pariente et al.18 (using Lémann scores to measure cumulative structural damage) showed that with time CD patients are more likely to develop strictures, fistulae/abscesses, and undergo surgery (Figure 1). The goal for CD is to treat early and control inflammation.
Figure 1: The progression of digestive damage and inflammatory activity in a theoretical patient with Crohn's disease.18
CDAI: Crohn's Disease Activity Index; CDEIS: Crohn's Disease Endoscopic Index of Severity; CRP: C-reactive protein.
Desired outcomes differ between early and late- stage CD. For early disease, they include complete absence of symptoms, no disease progression, no complications or disability, and normal quality of life (QoL), while for late-stage disease they include stabilisation of non-inflammatory symptoms, no progression of damage or disability, and improved QoL. The difference in goals emphasises that if the early treatment window of opportunity is missed, symptomatic remission will not be achieved. This is because patients may be left with chronic abdominal pain, or functional consequences leading to chronic diarrhoea, short bowel syndrome, and/or loss of the ileocaecal valve.
The concept of early treatment of disease needs to be reinforced, said Prof Panaccione, because it is here that the greatest benefits can be derived from therapy. New data presented at ECCO 2017 suggests that the window of opportunity may in reality be months rather than years. A retrospective analysis of the Alberta IBD Consortium, undertaken by Prof Panaccione and colleagues, showed CD patients prescribed thiopurines or anti-TNF-α agents at the inflammatory stage were significantly more likely to avoid surgery compared with those initiating treatment after complications (penetrating, ileal stricturing, or stricturing) had developed.19
Differences in early disease biology were highlighted by a subgroup analysis of the EXTEND study showing rates of healing with adalimumab decrease with disease duration. The data showed that patients with <2 years disease had mucosal healing rates of 44%, patients with 2–4 years of disease had mucosal healing rates of 40%, and patients with ≥5 years had mucosal healing rates of 21%.20 Such data, said Prof Panaccione, emphasises how early intervention can result in better outcomes.
The REACT trial, randomising community gastroenterology practices to conventional management or early combined immunosuppressants (anti-TNF-αs and antimetabolite), showed that the benefits of early treatment may not be realised until the second year of therapy.21 The study, exploring whether patients achieved remission (being off steroids) at different time points, showed combined immunosuppression did not deliver symptomatic remission benefits until after Month 24 of treatment (p=0.959 at Month 6, p=0.517 at Month 12, p=0.441 at Month 18, and p=0.083 at Month 24). At 24 months, the composite of major adverse outcomes (occurrence of surgery, hospital admission, or serious disease-related complications) was 27.7% for combined immunosuppression versus 35.1% for conventional treatment (hazard ratio [HR]: 0.73, p<0.0003).
An endoscopy sub-study of the ACCENT I trial (the infliximab trial) demonstrated that success of mucosal healing can be related directly to rates of hospitalisation.22 Among patients who achieved mucosal healing at both Week 10 and Week 54 after treatment, none required hospitalisation, compared to 18.8% of patients with mucosal healing at only one of those visits and 28% with no mucosal healing at either visit.22
The STRIDE treat-to-target recommendations, written in 2015 by 28 IBD specialists, define composite endpoints of clinical/patient-reported outcome remission (defined as resolution of abdominal pain and normalisation of bowel habit) and endoscopic remission (defined as resolution of ulceration at ileocolonoscopy).1 According to STRIDE, biomarkers (C-reactive protein and calprotectin) can be considered as adjunctive measures of inflammation, but not targets for CD monitoring. While histologic remission is not currently considered a target, said Prof Panaccione, new data is anticipated later this year exploring whether surrogate markers could be used for treat-to-target beyond improvements in symptoms.
Results of the Top-Down versus Step-Up Trial, comparing early use of combined immunosuppression (infliximab and azathioprine; 'top-down') with conventional management (corticosteroids and infliximab when needed; 'step-up'), suggested initiating more intensive treatment early in disease leads to better outcomes.23 At the end of 2 years, 73% of patients who received anti-TNF-αs as their initial therapy showed disappearance of ulcers compared with 30% receiving traditional step-up therapy (p<0.001).23
A subset analysis of 49 patients (taken from a study by Baert et al.24 of 133 patients comparing the combination azathioprine and infliximab with conventional steroids) showed mucosal healing (defined as an endoscopic score of 0) after 2 years treatment predicts long-term benefits. At Year 3+4, remission occurred in 71% of patients with mucosal healing after 2 years versus 41% without (p=0.073), remission off steroids occurred in 71% with mucosal healing after 2 years versus 27% without (p=0.05), and remission off steroids and no anti-TNF-α occurred in 63% with mucosal healing at 2 years and 18% without (p<0.05). Further insights into mucosal healing are likely to come from the ongoing REACT II study (currently two-thirds enrolled), which provides escalated therapy at Week 16, 32, and 48 if patients have not shown ileocolonoscopy improvements.
The holy grail for treat-to-target, said Prof Panaccione, is to demonstrate that mucosal healing changes long-term patient outcomes. Despite the wealth of evidence for biologic therapies (mostly anti-TNF-αs), uptakes around the world remain low. A 2015 review of the epidemiology of CD, by Burisch and Munkholm, showed that earlier and more frequent use of immunomodulators/biologics in CD to be associated with reduced surgery.25 The greatest fears for patients with CD are short and long-term side effects of therapies, with most wanting to come off therapy when they are well. Such concerns emphasise the importance of developing treatments that are not only safe and effective upfront, but also have long-term safety profiles.
Taking account of the possibility that long-term use of anti-TNF-αs prevents bowel damage, a 2011 treatment algorithm suggested patients with high risk factors for poor prognosis (including diagnosis at age <40 years, extensive anatomic involvement, perianal or severe rectal disease, deep ulcers, prior surgical resection, and structuring and/or penetrating behaviour) should receive early 'top-down' intervention with biologic therapy.26 For lower-risk patients, traditional 'step-up' therapy can be used with biologic therapy introduced if they fail to respond to therapy.
A financial analogy, suggested Prof Panaccione, can be used to explain the benefits of early treatment in CD. Just as people investing early and progressively during their working lives are wealthier in retirement than those waiting until later to invest, people with CD who have anti-TNF-α treatments early do better in the long-term.
The need for decisive early treatment to slow progression emphasises the importance of facilitating early diagnosis and identifying appropriate patients for early biologic therapy. The STRIDE recommendations should be adopted for a treat-to-target approach,1 with a rapid step-up approach being the rule, and tight monitoring of objective signs of inflammation (mucosal healing). The ultimate therapeutic goal for CD, concluded Prof Panaccione, is to return patients to normal life.
Early Use of Gut Selective Therapy in Crohn's Disease for Long-Term Remission
Doctor Iris Dotan
In the treatment of CD and ulcerative colitis (UC), there is currently a move away from the old goals of improving symptoms,1,27 achieving a clinical remission,1 or even a steroid-free clinical remission,28 to new ambitions around mucosal healing1,24,27 that ultimately achieve the goal of changing the course of disease.1,27
The evolving IBD environment makes it important to consider whether conventional therapies (5-ASA, steroids, thiopurines, methotrexate, and anti-TNF-α) meet the new treatment goals. Studies suggest that thiopurines and anti-TNF-α agents meet short-term end points of clinical remission, steroid-free clinical remission, and clinical and mucosal remission. It is less certain however, whether long-term goals of disease modification (involving reduction of surgical risk, disability, and damage) are significantly affected. For thiopurines there is conflicting evidence regarding reductions of surgical risk,29 with only anti-TNF-α shown to decrease the risk of surgery in CD and UC.30
Studies show the 'top-down' approach, using effective therapy early in disease, delivers benefits including higher efficacy, lower disease-related complications, higher mucosal healing and decreased rates of surgery and hospitalisation.27 However, the downsides of these treatments include higher risks of drug-related serious infections and increased costs.27 Such consideration led the 2017 ECCO consensus on diagnosis and medical management of CD to conclude there is a "complex benefit-risk balance" for early aggressive therapeutic strategies using immunosuppressants and biologics in CD.31
Clinicians need to be aware that the window of opportunity is small and that in IBD early intervention is key to prevent disease progression. A longitudinal prospective observational follow-up study in 154 newly diagnosed CD patients, by Dr Dotan and colleagues, showed that by 10 months 40% had experienced disease complications (defined as progression to complicated disease, CD-related hospitalisations, or surgeries).32 Such data, said Dr Dotan, suggest there is a need to intervene quite fast.
Vedolizumab, a gut selective anti-trafficking agent, is a newer option for the treatment of CD. Vedolizumab works by blocking α4β7 integrin (found on the surface of leukocytes), preventing them from binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) ligands (found on gut endothelial cells).33,34
Vedolizumab has been shown to improve outcomes in anti-TNF-α naïve patients. A post hoc analysis of the GEMINI II and GEMINI III trials showed rates of response and remission were higher in patients receiving vedolizumab as a first-line biologic than for patients who experienced prior anti-TNF-α failure (Figure 2).35 The analysis, involving 516 anti- TNF-α naïve patients and 960 anti-TNF-α failure patients, showed for both groups that beneficial effects of vedolizumab increased with time.
Figure 2: Biologic-naïve Patients have more prominent clinical remission (GEMINI II and III Pooled).45
CI: confidence interval; PBO: placebo; VDZ: vedolizumab; TNF: tumour necrosis factor.
A systematic meta-analysis presented at ECCO 2017 (98 studies involving 1,010 CD and 704 UC patients) further supports the concept of improvement associated with vedolizumab over time.36 Results show pooled clinical remission was 24% at Week 6, 30% at Week 14, 23% at 6 months, and 30% at 1 year, and that pooled steroid-free clinical remission was 13% at Week 6, 25% at Week 14,23% at 6 months, and 25% at 12 months.36
Undoubtedly, one of the most important new goals for CD treatments is to produce mucosal healing. A promising signal for vedolizumab comes from a 2017 retrospective chart review of 32 colonoscopies undertaken in 23 CD patients enrolled in the GEMINI long-term safety study. Results in patients (who had at least 1 year of continued vedolizumab treatment) showed 44% of colonoscopies were associated with complete healing, 47% with partial healing, and 9% with no healing.37
Additionally, three different 'real-world' cohort studies suggest benefits for vedolizumab in achieving mucosal healing. The first study (University of Chicago, Chicago, Illinois, USA) showed mucosal healing occurred in 17% after 3 infusions;38 the second (Mayo Clinic, Rochester, Minnesota, USA) showed mucosal healing occurred in 20%;39 and the third study (Washington University, Seattle, Washington, USA) showed at Week 14 mucosal healing occurred in 30% and endoscopic improvement occurred in 52% (Figure 3).40 Finally, in the VICTORY consortium study, which included 212 patients with moderate-severe CD, mucosal healing occurred in 20% of patients at Week 26, rising to 63% of patients at Week 52.41
Figure 3: Mucosal Healing with Vedolizumab for Treatment of Crohn's Disease in the Real World.40
What will be of vital importance, said Dr Dotan, is the ability to determine predictors of remission and mucosal healing since this helps therapies to be positioned in the clinical setting. From the US VICTORY Consortium data, it is clear patients with no prior anti-TNF-α exposure experienced more clinical remission than patients with anti-TNF-α exposure (HR: 0.40) and that patients with moderate disease experienced more clinical remission than those with severe disease (HR: 0.54).41 Regarding mucosal healing, patients with no anti-TNF-α exposure experienced more mucosal healing than patients with anti-TNF-α exposure (HR: 0.29), and patients with moderate disease experienced more clinical remissions than those with severe disease (HR: 0.54).41
New data presented at ECCO 2017 reported on the effectiveness and safety of vedolizumab in CD patients who had completed GEMINI II and enrolled in the GEMINI open label extension study. Data showed long-term vedolizumab therapy (˜5-years) was associated with clinical benefits including clinical response, clinical remission, and health-related QoL improvements in patients with moderate-to-severe active CD.42
Another study, comparing vedolizumab (n=81) versus infliximab (n=162) in biologic-naïve IBD-patients suggested that at 12 months vedolizumab was associated with a reduction (12.3%) in hospitalisation compared to infliximab (17.9%); although the result was not statistically significant.43
Confidence in the safety of vedolizumab was reported by Colombel et al.44 showing no increase in the incidence of adverse events (including gastrointestinal adverse events, infections and serious infections) with long-term exposure of over 3 years. Notably, as of November 2016, vedolizumab has 77,382 patient-years of post-marketing exposure worldwide.2
The latest ECCO guidelines state: "decisive treatment with a potent agent ('top-down' approach) at an early stage may be preferred by the patient suffering symptoms from active disease". The guideline continues: "The therapeutic goal should be to induce clinical remission for every patient, but even at diagnosis it is essential to keep in mind how remission will be maintained after medical induction therapy".31
Dr Dotan concluded that vedolizumab is associated with improved remission in anti-TNF-α naïve patients, suggesting optimal positioning early in the disease course. The favourable risk-benefit profile of vedolizumab shown in the 5-year analysis supports its early and long-term use in moderate- to-severe CD. ECCO guidelines recommend the use of vedolizumab in patients with moderate-to-severe localised ileocaecal and colonic CD refractory to steroids and/or anti-TNF-αs.
Peyrin-Biroulet L et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Determining Therapeutic Goals for Treat-to-Target. Am J Gastroenterol. 2015;110(9):1324-38. "Estimated Exposure and Use Patterns," in PSUR for Vedolizumab. 2016. [Unpublished confidential document]. Mulder DJ et al. A tale of two diseases: the history of inflammatory bowel disease. J Crohns Colitis. 2014;8(5):341-8. Botoman VA et al. Management of inflammatory bowel disease. Am Fam Physician. 1998;57(1):57-68. Targan SR et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 1997;337(15):1029-35. EMA. Remicade® (infliximab): EPAR Product Information - Summary of Product Characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000240/WC500050888.pdf. Last accessed: 20 March 2017. EMA. Humira® (adalmumab): EPAR Product Information - Summary of Product Characteristics. 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000481/WC500050870.pdf. Last accessed: 20 March 2017. EMA. Remsima® (infliximab): EPAR Product Information - Summary of Product Characteristics. 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002576/WC500150871.pdf. Last accessed: 20 March 2017. EMA. Inflectra® (infliximab): EPAR Product Information - Summary of Product Characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002778/WC500151489.pdf. Last accessed: 20 March 2017. EMA. Entyvio® (vedolizumab): EPAR Product Information - Summary of Product Characteristics. 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002782/WC500168528.pdf. Last accessed: 20 March 2017. EMA. Stelara® (ustekinumab): EPAR Product Information - Summary of Product Characteristics. 2016. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000958/WC500058513.pdf. Last accessed: 20 March 2017. Hanauer SB et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's diease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323-33. Schreiber S et al.; CDP870 Crohn's Disease Study Group. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology. 2005;129(3):807-18. Sandborn WJ et al.; PRECISE 1 Study Investigators. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007;357(3):228-38. Hanauer SB et al.; ACCENT I Study Group. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2002;359(9317):1541-9. Schreiber S et al.; PRECISE 2 Study Investigators. Maintenance therapy with certolizumab pegol for Crohn's disease. N Eng J Med. 2007;357(3):239-50. Colombel JF et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132(1):52-65. Pariente B et al. Development of the Crohn's disease digestive damage score, the Lémann score. Inflamm Bowel Dis. 2011;17(6):1415-22. Moran GW et al.; Alberta Inflammatory Bowel Disease Consortium. Clin Gastroenterol Hepatol. 2014;12(3):434-42.e1. Sandborn WJ et al. S1031 Crohn's Disease Mucosal Healing in Adalimumab-Treated Patients is Affected by Disease Duration: Results from Extend. Gastroenterology. 2010;138(5 Suppl 1):S-164. Khanna R et al.; REACT Study Investigators. Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial. Lancet. 2015; 386(10006):1825-34. Rutgeerts P et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endosc. 2006;63(3):433-42. D'Haens G et al.; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomized trial. Lancet. 2008;371(9613):660-7. Baert F et al.; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology. 2010;138(2):463-8. Burisch J, Munkholm P. The epidemiology of inflammatory bowel disease. Scand J Gastroenterol. 2015;50(8):942-51. Ordás I et al. Early use of immunosuppressives or TNF antagonists for the treatment of Crohn's disease: time for a change. Gut. 2011;60(12):1754-63. Sandborn WJ et al. Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases. J Crohns Colitis. 2014;8(9):927-35. Colombel J. Infliximab, Azathioprine, or Combination Therapy for Crohn's Disease. N Engl J Med. 2010;362:1383-95. Lakatos PL et al. Has there been a change in the natural history of Crohn's disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009. Am J Gastroenterol. 2012;107(4):579-88. Peyrin-Biroulet L et al.; Scientific Committee of the European Crohn's and Colitis Organization. Results from the 2nd Scientific Workshop of the ECCO (I): Impact of mucosal healing on the course of inflammatory bowel disease. J Crohns Colitis. 2011;5(5):477-83. Gomollón F et al. ; ECCO. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 1: Diagnosis and Medical Management. J Crohns Colitis. 2017;11(1):3-25. Yani H. Frequent Rapid Clinical Progession of Newly Diagnosed Crohn's Disease: Results of a Prospective Inception Cohort. United European Gastroenterology Journal;2015:2 (Supplement 1). Soler D et al. The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp Ther. 2009;330(3):864-75. Briskin M et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol. 1997;151(1):97-110. Sand BE et al. Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm Bowel Dis. 2017;23(1):97-106. Schreiber S et al. P-059 Real-World Effectiveness of Vedolizumab as Induction Therapy in Inflammatory Bowel Disease: A Meta-Analysis. Inflamm Bowel Dis. 2017;23. Norman M et al. Mucosal healing and dysplasia surveillance in a large referral Centre cohort of patients with Crohn's disease and ulcerative colitis treated with vedolizumab. Abstract OP024. 11th Congress of ECCO, 16-19 March, 2016. Christensen B et al. Endoscopic and Histologic Response and Remission in Inflammatory Bowel Disease Patients Initiating Vedolizumab. Am J Gastroenterol. 2015;110, Abstract 1843. Chaudrey K et al. P-033 YI Efficacy and Safety of Vedolizumab for Inflammatory Bowel Disease in Clinical Practice. Inflamm Bowel Dis. 2016;22. Vivio EE et al. Vedolizumab Effectiveness and Safety Over the First Year of Use in an IBD Clinical Practice. J Crohns Colitis. 2016;10(4):402-9. Dulai PS et al. The Real-World Effectiveness and Safety of Vedolizumab for Moderate-Severe Crohn's Disease: Results from the US VICTORY Consortium. Am J Gastroenterol. 2016;111(8):1147-55. Vermeire S et al. Long-term effectiveness and safety of vedolizumab in patients wth Crohn's disease: 5-year cumulative exposure of GEMNI open label extension study. Abstract DOP021. 12th Congress of ECCO, 15-18 February, 2017. Alam N et al. Comparative effectiveness analysis of flares, hospitalizations, and corticosteroid use among biologic naïve patients with inflammatory bowel disease within 12 months of initiation of vedolizumab or infliximab. Abstract P470. 12th Congress of ECCO, 15-18 February, 2017. Colombel JF et al. The safety of vedolizumab for ulcerative colitis and Crohn's disease. Gut. 2017. [Epub ahead of print]. Sands BE et al. Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy. Inflamm Bowel Dis. 2017. [Epub ahead of print]. Kochhar G et al. Mucosal Healing with Vedolizumab in Ulcerative Colitis and Crohn's disease: Outcomes from the VICTORY Consortium. Abstract PD-002. AIBD Annual Conference, 8-10 December, 2016.
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Anti-TNF Treatment in Crohn's Disease Complicated by Intra-abdominal Abscess
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EMJ Gastroenterology 11 [Supplement 9] 2022


