An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. METHODS: This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. RESULTS: Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (-0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score -5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

Neutrophil transepithelial migration: role of toll-like receptors in mucosal inflammation

The symptomatic phases of many inflammatory diseases are characterized by migration of large numbers of neutrophils (PMN) across a polarized epithelium and accumulation within a lumen. For example, acute PMN influx is common in diseases of the gastrointestinal system (ulcerative colitis, Crohn's disease, bacterial enterocolitis, gastritis), hepatobiliary system (cholangitis, acute cholecystitis), respiratory tract (bronchial pneumonia, bronchitis, cystic fibrosis, bronchiectasis), and urinary tract (pyelonephritis, cystitis). Despite these observations, the molecular basis of leukocyte interactions with epithelial cells is incompletely understood. In vitro models of PMN transepithelial migration typically use N-formylated bacterial peptides such as fMLP in isolation to drive human PMNs across epithelial monolayers. However, other microbial products such as lipopolysaccharide (LPS) are major constituents of the intestinal lumen and have potent effects on the immune system. In the absence of LPS, we have shown that transepithelial migration requires sequential adhesive interactions between the PMN beta2 integrin CD11b/CD18 and JAM protein family members. Other epithelial ligands appear to be abundantly represented as fucosylated proteoglycans. Further studies indicate that the rate of PMN migration across mucosal surfaces can be regulated by the ubiquitously expressed transmembrane protein CD47 and microbial-derived factors, although many of the details remain unclear. Current data suggests that Toll-like receptors (TLR), which recognize specific pathogen-associated molecular patterns (PAMPs), are differentially expressed on both leukocytes and mucosal epithelial cells while serving to modulate leukocyte-epithelial interactions. Exposure of epithelial TLRs to microbial ligands has been shown to result in transcriptional upregulation of inflammatory mediators whereas ligation of leukocyte TLRs modulate specific antimicrobial responses. A better understanding of these events will hopefully provide new insights into the mechanisms of epithelial responses to microorganisms and ideas for therapies aimed at inhibiting the deleterious consequences of mucosal inflammation.

Failure of neutrophil migration toward infectious focus in severe sepsis: a critical event for the outcome of this syndrome

Sepsis is a systemic inflammatory response commonly caused by bacterial infection. We demonstrated that the outcome of sepsis induced by cecal ligation and puncture (CLP) correlates with the severity of the neutrophil migration failure towards infectious focus. Failure appears to be due to a decrease in the rolling and adhesion of neutrophil to endothelium cells. It seems that neutrophil migration impairment is mediated by the circulating inflammatory cytokines, such as TNF-alpha and IL-8, which induce the nitric oxide (NO) production systemically. It is supported by the fact that intravenous administration of these cytokines reduces the neutrophil migration induced by different inflammatory stimuli, and in severe sepsis the circulating concentrations of the cytokines and chemokines are significantly increased. Moreover, the neutrophil migration failure and the reduction in the rolling/adhesion were not observed in iNOS-/- mice and, aminoguanidine prevented this event. We also demonstrated that the failure of neutrophil migration is a Toll-4 receptor (TLR4) dependent mechanism, since it was not observed in TLR4 deficient mice. Furthermore, it was also observed that circulating neutrophils obtained from septic patients present failure of neutrophil chemotaxis toward fMLP, IL-8, and LTB4 and an increased in sera concentrations of NO3 and cytokines. In conclusion, we demonstrated that, in sepsis, failure of neutrophil migration is critical for the outcome and that NO is involved in the process.

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships

Ireland, as a small, open European economy, relies fundamentally on international engagement. An internationalised education system in Ireland has a crucial role to play in maintaining Ireland’s international profile and attractiveness by educating the next generation of leaders, entrepreneurs and decision-makers in our partner-countries, by giving our own students the intercultural expertise demanded in the global economy, and by enhancing the direct link with Ireland for members of our global diaspora who choose to come home to study. The High-Level Group on International Education takes the view that, from a national perspective, the most compelling rationale for internationalisation is investment in future global relationships: with students educated in Ireland who will become our advocates overseas, with educational institutions that will be the research and teaching partners of the future, and with the countries that will be Ireland’s next trading and business partners

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report

Ireland, as a small, open European economy, relies fundamentally on international engagement. An internationalised education system in Ireland has a crucial role to play in maintaining Ireland’s international profile and attractiveness by educating the next generation of leaders, entrepreneurs and decision-makers in our partner-countries, by giving our own students the intercultural expertise demanded in the global economy, and by enhancing the direct link with Ireland for members of our global diaspora who choose to come home to study. The High-Level Group on International Education takes the view that, from a national perspective, the most compelling rationale for internationalisation is investment in future global relationships: with students educated in Ireland who will become our advocates overseas, with educational institutions that will be the research and teaching partners of the future, and with the countries that will be Ireland’s next trading and business partners. Internationalisation also provides a means of enhancing the quality of learning, teaching and research in Ireland and makes a significant contribution to our broader ambition as a global innovation hub.

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Arabic

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Arabic. Provided by the Department of Education and Skills, Ireland.

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Chinese

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Chinese. Provided by the Department of Education and Skills, Ireland.

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Korean

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Korean. Provided by the Department of Education and Skills, Ireland.

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Portuguese

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Portuguese. Provided by the Department of Education and Skills, Ireland.

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Russian

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Russian. Provided by the Department of Education and Skills, Ireland.

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Spanish

Ireland's International Education Strategy 2010 - 2015: Investing in Global Relationships Summary Report - Spanish. Provided by the Department of Education and Skills, Ireland.

Review of Ireland's International Education Strategy 2013 - consultation Paper

Investing in Global Relationships: Ireland’s International Education Strategy 2010 – 2015 was published in September 2010. Significant progress has been made in implementing this strategy, to complement and support the work undertaken at institutional level: - A strong national brand is now in place: Education in Ireland, managed by Enterprise Ireland. - There is much closer alignment between education and immigration policies. - A new Government of Ireland Scholarship has been established, managed by the Higher Education Authority. - An International Education Marketing Fund has been developed which allows institutions to collaborate in Enterprise Ireland- led national marketing initiatives. - Promotional efforts are taking place in the priority markets of the USA, Brazil, China, India, SE Asia and the Gulf. Ministers have visited each of the priority markets in the last two years. - Ireland is participating at national level in major international scholarship schemes such as Science Without Borders (Brazil) and the King Abdullah Scholarship Programme (Saudi Arabia). - Statutory provision is now in place for an international education mark and code of practice, which will be rolled out in 2014 by Qualifications and Quality Assurance Ireland (QQI). - International student numbers have risen in priority sectors: 14% growth in the English language sector and 9% growth in higher education since 2010. - Ireland’s international education offering has also diversified, including with increasingly significant levels of cross- border provision. However, global demand for education continues to change rapidly. There continues to be a massive expansion in demand for education around the world, particularly in emerging markets with growing middle classes.

Regulatory Reform of the International Education Sector and the Student Immigration Regime

Ireland has a strong reputation for delivery of high-quality education services both to our own citizens and those who come here from abroad. A degree from an Irish university, Institute of Technology or high-quality private sector provider is an indicator of significant educational achievement, highly valued by our students and employers alike. Ireland is also a specialist in high-quality English Language tuition. Many thousands of students from the EU and around the world come to Ireland for full-time or short-term programmes.