If You Disagree With Me…You're Probably Wrong.
YOUR WORLD AIN'T THEIR WORLD.
Lest you fret gentle consumer, our world's corporate and financial leaders seem to be taking giant strides in the areas of reform.
Reforms that would make the likes of Adam Smith shake his head… and maybe go play some pinball.
Our financial and fiduciary leaders bring us INSIGHTS, such as SAVINGS and COLLATERAL!
Alas, the world these titans operate in hardly seems to resemble the one inhabited by us lesser mortals.
"The idea is that the cost of a huge bank's failure would fall on investors in the bank's equity or debt, not on taxpayers." -hmm, how novel!
Please read the article below.
This entry was posted in Uncategorized and tagged 2008, banks, boon2you, boon4you, capitalism, collapse, corruption, depression, finance, too big to fail. Bookmark the permalink.
Boon Tarkas on Meteorology is a Science!


This year your hosts very much wanted to take Salon to a summer festival, you know, one with camping and halloumi burgers. We had our tick list: we wanted a clever one run by doers, one not afraid of dressing up of a Saturday night and one that knew how to shake its tail-feather, baby.
So if I say . . . the grounds of a beautiful 16th century manor house, an outdoor swimming pool, and an all night dance-floor which, after several Smirnoff Ices is exactly like the terrace at Pacha. Yes, Salon is at Standon Calling, and we're bringing back the best of our delighters.
Kicking off on Friday, we have world class illusionist/conman Philip Escoffey who will not only read your mind but tell you how he does it, Lucy Tesco who will be picking out musical highlights of the three day festival (hope she says Casio Kids, we heart them), and an interactive session on campfire cocktails in which you can learn how whisky hot toddies turns any tent in to a glamper puss experience.
On Saturday our own Juliet Russell will be telling all she told Will.i.am when coaching on The Voice UK in a pre-rockeoke voice coaching session. We have Robert Rowland Smith who will be doing a late, late, late Philosophy breakfast (you bring the croissants we'll bring the life-changing knowledge), we have forensic psychologist Kerry Daynes who will help you find out just who is the highly functioning psycho in your life and how to deal with them, and a workshop with Mark Bolitho to make origami boats to race on the swimming pool. We mentioned the swimming pool, right?
On the Sunday join the sublime David Lindo on a bird-watching, wild-life walk around the grounds. At lunch join Professor Suzy Lishman as she presents her virtual autopsy, Natalie Haynes as she explains ancient civilisations in the most entertaining history lesson you've ever had, and learn how to dance MTV style with Move Your Frame dance guru Kayleigh Holbourne. We'll be closing our Salon summer experience with a music appreciation session as renowned DJ Greg Wilson takes us through the roots of dance music.
Come and join us . . . there is more, much more to Standon Calling here, and much more on us here . . . but why not combine the two and see us both full throttle: Salon at Standon Calling.
The first two Saloners who book tickets qualify for Diccon's breakfast sandwich.


Philip Hammond delivered his plans for the budget yesterday afternoon; he stated that austerity is "finally coming to an end" and upgraded the 2018 growth forecast from 1.3% to 1.6%.
Much to the chagrin of many school workers and unions, Hammond's only mention of what schools will receive is a £400m "bonus" to help schools buy "the little extras they need", despite the requests of various unions to offer more.
"To suggest that all schools need is a nominal sum to fund the 'little extras' when schools have faced years of real terms cuts to their budgets and teachers are thousands of pounds worse off from years of real terms pay cuts is deeply insulting and disingenuous.
"A modest one-off capital payment to schools will not help schools continue to meet the increasingly complex needs of children and young people and ensure that pupils have the resources they need to learn.
"By failing to address the issue of teachers' pay, many more teachers will be lost to the profession and the education of children and young people will continue to suffer.
"It is clear that this government still has its head in the sand over the crisis it has created in education.
"The chancellor has shown in this budget the depth of his ignorance on school funding. Schools have a £2 billion shortfall in funding a year – which is set to get worse. Capital funding has been cut by a third. A £400m one-off payment for 'little extras' will do nothing to address this.
'The government has promised more money for potholes than schools in this Budget. Schools are struggling to provide a full and well-rounded education and many schools have fallen into debt – money for 'little extras' won't cut it. Parents, teachers, headteachers and school staff will be dismayed.


Kabobo Natural Reserve, which was created today thanks to Rainforest Trust's local partner, donors and other supporters, protects 364,975 acres of vital wildlife habitat in the Democratic Republic of the Congo (DRC).
In 2015, DRC government decentralization resulted in the creation of multiple new provinces, and the area originally proposed as Ngamikka National Park was suddenly contained within two provinces. Because of this division, local leaders and communities opted to establish the section of the proposed park in South Kivu Province as the M'Mbondo Reserve. On August 3, 2016, the Governor of South Kivu designated this protected area, whose name was changed to the Ngandja Natural Reserve to reflect the local culture and heritage of the region. On December 21, 2016, the second section of the proposed park located in Tanganyika Province was declared as Kabobo Natural Reserve, completing the priority protected area complex.
Protection of the massif was supported by elders from every village, including indigenous people such as the Efe pygmies. Now that the reserve has been declared, Rainforest Trust's partner is holding regular meetings with traditional chiefs and local authorities to assess management and protection activities moving forward.
Rainforest Trust thanks all of its supporters that helped to make possible the creation of Kabobo Natural Reserve, especially Bernie Han, Leslie Danoff and Larry Robbins, and Geo Chen and Angela Huang.
Rainforest Trust supported the Albertine Rift Program of the Wildlife Conservation Society in a joint collaboration with World Wide Fund for Nature-DRC and AfriCapacity in the creation of Kabobo Natural Reserve. The United States Agency for International Development (CARPE/USAID), U.S. Fish and Wildlife Service, the Critical Ecosystems Partnership Fund and IUCN SOS grants supported the surveys, consultations and participatory mapping with local communities by WCS.
Header photo: Kabobo escarpment. Photo courtesy of A.J.Plumptre/WCS.


Our client, Boston Scientific, a leading medical device company have a number of Engineering roles open in Galway.
This vacancy is for an Associate Project Manager for their Galway site.
Strong experience in project managing significant new product activities that require collaboration with Divisional R&D, Program Management, Regulatory Affairs, Design Assurance, Process Development, Sustaining Engineering and Operations.
BS degree (min HETAC level 8/ 240 credits) in Engineering: electrical, mechanical, industrial, software, manufacturing; and a Masters or Qualification in Project Management would be preferred.


This year's three lectures illuminate how deeply an intimate garden like Wave Hill is embedded in the larger world of horticulture. Colin Cabot, co-founder of Sanborn Mills Farm, has also been a theatrical producer, musician, philanthropist, entrepreneur and—avocationally—blacksmith and farmer. Located near Concord, NH, Sanborn Mills draws on Cabot's childhood experience of farming and gardening, focusing on preserving and renewing the skills of our northern New England forebears. Cabot's talk considers how best to respond to parental achievements in knowing, growing and using gardens, reflecting on 60 years of living in the masterpieces created by his parents, Frank and Anne Cabot. Wave Hill's annual horticultural lecture series is held at the New York School of Interior Design. The second lecture of the series takes place on February 20, when Chanticleer gardener Lisa Roper speaks about the design evolution of Chanticleer's Gravel Garden.
Three-lecture series: $72. Wave Hill Members and students save 10%. Individual tickets: $30, with a 10% discount for Wave Hill Members and students. Seating is limited, and advanced reservations are recommended, online. Student tickets available lecture evening only, at the door, space permitting and with a valid ID.


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Trump: 'INVESTIGATE THE INVESTIGATORS!'
With the Mueller report due out this week, President Trump is doubling down on his criticism of the special counsel's probe into alleged campaign collusion with Russia and blasting Hillary Clinton, the Democratic National Committee, and "dirty cops."
Attorney General William Barr said last Wednesday that Robert Mueller's report would be redacted by Justice Department officials and released "within a week." In an effort to get ahead of what will surely be a feeding frenzy for the mainstream media, Trump on Monday demanded that someone "investigate the investigators."
"Mueller, and the A.G. based on Mueller findings (and great intelligence), have already ruled No Collusion, No Obstruction. These were crimes committed by Crooked Hillary, the DNC, Dirty Cops and others! INVESTIGATE THE INVESTIGATORS!" Trump wrote on Twitter in an early morning post.
Mueller, and the A.G. based on Mueller findings (and great intelligence), have already ruled No Collusion, No Obstruction. These were crimes committed by Crooked Hillary, the DNC, Dirty Cops and others! INVESTIGATE THE INVESTIGATORS!
Trump also ripped the U.S. intelligence community, saying: "THEY SPIED ON MY CAMPAIGN (We will never forget)!"
THEY SPIED ON MY CAMPAIGN (We will never forget)!
The attorney general testified last week that intelligence agencies spied on the Trump campaign in 2016. "I think spying did occur," Barr told lawmakers. "But the question is whether it was adequately predicated and I'm not suggesting it wasn't adequately predicated, but I need to explore that." Barr did not say who did the spying or who was spied on.
The "predicate" Barr referred to is a warrant from the secretive Foreign Intelligence Surveillance Act (FISA) court, which hears classified testimony collected by U.S. intelligence agencies and then decides whether to take action. A Justice Department inspector general investigation is currently investigating the issuance of several warrants that involved surveilling members of the Trump campaign, or officials tangentially connected with the campaign.
"I want to make sure there was no unauthorized surveillance," Barr testified.
Trump has repeatedly quoted the attorney general, saying his claim is "absolutely true." "There was absolutely spying into my campaign," Trump said at the White House last week. "I'll go a step further and say it was illegal spying. Unprecedented spying."
While the full Mueller report, said to be some 400 pages, has not yet been released, Barr did send a four-page summary of the special counsel's findings to Congress. In his letter, Barr wrote "that the evidence developed during the Special Counsel investigation is not sufficient to establish that the President committed an obstruction-of-justice offense."
Trump also said Monday that no matter what the Mueller report says, Democrats won't be "satisfied." "The Radical Left Democrats will never be satisfied with anything we give them. They will always Resist and Obstruct!"
The Radical Left Democrats will never be satisfied with anything we give them. They will always Resist and Obstruct!
Appearing last Wednesday before the House Appropriations Committee for a hearing on the Justice Department's budget, Barr said the redacted report will be released "within a week." Barr added that his redactions will be broken down into four categories so readers can see why the information was omitted.
"First is grand jury information," Barr told lawmakers. "The second is information that the intelligence community believes would reveal intelligence sources and methods. The third are information in the report that could interfere with ongoing prosecutions. You'll recall that the special counsel did spin off a number of cases that are still being pursued. And we want to make sure that none of the information in the report would impinge upon either the ability of the prosecutors to prosecute the cases, or the fairness to the defendants."
"And finally, we intend to redact information that implicated the privacy or reputational interest of peripheral players where there is a decision not to charge them," Barr said.
Read More: Democratic Party Donald Trump Hillary Clinton Robert Mueller William Barr

redpajama_set_name: RedPajamaCommonCrawl


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[Spoilers] "New Ranks" Release Date & Plot
The last chapter was filled with a lot of action and drama. Both from the side of the teachers and the students, the chapter made sure things got closure. In the opening, Principal Sullivan took his leave to visit Babel. In the meantime, Opera was going to look after things for him. The raw scans of the next chapter are out as well. Thus, the aftermath of the final well will be taken into account. So, here is everything that you need to know about Welcome To Demon School Iruma-Kun Chapter 265.
In the upcoming storyline, Iruma and the rest of his friends will join the audience to witness the prize distribution ceremony. Moreover, they will also get to see what the school is planning ahead of these championships. Keep reading further to know what comes next as this line of events continues!
Welcome To Demon School Iruma-Kun Chapter 265: What Will Happen Next?
In the next chapter, all the students will be gathered in the stadium to announce the winners. And along with this, the new ranks will also be distributed. The entire panels of Welcome To Demon School Iruma-Kun Chapter 265 seem filled with joy and fun. Iruma will have the time of his life becoming a part of this extravaganza.
In addition, the students will also get to see who are the final winners of this outing. Well, the last chapter did confirm that Team Asmo-Dues was the winner of all tasks. Thus, they will be the ones called on the stage to be crowned then and there. It is only after this filler outing that things will get into the next arc.
Previous Chapter Recap!
The title of Welcome To Demon School Iruma-Kun Chapter 264 was "The Final Bell." The chapter opened with Principal Sullivan confirming to Opera that he was leaving for Babel and that he would be in charge of things until the time he came back. He also asked for an open investigation on who the intruder was. The man gave a final hug to Iruma and took his leave from school.
However, the children then came to know that the exam was not over just yet. For the last thirty seconds also, the entire class broke into a fight for the remaining points. Azz, Kalego, Iruma, and everyone else enjoyed the final bits of the fight. The chapter came to an end with Team Asmo-Deus winning and getting away with the victory crown being the sole survivor.
Welcome To Demon School Iruma-Kun Chapter 265: Release Date
"The Final Bell" gives closure to a lot of ongoing conflicts in the story. But now, other storylines will open up for the next arc. So now, Welcome To Demon School Iruma-Kun Chapter 265 will release this week to hint at what will begin next. The final release date of the chapter is August 28, 2022. Fans will be able to catch all the chapters only on the official pages of Shonen. Thus, keep an eye on The Anime Daily to get more updates right here!
Tags: ambrionicbitcoinbitcoin newsbreaking newscrypto newsDategaminggaming newslatest gaming newslatest newsPlotRanksReleaseSpoilers
Minor Threats #1 Review Roundup :: Blog :: Dark Horse Comics
Hishin's Final Attack At Gian! Release Date
Hishin's Final Attack At Gian! Release Date


The building blocks of proteins are amino acids. An amino acid contains an amino group (-NH2), a carboxylic acid group (-COOH), and a side chain (R). The carbon at the center is called the alpha-carbon (Figure 11-16). Although there are many amino acids, only 20 different amino acids are present in humans. The unique characteristics of the 20 amino acids are due to the side chain.
Figure 11-17 shows the 20 amino acids (with three-letters and one-letter abbreviations following the full name). Nonpolar amino acids are not soluble in water, which makes them hydrophobic. Polar amino acids have hydrophilic side chain, which forms hydrogen bonds3 with water. Acidic amino acids have side chains that can ionize as a weak acid. The side chains of the basic amino acids contain an amino group that can ionize as a weak base. The numbers at the bottom of each graph is the value of isoelectric point (pI). The isoelectric point is a value of pH at which the amino acid gives an overall charge of zero and not accepting or donating any H+ ion in a solution. The hexagon is the benzene ring C6H6. Amino acids on earth are all left-handed with the NH2 group to the left. Essential (E in Figure 11-17) amino acids cannot be synthesized by the human body and must be provided through diet, while non-essential (NE) amino acids are synthesized by the body from carbon, nitrogen, hydrogen, oxygen, and sulphur.
There are more amino acids beside those 20's used by biological system as listed in Figure 11-17.
The bond that joins 2 amino acids is called a peptide bond. The NH2 and OH group at the end of the peptide are available for adding more amino acids to the chain. (Figure 11-18a). Combining amino acids to form peptide will release water, while adding water to peptide will break it up into individual amino acids.
circularly polarized light can itself be either left-handed or right-handed, depending on how it rotates, molecules in different interstellar clouds (or even in different parts of the same cloud) may be affected in different ways. Thus, there is still a chance that stranded space travelers will starve amidst plenty because their metabolisms could not cope with the food found on other worlds.
3The bonding energy for the various chemical bonds are roughly in the ratio - Van der Waals : Hydrogen Bonds : Covalent Bonds = 1 : 10 : 100. Formation of hydrogen bonds releases 3 - 10 kcal/mole (~ 0.1 - 0.4 ev). Hydrogen bonds are found between only a few elements of the periodic table. The most common are those in which H connects two atoms from the group F, O, N, and, less commonly, Cl. The hydrogen bond in water has the configuration: H-O-H(+)……..(-)O=H2. Covalent bonds are created with sharing electrons in between two atomic nuclei. A stable configuration can be achieved by sharing up to three pairs of electrons. Van der Waals forces are the intermolecular attractions produced by temporary dipoles (shifting of electrons).


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Alzheimer's Drug Discovery Foundation alzdiscovery.org
Alzheimer's Drug Discovery Foundation - Key People
Hannah Elkin In her role as Development Assistant for Institutional Partnerships, Hannah Elkin helps engage corporations, foundations, and government agencies to act as partners in support of the ADDF's scientific conferences and programs. Additionally, she assis show more…
Howard Fillit Howard Fillit, MD, a geriatrician and neuroscientist, is the founding Executive Director of the Institute for the Study of Aging (ISOA), an Estée Lauder family foundation founded in 1998, and the Alzheimer's Drug Discovery Foundation (AD show more…
Adam Liebling Adam Liebling has ten years' experience in grants management. Prior to joining ADDF, Adam held similar roles at the Carnegie Corporation of New York and Autism Speaks. Adam has served as board member of the Grants Managers Network (GMN), a national m show more…
Nancy Lynn Nancy Lynn was appointed Executive Vice President of the Alzheimer's Drug Discovery Foundation in October, 2009. In this position, Ms. Lynn is responsible for strategic planning, board development, fundraising, external relations, and marketing. Pri show more…
Filomena Machleder Filomena Machleder performs essential fundraising and editorial functions for the organization in her role as Assistant Director of Institutional Partnerships. Ms. Machleder's primary responsibility is to raise funds from corporate, foundation and go show more…
See all 8 people


Welcome to your new social circle!
B.Social was established in August 2015, with the director's idea to create a venue where simply 'everybody' was welcome. B.Social is about communal eating, shared platters, wood oven pizzas and Italian cooking, all fused together to create memorable moments.
Tickets only $5.00 each. Do you have yours?
Every restaurant transaction of $60-$100 will give you 1 FREE ticket into the draw. For each single transaction over $100, you receive 3 free tickets into the draw.
The 3 draws have a total prize pool of $531!! (1x10kg Toblerone with mini eggs, valued a $146, 1x5kg Favourites with mini eggs valued at $175 & 1x10kg milk chocolate valued at $210. Each entry will need to provide their full name, mobile number and email address to be entered into the draw. All information will be kept with B.Social and used for marketing purposes. You can cancel this at any time. Your details will not be shared. The draw is open to customers who buy tickets from January 20th to April 10th 2019.
The draw will take place at B.Social on 11th April at 8.30pm.


Pagina pro discussion concernente mi editiones in Wikipedia in Interlingua. Clicca super "Modificar iste pagina" e insere vostre commentos. Respecta per favor lo scribite per alteres.
1 Ubi poner questiones technic?
26 Que pensa tu de isto nove portal de cursos?
Salute, McDutchie, io me gaude de ser hic e salutar te anque hic. Gratias pro tu message a me hic, qui es un nove usator e redactor futur (sperabilemente diligente... :-) ) de Wikipedia.
Sci tu como crear un template pro le taxonomia? Actualmente, io crea un tabula per cata pagina biologic (como in orangutan e banana), sed iste methoda non me sembla un methoda bon. Gratias!
Io intende crear files pro YouTube del alteres anque. Io pensa que vostre pronunciation es multo bon e servi ben pro monstrar le pronunciation ideal del lingua.
Si isto es utile a te, pro favor scribe a me.
'integr-e', 'dis-integr-ar', 'integr-itate', 're-integr-abile', etc.
– totes basate in un mesme radice.
Que le sembla Santiago ruiz ?
Mi intendimento es que le administrator debe verificar le historia del articulo ante deler le articulo, perque mesmo usator experiente pote committer equivoc. Ma, per su demanda, altete (altiente?) mie monobook.
Io spera que nos pote incontrar nos personalmente in le futuro (non distante).
Hi McDutchie, how are you? Mate, I am trying to find an editor/s who can help by translating User:Russavia/Polandball into Interlingua. I was wondering if we could make a trade?
If you could translate that article into Interlingua for me, I would be happy to upload approximately 50 aviation photos to Commons from amongst the 200,000 I have permission to upload. I have uploaded a number of photos to give you a brief idea of what I can upload, and I am keeping a gallery at User:Russavia of photos uploaded.
Please check editing in Hjalmar Söderberg. I undid the edition by assuming vandalism, but not sure.
Please check editing Luiz Inácio Lula da Silva. I ask for page protection (temporary) to prevent further vandalism.
It's the only way to keep Tobias Conradi's "anonymous" vandalism out; he uses an ISP with dynamically assigned addresses so they will change each time he reconnects, which he can (and does) trivially use to circumvent a single-IP ban. I verified with whois that these ranges all belong to the same ISP which he uses. Note that these IPs are not blocked for editing from registered accounts.
Iste pagina esseva modificate le plus recentemente le 12 april 2018 a 13:18.


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Jungle Emperor - first anime in color
1965. "Jungle Emperor" is the first anime in color (first animated TV series) in Japan. It was aired on Fuji Television. The broadcasting started on October 6, 1965. and ended on September 28, 1966. It was shown every Wednesday at 7:00 PM, 1 episode per day.
The opening sequence (RealVideo clip, 1,5 MB; from Kimba W.Lion)
MIDI file of this theme (28 kB; source page)
1966. "Kimba the white lion" anime was shown in USA.It was distributed by NBC Films, and it was aired for the last time in 1978.
Production credits Lyrics of the opening themes
The opening sequence (RealVideo clip, 1,1 MB; from Kimba W.Lion
1967. "Kimba the white lion" anime was shown in Australia on Melbourne TV. It started at 4:00 PM.
1969. "Kimba the white lion" anime was aired as "Kimba el leon blanco" in Spain on TVE for the first time. Also, it's interesting that "Kimba" was the first Japanese anime that was ever aired in Spain. These series were later released on video in Spain in the 80s (the exact year is not known). (Many thanks to Mazochungo for this info!)
1977. 39 episodes of the 1966 "Kimba the white lion" TV series were aired under the title "Kimba der weisse Löwe" in Germany (on ZDF) and in Austria (on ORF 1). On ZDF it was aired every Tuesday, from January 4 to October 4.
Production credits Lyrics of the opening theme
The opening theme (streaming RealAudio clip)
The "Jungle chorus" video clip (RealVideo clip, 1,5 MB, with mkolle's permission)
The complete "Jungle chorus" song (MP3 clip, 600 kB, many thanks to Joachim from Germany!!!) Lyrics (many thanks to Joachim from Germany!!!)
The "Jungle friendship" song (Windows Media Audio 9 clip, 490 kB; many thanks to Swen Steffens!) Lyrics (many thanks to Joachim from Germany!!!)
7 LPs and 7 MCs containing slightly shortened versions of 29 episodes from the above TV series were released in Germany by Poly (a division of Polydor/PolyGram).
"Kimba the white lion" anime was aired in Italy under the title "Kimba il leone bianco" for the first time in September 1977 (in Rome on "TV Voxson"; in Lazio on "GBR" on September 5), and these italian-dubbed episodes that actually came from the U.S. (from NBC Films) were aired on several TV stations to date (excluding the "new" italian Kimba series from 1999). During these years there were two opening themes - in the beginning the show used the U.S. (NBC) opening theme, which was replaced with the italian opening theme in 1982. The show had two dubbings - the first one (in which Kimba had a female voice) ran from 1977 to 1990, and the second one that featured Kimba with a male voice was introduced in 1983 and it was aired even recently (in 2001). In the 80s both of these two dubbings were used. (Many thanks to Francesco Piccardo for these infos!) Production credits
1978. "Kimba il leone bianco" TV series were aired in Italy on "Antenna Nord". The broadcasting started in Spring 1978.
1979. From January 25 to April 14 "Kimba il leone bianco" TV series were aired in Italy on "Quinta Rete" (future "Italia 1") during the "Ora dei ragazzi"("The boys' hour") TV programme. (Many thanks to Francesco Piccardo for the initial correction!)
1980. From August 5 to August 25 "Kimba il leone bianco" TV series were aired in Italy on "La Uomo TV", from Monday to Friday.
1982. "Kimba the white lion" TV series were again shown in Australia on Melbourne TV.
"Kimba il leone bianco" TV series were aired in Italy, but this time with a new (italian) opening theme instead of the previously used (U.S.) one. This opening theme was composed by Riccardo Zara, and performed by "I Cavalieri del Re" ("The King's Horsemen"). It was originally recorded in 1979.
The first airing started on "Telearcobaleno" on March 2 at 1:30 PM and 6:15 PM.
There was also another airing on "T.R.E." (part of the "TV Port" network) that started on March 9 at 6:00 PM and that was aired from Tuesday to Friday.
The opening theme (new and improved version; Windows Media Audio clip, 1,5 MB)
The opening theme - 2000 version (streaming RealAudio clip; source)
The opening sequence (RealVideo clip, 3,51 MB; new version)
The opening sequence, 2nd version (RealVideo, 3,51 MB; from Regno delle Anime)
Italian version of the "A-I-U-E-O mambo" jap.song (and the lyrics; Windows Media Video clip, 1,9 MB)
1983. "Kimba the White Lion" has been released in the UK on video by Entertainment In Video (distributor: CBS). A total of 2 volumes were released, and the first one was released on July 29, 1983. Each volume had a running time of 90 minutes (contained 4 episodes).
A new italian dubbing of "Kimba the white lion" episodes, which starred Franco Latini as Kimba, was aired in Italy for the first time. It's important to mention that this dubbing, instead of having only the wonderful Isao Tomita's music, had just 50% of the background music that was composed by Isao Tomita, while the other 50% was replaced by the instrumental version of the italian opening theme.(Many thanks to Francesco Piccardo for these infos!)
1985. "Kimba der weisse Löwe" TV series (33 of total 38 episodes) was again aired in Germany, this time on Sat 1. It was aired every Monday, at first (in 1985) at 1:30 PM CET, and then (in 1986) at 3:00 PM. The airing started on September 2 and ended on April 21, 1986.(Many thanks to Joachim and to Marc from Germany for these infos!)
1986. "Kimba der weisse Löwe" was released on video by Taurus Video in Germany. It was re-released in 1995. Video releases
1988. "Kimba der weisse Löwe" TV series was again aired in Germany on Sat 1, every day at 2:10 PM CET, with repeats on the following day at 9:10 AM or at 9:35 AM. This airing started on March 31 and ended on May 7. (Many thanks to Marc from Germany for these infos!)
1989. "Kimba der weisse Löwe" TV series was again aired in Germany on Sat 1, every Tuesday at 2:05 PM CET, with partial repeats on the following day at 9:35 AM. This airing started on April 4 and ended on January 1, 1990. (Many thanks to Marc from Germany for these infos!)
"Kimba the white lion" was released in Finland on video under the title "Kimba valkoinen leijona". These episodes are actually the italian 1979 episodes with finnish subtitles. Each cassette was 45 minutes long and it contained 2 episodes (probably). (Many thanks to Lauri Welling from Finland for this info!)
The opening theme of the Finnish Kimba episodes, recorded in 1986, is actually the 1977 German opening theme translated into Finnish by Ari Pauli Meriläinen. It is performed by Hannu Takala, and it was available only on the "Children TV favorites" LPs and cassettes, released by a Finnish company called Sateenkaari in 1987.
The opening theme (Windows Media Audio 9 clip; 436 kB) Lyrics of this opening theme
Note: Again many thanks to Lauri Welling from Finland for the theme and the lyrics! Sorry for the fair quality of the sound, I've improved it a bit, but I couldn't do anything else. But, if you're still interested in it, download it and enjoy!
1990. From September 3 to November 23 "Kimba il leone bianco" TV series were aired in Italy on "Odeon" during the "Sugar" TV programme, from Monday to Friday.
The complete 1965 "Jungle Emperor Leo" anime was aired as "Le Retour de Léo" in France on "La 5" ("La Cinq"). They were followed by the complete 1966 "Leo" anime, but this time the 1966 "Leo" was recorded with new french voice actors. The airing started on September 17.
The above episodes were later aired on TF1 in 1995 (under the title "Le Retour du Roi Léo") and on FR3 (France 3) in 1996 as well.
The opening theme was sung by Claude Lombard, and pictured here is the scan of the 45rpm record with the theme. This song is actually based on the opening theme of the italian TV series "Sabato al circo"("Saturdays at the circus") - the music (by N.Carucci) is the same in both songs, only the italian lyrics (by A.Valeri Manera) were replaced with the french lyrics by Charles Level.
The opening theme (from the 45rpm record; Windows Media Audio 9 clip; 1,41 MB)
Lyrics of the opening theme (with translation)
Note: Although the image on the cover of the 45rpm record suggests that the 1989 Kimba series were also aired on "La 5", there is no further information on this.
1991. 14 episodes of the "Kimba der weisse Löwe" series that were never shown in 1977 (but which were newly dubbed - including the episode "The Return of Fancy Prancy" that was initially aired in 1977 but which was damaged immediately after that first airing, and so it had to be retaken and redubbed for the "Bou Bou" series), and all 26 episodes of the "Onward, Leo!" series were all together aired on Pro7 as "Bou Bou - König der Tiere". The name was changed because of the copyright reasons. (Many thanks to Swen Steffens for these explanations!)In addition to Pro7, "Bou Bou - König der Tiere" was also aired on TV München, but the year is not known.
The opening theme (Windows Media Audio 9 clip, 336 kB; many thanks to Swen Steffens!)
"Kimba il leone bianco" video has been released in Italy by a company called Pretty Video.
The shown video contains two episodes from the italian 1970s airings, "Invasione degli insetti" ("Insect invasion") and "Distruttori del deserto" ("Destroyers from the desert"). This video is a very rare item.
1992. "Jungle Emperor" (aka "Kimba the White Lion") anime was aired in Japan on TV Tokyo every Tuesday and Thursday at 7:30 AM.
1994. "Kimba der weisse Löwe" TV series were aired in Germany on RTL 2. They were aired almost at the same time "Lion King" was shown in movie theaters.
1998. In Germany in the City's library of Munich (München) on two Wednesdays, August 5 and 12, starting at 3:00 PM CET four episodes from the "Kimba der weisse Löwe" series were shown to children on video.
The original Kimba 1966 episodes were finally released on video by Right Stuf International. These episodes were also released on DVD in 2003 and in 2005. Video releases DVD releases
38 episodes of the "Jungle Emperor" TV series were aired in Germany on Junior, part of the pay-TV Premiere World, Monday to Friday, starting at 6:15 AM and 10:55 AM.
The broadcasting started on June 21 and ended on August 9.
2001. "Kimba il leone bianco" anime was shown in Italy on 4 local TV stations:
- on TeleNapoli 34 (Campania) everyday, starting at 5:20 PM CET (this airing ended in July 2001.)
- on Telenuovo (Veneto) everyday, starting at 6:00 PM CET (this airing ended in 2002.)
- on ReteSette (Piemonte), everyday, starting at 3:00 PM CET (this airing ended in January 2002.)
- on TeleRoma 56 (Lazio), everyday, starting at 7:15 AM CET (this airing ended in January 2002.)
On September 7, 2001. Billie Lou Watt, the voice of Kimba in 1966. U.S. Kimba TV series, dies. See the announce taken from the New York Times from September 13, 2001.
From March 14 to May 7, 38 episodes of the "Jungle Emperor" TV series were again aired in Germany, and again on "Junior", part of the pay-TV "Premiere World". The airing was from Monday to Friday, at 7:00 AM CET.
"Kimba the white lion" TV series was again aired in Germany on "Junior" (part of the pay-TV "Premiere World") from Monday to Friday at 7:20 AM CET under the name "Leo der kleine Löwenkönig" (Leo the Little Lionking). This airing started on September 20.
On March 25 2003 26 episodes from the 1966 U.S. "Kimba" TV series were available for the first time on DVD by Right Stuf. SeeDVD releases for more information!
The italian Kimba airing called "Una giungla di avventure per Kimba" has repeated its broadcast after exactly 4 years in Italy on channel Italia 1. The broadcasting started on September 8 (and it was aired from Monday to Friday at 08:15 AM CET), but it temporarily ended on September 19, and it seems that the airing has been interrupted for good.
The original 1965 episodes were aired on TV on the Nihon Eiga Senmon satellite channel. It is carried on three Japanese satellites as a part of three packages: on Superbird C (at 144.0°E, freq.12583 horizontal) as a part of the I-HITS package, on JCSAT 4A (at 124.0°E, freq.12508 vertical) as a part of the Sky PerfecTV package (channel 707), and on N-Sat 110 (at 110.0°E, freq.12371 R) as a part of the Sky PerfecTV 110 package.
It was aired every Sunday at 11:00 AM, one episode per week (this episode was repeated every Wednesday morning at 06:00 AM). The airing started in the middle of July 2004, and it ended on August 7, 2005.
Also, it is interesting to mention that, along with Kimba, three other popular animes by Osamu Tezuka were aired in the same part of day - an episode of "Astro Boy" and "Princess Knight" was aired before Kimba, while an episode of "The Amazing Three" was aired immediately after Kimba.
From September 24 to November 16 "Kimba the white lion" TV series were aired in Germany on "Junior" (part of the pay-TV "Premiere World") from Monday to Friday at 10:40 AM CET. These are the original 1966 episodes dubbed in Germany in 1977 (38 episodes).
"Kimba el Leon Blanco" was aired in Latin America on Cartoon Network Latin America in the Boomerang section. It was aired from June 6, and it was aired from Monday to Friday at 6:00 AM ET, 2:00 PM ET and 10:00 PM ET. It seems that this airing has ended in the meantime (exact ending date is unknown).
The first 26 episodes of the 1965 "Jungle Emperor" series have been published in France on DVD for the first time. It has been released in a DVD box titled "Le roi Léo - tome 1" by a french firm called Rouge Citron Production on June 21. Note that this is a french release, with french audio only. DVD releases
Madman Entertainment from Australia has released on DVD all 52 episodes of the original Kimba series aired in the U.S. and Australia in the 60s and 70s. It was released on September 21.
After the airing of the original 1965 episodes has finished on the Nihon Eiga Senmon japanese satellite channel on August 7, 2005, airing of the 1966 ("Go ahead, Leo!" or "Onward, Leo!") series was started.
It was aired at the same time: every Sunday at 11:00 AM (also one episode per week), with repeated airing every Wednesday morning, and ended on February 21, 2006.
Along with it, other Tezuka animes were aired in the same part of day as well: an episode of "Astro Boy" and "Blue Blink" (instead of "Princess Knight") was aired before "Leo", while an episode of "The Amazing Three" was aired immediately after "Leo".
On November 29 Right Stuf released a special DVD box that every true Kimba fan should have: this DVD box contains all 52 episodes of the original Kimba episodes aired in the U.S. in the 1960s and 70s newly remastered with image quality never before seen on previous Kimba DVD releases. More info about it can be found on the DVD releases page.
The 1977 german-dubbed Kimba episodes were once again aired in Germany and Austria on pay-TV "Premiere" - they were aired on "Junior" from Monday to Friday at 08:45 AM CET, and on "Premiere Start" and "Premiere Austria" every Saturday at 08:45 AM CET.
The airing on "Junior" started on August 24 and ended on October 14, while the airings on "Premiere Start" and "Premiere Austria" started on August 27 and ended on October 15.
German Kimba fans finally got a chance to see some of the 38 episodes of the Kimba series that were dubbed in german and aired in Germany in 1977. On November 11 Koch Media has released on 4 DVDs 16 episodes from the series, while the next 10 episodes were released on March 17, 2006. For more info please visit the DVD releases page.
On November 17 a DVD box set titled "La leyenda de Kimba, el león blanco" that contains 15 episodes from the 1965 series was released in Spain by Premium Video. What is strange, though, is that the image on the front cover of the DVD box suggests that these are the 1993 series. The box set contains 5 DVDs, and the episodes have both Spanish and English soundtracks. The DVDs feature interactive menus, chapter selectors, and infos about habits and customs of the animal that is shown on each DVD.
(Many thanks to Lauri Welling from Finland for info about this DVD release!)
Gilbert Mack, the voice of Pauley Cracker (and the voice of Mr. Pompus) in the original U.S. Kimba series, passed away on December 5 at the age of 93.
The german-dubbed Kimba episodes from 1977 were again aired in Germany on "Junior", part of the pay-TV "Premiere". These episodes were aired from January 11 to June 24 on "Premiere Start" and from January 14 to June 26 on "Premiere Austria". They were aired on "Junior" from Monday to Friday at 7:35 AM CET (since March 17), and on "Premiere Start"/"Premiere Austria" Saturdays at 9:25 AM CET.
A DVD box with the next 26 episodes of the 1965 "Jungle Emperor" (aka "Kimba the White Lion") series, titled "Le roi Léo - tome 2", has been released on January 24, again by Rouge Citron Production. This is a french release as well, with french audio only. DVD releases
Yet more DVD box sets with french-dubbed episodes of the 1965 "Jungle Emperor" series were released - 2 DVD box sets titled "Le Roi Leo" with 12 DVDs containing all 52 episodes have been separately released by Déclic Images on March 9 and on June 7, and another, 3rd DVD box set, containing 26 episodes of the 1966 "Leo" series has been announced, however it never made to the stores. These DVD sets were discontinued in the meantime, and instead five 4-DVD sets were made available in 2007 and 2008 - first three sets contain the 1965 "Jungle Emperor" episodes, and the last two sets contains the 1966 "Leo the Lion" series. DVD releases
Starting August 7 the 1965 "Jungle Emperor" series were again aired in Japan, this time on Cartoon Network Japan as a part of the "Boomerang" program. It was aired from Monday to Friday at 6:00 AM, 1 episode a day (with repeats on the same day at 11:00 PM). This airing lasted until October 16. However, a repeated airing of the series has started on CNJ on December 11, and this time it is aired from Monday to Friday at 6:30 AM, with the repeat of the episode at 11:30 PM. After January 1, 2007 the episodes were aired Monday-Friday at 10:30 AM. This airing ended on February 19, 2007.
In Germany a 10-DVD box set called "Superbox" and containing all 38 episodes of the Kimba series that were dubbed in german and aired in Germany in 1977 has been released by Koch Media Entertainment on March 23. DVD releases
From July 13 to September 21 the original 1965 "Jungle Emperor" series were again aired in Japan on Cartoon Network Japan, 1 episode every day from Monday to Friday at 10:00 AM, with a repeat on the same day at 11:00 PM.
From July 15 to August 21 the german-dubbed Kimba episodes from 1977 were again aired in Germany on "Junior", part of the pay-TV Premiere (now Sky), every day at 6:00 AM CET. Just like on "Junior", 5 episodes from this dubbing were aired on the other two pay-TV channels, "Premiere Start" and "Premiere Austria", every Saturday from July 21 to August 18 at 6:00 AM CET.
From February 19 to March 27 the german-dubbed Kimba episodes from 1977 were again aired in Germany on "Junior", part of the pay-TV Premiere (now Sky), every day at 6:00 AM. The episodes aired on Saturday were aired on the same day at the same time on "Junior", and also on "Premiere Start" and in Austria on "Premiere Austria".
From April 2 to May 8, 14 years after the last airing, the 2nd german airing of Kimba from 1991 known as "BouBou - Koenig der Tiere" has been once again aired on TV in Germany. This time it was aired on "Junior", every day at 11:45 AM, but instead of all 40 episodes, only 37 episodes have been aired.
From July 1-18 only 18 episodes from the german-dubbed Kimba episodes from 1977 were having another airing in Germany on "Junior". They were aired every day: Monday to Friday at 8:30 AM, and Saturday & Sunday at 7:20 AM. The episodes aired on "Junior" on Saturday were aired on the same day at 8:20 AM on "Premiere Start" and in Austria on "Premiere Austria".
From August 10 to October 20 the original 1965 "Jungle Emperor" series were again aired in Japan on Cartoon Network Japan, 1 episode every day from Sunday to Thursday at 12:00 AM.
Good news for Kimba (and Tezuka) fans in the UK: both "Jungle Emperor" movies, along with the first episode from the 1965 series, were screened during the "Osamu Tezuka: Movies into Manga" festival (September 18-24) held in the London's Barbican Centre. The first episode from the original Jungle Emperor series was screened on September 19 from 5:45 PM as part of the "Tezuka on the Telly 1" programme, the 1997 movie was screened on September 20 at 11:00 AM, and on September 23 at 10:30 AM GMT ("Schools' screening"), and the 1966 movie was screened on September 21 at 12:00 AM GMT. All the screenings were in the Centre's Cinema 1. The 1997 movie was dubbed in English, while the 1966 movie were subtitled in English - for the very first time, which made this screening very special.
On September 22 the japanese Internet TV Branco added a new channel called "Tezuka Osamu Animation World", which showed Tezuka's works/series like Astroboy, Princess Knight, The Three-Eyed One, BlackJack, One Million-Year Trip: Bander Book and Fumoon. The 1965 Jungle Emperor (later known as Kimba the White Lion) series has also been aired. However, on January 30, 2009 Branco ceased to exist as an Internet TV service.
2009. From Wednesday, February 18 to Thursday, April 30, the original 1965 "Jungle Emperor" series were again aired in Japan on Cartoon Network Japan, 1 episode every day from Sunday to Thursday at 12:00 AM.
2010. From April 22 (from July 12 for "Sesta Rete") "Kimba il leone bianco" anime was shown on 3 local TV stations (all airings ended in August):
- on Telestudio (Piemonte) everyday, starting at 6:45 AM and at 8:30 PM CET
- on Quinta Rete (Piemonte) everyday, starting at 8:00 AM and at 5:00 PM CET
- on Sesta Rete (Piemonte), everyday, starting at 4:00 PM and at 7:15 PM CET
From October 2 to January 15, 2011, "Kimba il leone bianco" anime was shown on D1 Television (Sicily), every Monday and Saturday at 5:35 PM CET.


Human Resources White Papers - Family Law White Papers | National Legal Research Group, Inc.
Business use of the Internet has experienced extraordinary growth in recent years. It is now commonplace for employees to have access to the Internet, and as the United States moves ever closer to an information worker/service type of economy, even more employees will need access to the Internet to do their job effectively. Although the business uses of the Internet are many, much of the information available to employees on the Internet is not related to job performance. Thus, many employers have recognized that unrestricted use of the Internet by employees has the potential to drain, rather than enhance, productivity. The solution may be to implement a policy outlining the permissible parameters of employee Internet use, or an Internet acceptable use policy ("IAUP").
The ADA Amendments Act of 2008 ("ADAAA"), Pub. L. No. 110-325, 122 Stat. 3553 (200), which amends the Americans with Disabilities Act of 1990 ("ADA"), was signed by the President on September 25, 2008. The changes brought about by the ADAAA are likely to increase significantly the number of requests for accommodation and the number of claims of disability discrimination.
For most professional, commercial, and retail establishments, maintaining a website has become a matter of business necessity. Yet with its undisputed advantages, the operation of a website also presents new areas of exposure to liability for its owner or operator. Sources of potential liability include infringement (either in the domain name itself or in the content of the website), privacy (relating to the use of website user information or the posting of website content containing the name or likeness of a person), defamation (in the form of web content), reliance (based on information contained on the website and the use of that information), or accessibility (for visually impaired individuals).
Active appreciation is appreciation in separate property that is caused by contributions of marital funds or marital efforts. In almost all dual classification states, active appreciation is marital property.
When valuing a business for purposes of division upon divorce, all states agree that the hard assets and liabilities of the business are marital property. But the value of a business as an ongoing concern is often greater than the total value of its assets and liabilities. This difference in value is known as goodwill.
Some of the most controversial issues in all of family law concern the growing acceptance of committed relationships and parenthood in the gay and lesbian communities. Law on this subject differs immensely from state to state. Regardless of state law, however, gay and lesbian couples are raising children in unprecedented numbers.


text:
Indywidualne Mistrzostwa Świata na długim torze 1989

Wyniki
 20 sierpnia 1989 r. (niedziela),  Mariańskie Łaźnie

1989
1989 w long tracku
1989 w Czechosłowacji

redpajama_set_name: RedPajamaWikipedia


In line with the call to be conscious consumers, Pinko launches their latest collaboration with Treedom on the #StartWithaTree Campaign. The collaboration aims to plant a "Pinko Forest" in Kenya this year, which will feature 10,000 Avocado, Mango, Macadamia, Banana, and African Cherry trees. Not only will the project impact the region's environment in a positive way, it will also help the local community by supporting basic food needs, and creating sustainable agriculture-based livelihoods.
In addition to this, Pinko also bangs the drum for social responsibility with the launch of their exclusive T-shirt range that pushes consumers to take action for the environment through small but significant changes in their consumption habits. According to Pinko's Founder and CEO, Pietro Negra, "We have the responsibility to support the dream of a world resurrected from this terrible state!" — and if we can do that with an organic cotton tee (in Eco-friendly packaging of course) why not? Every conscious purchase is a step towards the right direction.


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Nicolás Terol Peidro (Alcoi, 27 september 1988) is een Spaans motorcoureur. Hij werd op zijn Aprilia in 2011 de laatste wereldkampioen wegrace in de 125cc-klasse. Vanaf het seizoen 2012 rijdt hij in de Moto2-klasse.

Loopbaan
Nicolás Terol begon zijn carrière in 1999 op pocketbikes, in 2002 werd hij vice-kampioen in de Spaanse Formula-Bancaja-serie. Het jaar daarop legde hij de hand op de 16e plaats in het algemeen klassement van de 125cc-klasse in het Spaans kampioenschap wegrace. 2004 sloot hij op de vierde plaats af. In het wereldkampioenschap wegrace 2004 maakte hij op een Aprilia (motorfietsmerk)Aprilia zijn debuut als vervanger van Mike Di Meglio bij de Grand Prix-wegrace van Valencia.

In het seizoen 2005 reed Terol, voor Caja Madrid – Derbi Racing op een Derbi, voor het eerst als vaste coureur in het 125 cc wereldkampioenschap. De Spanjaard behaalde echter slechts één WK-punt en werd 35e in het eindklassement. Het jaar erop, in 2006, steeg Terol in de tweede seizoenshelft door zijn constante plaatseringen in de WK-punten op naar de 14e plaats in het kampioenschap. In 2007, zijn derde op Derbi, vormde Nicolás Terol samen met de Tsjech Lukáš Pešek het coureursduo van het Valsir-Seedorf-Derbi-Team, het door de Nederlandse voetballer Clarence Seedorf ondersteunde team. Het lukte Terol echter niet meer constant in de punten te rijden en werd met 19 punten 22e in de eindrangschikking.

In 2008 kwam Terol uit voor het Jack & Jones WRB-team en vormde samen met de Italiaan Simone Corsi het rijdersduo op Aprilia. Zijn eerste podiumplek behaalde hij tijdens de GP van Spanje. Hij werd tweede achter teamgenoot Corsi. Tijdens de race op Indianapolis behaalde hij zijn eerste overwinning. Met 176 punten werd Terol vijfde in de eindrangschikking. In 2009 kwam Terol uit voor hetzelfde team, won de Grand Prix van Tsjechië en werd in het algemeen klassement derde.

In 2010 kwam Nicolás Terol uit voor het Aspar Team van viervoudig wereldkampioen Jorge Martínez, dat het jaar ervoor met Julián Simón de titel had gewonnen. De Spanjaard won op Aprilia de eerste Grand Prix en daarnaast ook in Tsjechië en Indianapolis. Uiteindelijk werd Terol tweede in het klassement. 2011 was het laatste jaar dat er in de 125cc-klasse werd gereden en Terol domineerde dit seizoen door acht Grand Prix overwinningen te behalen. Terol werd daarmee met 302 punten de laatste wereldkampioen 125 cc, de klasse die in het seizoen 2012 overging in de nieuwe Moto3-klasse.

Terol maakte in het seizoen 2012 de overstap naar de Moto2-klasse.

Statistieken
(Stand: Seizoenseinde 2011)

Externe link

Spaans motorcoureur


What would you do if your child was dying? What would you do if the only person who could save your child was someone you thought killed your husband, and your other child? These are the questions that Change of Heart asks you. These truly are impossible choices to make. Jodi Picoult takes you through an emotional story that has you wondering about a lot of things. Is the bad guy really the bad guy? What would you do if you were faced with this same choice you had to make? What is the difference between religion and faith? Change of heart takes on so many heavy issues that it is impossible to call this a light read. It takes on Capital punishment, Organ Donation, the United states Justice System as a whole, and religion. Everywhere you turn in this story there is a topic that is mostly spoken of in whispers and hushes, so not to offend anyone. This is one of the reasons that this book is so good. When you read a Picoult novel you know you are going to get something emotional that will pull at your heart strings. I could not believe just how pulled in I got though, I found myself not wanting Shay Bourne to be killed, wondering if he truly did the crime he had been convicted of and yet wanting the little girl Claire to live. There is no denying that there are some shadows of the Green Mile in this book with some of the things that happen in the prison with Shay there, and even the relationships with some of the guards. That being said the book makes no secret of that and even makes a small joke of it in calling Shay Bourne "green Mile" in one passage. This book is not Green Mile, and while it has some similar themes stands fully on its own, and gets a hearty MUST READ from me.
This entry was posted on Monday, March 7th, 2011 at 5:33 am	and is filed under Contemporary, Review. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.


Have You Been Arrested in Kensington?
If you have been arrested in Kensington for DUI, it is a good idea to work with an attorney who is both experienced and familiar with the location. Lynn Gorelick has worked in this area for more than 30 years. Ms. Gorelick has dedicated her career to defending those who have been accused of crimes in Kensington and the surrounding areas.
It is important to understand that DUI charges carry administrative as well as criminal penalties. After a Kensington DUI arrest, you have only 10 days to petition for an administrative hearing in order to dispute your automatic license suspension. The 10-day policy is very strict. If you fail to request a hearing within those 10 days, you will have forfeited your right to a hearing.
If you have been arrested for DUI in Kensington and are facing charges, it is in your best interest to work with a local and skilled attorney. Ms. Gorelick can assist you with your Kensington case and provide you with the proper defense. To schedule a free consultation, call (510) 785-1444 or (925) 847-3006.


More than 10,000 of you voted last year in the very first election for Multihull of the Year 2018.
Create a notification for "Multihull of the year"
And we know you are looking forward to discovering the 2019 nominees.
The journalists at Multihulls World and Multicoques Mag as well as the organizers of the International Multihull Show, got together to select the 2019 nominees, which you can discover below.
The finest of the world's new multihulls is this year again divided into 4 categories.
Make sure you vote for YOUR multihull of the year!
Election for the 'multihull of the year' 2019: vote for your favorite multihull!
Electric propulsion when blue-water cruising - for or against?


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If you register for any of our program or enquire about any of our courses or request for our newsletter we ask for some personal information from you to fulfill your request. We use this information to communicate with you. We do not share your confidential information with any third party. However in rare cases where your confidential information needs to be shared it is done after getting a prior written approval from you except in rare legal circumstances.


text:
Aangeleerde hulpeloosheid  (Engels: learned helplessness of learnt helplessness) is het verschijnsel waarbij een mens of dier geleerd heeft dat hij geen invloed kan uitoefenen op de gebeurtenissen die hem overkomen.

Martin Seligman publiceerde in 1967 de resultaten van een dierproef die in duidelijke tegenspraak waren met de toen heersende opvatting uit het behaviorisme van Burrhus Skinner. In dit zogenaamde "yoked control"-experiment ondergaan twee dieren meermaals elektrische schokken. Het eerste dier heeft de mogelijkheid de duur van de schok te bekorten, door bijvoorbeeld op een knop te drukken. Voor beide dieren stopt dan de schok. Het dier dat de schok niet kan beïnvloeden heeft na verloop van tijd een aanmerkelijk slechtere gezondheid. Het is ook niet meer in staat te leren. In een vervolgexperiment werden beide dieren in een zogenaamde "shuttle-box" gezet: een kooi die door een lage afscheiding in tweeën gedeeld is. In de ene helft ondergaan beide dieren regelmatig een schok, maar door over de afscheiding te springen, kunnen ze de schok vermijden. Het dier dat in het eerste experiment de controle had, leert dit, zoals door het behaviorisme voorspeld, snel. Het tweede dier leert dit echter niet: het lijdt weliswaar onder de schok, maar onderneemt niets om deze te vermijden: het heeft geleerd passief en hulpeloos te zijn.
Volgens Seligman zou bij mensen aangeleerde hulpeloosheid het mechanisme kunnen zijn dat op den duur leidt tot psychische stoornissen zoals depressie.

Meer algemeen treedt aangeleerde hulpeloosheid op wanneer mensen of dieren geen adequate terugkoppeling krijgen over hun eigen handelen. Ze kunnen zo niet leren welke handelingen effectief zijn in het bereiken van een bepaald doel, waardoor ze zich uiteindelijk hulpeloos en passief zullen opstellen.
Finkelstein en Ramey (1977) vonden dit verschijnsel ook bij baby's. De eerste baby kon een mobile boven de wieg laten bewegen door zijn hoofd te bewegen, de tweede kon alleen naar het bewegende mobile kijken. Als de tweede baby de beweging van het mobile kon aansturen, ontdekte hij niet meer dat hij invloed kon uitoefenen op het mobile.

In de dagelijkse praktijk is het concept van "aangeleerde hulpeloosheid" belangrijk bij de opvoeding van kinderen, maar ook in ziekenhuizen, verpleeghuizen, gevangenissen, in rampsituaties als hongersnood en oorlog en in concentratiekampen.

Niet ieder mens reageert op hulpeloosheid met passiviteit en depressie. Dit is mede afhankelijk van de attributie, dat wil zeggen waar iemand de oorzaak van zijn lijden zoekt: in zichzelf of buiten zichzelf.

Zie ook
Conditionering
Motivatie

Psychologie


text:
Pakistan's Kartarpur corridor initiative
Posted on December 4, 2018 By Maroof Raza
The proposal for the Kartarpur corridor was floated by India more than two decades ago and emphasised by Mr Vajpayee on his trip to Lahore.
The recent excitement at the formal inauguration of the Kartarpur corridor to facilitate a short and easy passage for Indian Sikh pilgrims to the holiest Sikh shrine (Gurudwara Nankana Sahib) that lies in Pakistan, led many in India to suggest that this could be a bridge to eternal peace (as Navjot Sidhu did), between the two countries. India's prime minister had even suggested that the initiative was akin to bringing down of the 'Berlin wall' for the region. But thereafter India's foreign minister came out strongly against any assumption that the opening of the corridor could see a thaw in bilateral ties. It has raised questions on whether Mr Modi's government was divided over what to do with Pakistan. On the other hand, Pakistan's prime minister went on to assert that his government, all political parties in Pakistan, and Pakistan's Army were all on the same page on ties with Pakistan. But the question is: "what is it that they've agreed on?". Certainly not over a settlement on Kashmir, on an as is basis; a position that India was willing to take both after the 1965 and 1971 wars. Because if you take the Kashmir dispute away from Pakistan, it'll be left rudderless.
In fact, the proposal for the Kartarpur corridor was floated by India more than two decades ago, and emphasized by Mr Vajpayee on his trip to Lahore. Having dragged its feet for all these years, Pakistan has suddenly gone ahead with the inauguration now, after Imran Khan was sworn in as their PM. And though it is commonly believed that Imran is the army's man in the hot seat, there are clearly other reasons for formalizing this proposal on 25th November. For one, it was announced a day prior to the tenth anniversary of the gruesome 26/11 attacks in Mumbai that was carried out by Pakistan and its proxies. The expected media hype over the announcement of the setting up of the corridor would help overshadow the negative press coverage – at least in India – that Pakistan's 'deep state' was expecting. And the other diplomatic benefit, hoped Pakistan, was that the Kartarpur initiative will allow it to come out looking good – and not the epicentre of terrorism in the region- by seeking talks with India, as Imran Khan did at the grand function organised for the event. (Strangely, Pakistan's establishment had expected India to ignore their support to pro-Khalistan rabid anti-India baiters at this very venue, both prior to and during the event!).
Kartarpur corridor Pakistan's Prime Minister Imran Khan, cricketer-turned-Indian politician Navjot Singh Sidhu, minister for food processing industries Harsimrat Kaur Badal during ground breaking ceremony for Kartarpur corridor | Photo Credit: PTI
If there is one thing that Imran Khan had wanted with his 'faustian bargain' with the Pakistan Army's brass hats, (when they made it known that he was 'elected' to his post, even before the voting was done), was to enjoy the importance he expected to get, as prime minister of a nuclear weapon state. But what he has ended up seeking is desperately needed a financial bailout from the IMF, but that looks unlikely for now. With its forex reserves down to less than $7billion, Imran managed some reprieve with a Saudi promise of $3billion cash and other $3billion of oil. More could come quietly, as some experts suspect. Pakistan has provided military units in the past, to the Saudis and is said to stock a reasonable nuclear arsenal for that Gulf nation, which can be called to use, if Iran comes out formally with its own nukes. And Islamabad's other hope lies with Beijing, with Pakistan now all but a vassal state, that China controls in so many ways. It virtually funds all major projects in Pakistan now – at unbearably high rates of interest, as Imran knows – from dams in the northern areas of POK to fibre optics cables that connect the Chinese military in Kashgar to GHQ Rawalpindi, all part of the now $60 billion-plus CPEC (China Pakistan Economic Corridor), the flagship part of Chinese President Xi Jinping's Belt and Road Initiative (earlier OBOR). But China has linked Imran's call for financial assistance to 15 more projects within Pakistan as part of the CPEC. Ironically it was the CPEC projects that Imran and his advisers had been openly critical off, as Imran was sworn in.
Therefore, an engagement with India would not only ease Pakistan's sense of isolation but help it convey to the world that even India was willing to overlook its own charges of Pakistan being the epicentre of terrorism and that it wasn't doing enough to confront the menace of terror on its soil. But India apart, much of the international community led by the US has now had enough of Pakistan's devious games. Pakistan was thus put on the 'grey list' by a UN-approved body, the Financial Action Task Force (FATF) – that monitors funding of terror groups – and its members have been insisting that Pakistan does more, to move out of its grey-list or could it be put on the FATF 'blacklist', for being a state sponsor of terrorism. That Imran Khan cannot do, and his Armymen won't do. Anti-India terror groups within Pakistan are both an asset and a liability for them, but more importantly, Pakistan's Army is now unable to confront them militarily, since the public support they enjoy will have enormous social implications, if they do so.
Pakistan and the price of sponsoring terrorismOlder Post
Rafale deal: The tussle about the apex court's orderNewer Post
Posted on October 4, 2015 By dev
The mighty Indian retaliation
All through the month of September, India's military establishment celebrated as the 50th year of—what is now being


text:
Pyramidion is a 5 track EP by English band Ozric Tentacles. It was released in 2001 on Snapper Music. Only the title track on this EP is a new song; the rest are older tunes recorded live at the Boardwalk in Sheffield, England.

Track listing
 "Pyramidion" - (6:21)
 "Xingu" (live) - (7:42)
 "Pixel Dream" (live) - (12:12)
 "Sultana Detrii" (live) - (9:18)
 "Aramanu" (live) - (5:50)

Personnel
 Ed Wynne – guitars, synthesizers, samps
 Seaweed (Christopher Lenox-Smith) – synthesizers
 John Egan – flutes
 Zia Geelani – bass
 Johnny Morgan – drums
 Rad (Conrad Prince) – drums

Trivia
A Pyramidion is the uppermost piece of an Egyptian pyramid.

References

Ozric Tentacles albums
2001 EPs