Regional and global impacts of the 2007 Port-of-Spain Declaration on noncommunicable diseases.

OBJECTIVE: To assess how well Caribbean regional institutions (RIs) met their commitments from the 2007 Port-of-Spain Summit (POSS) declaration on noncommunicable diseases (NCDs), and evaluate the POSS impact on the United Nations High-level Meeting (HLM) on NCDs in 2011 (2011 HLM), HLM NCD review in 2014 (2014 HLM), World Health Organization's 2025 NCD targets (2025 WHO), and 2030 Sustainable Development Goals (SDGs) agreed upon in 2015. METHODS: This study uses a method developed by the University of Toronto's Global Governance Program to measure institutions' compliance with commitments from a summit and the match with commitments from earlier summits. This approach was supplemented using data from published literature, primary documents, and semistructured key informant interviews to detail how and why Caribbean RIs met the 2007 POSS commitments, how the 2007 POSS commitments led to compliance, and how the 2007 POSS influenced international NCD commitments. RESULTS: Caribbean RIs implemented the 2007 POSS commitments better when they had more public legitimacy, when their missions aligned with those commitments, and when more resources were available to them. Implementation constraints arose from multiple, sometimes competing, interests of the decision-making and national implementing bodies of the Caribbean Community (CARICOM). Internationally, the early, expanding efforts of the POSS pioneers had an initially important but subsequently diminishing impact on the HLMs. CONCLUSIONS: For the Caribbean region, the Caribbean Public Health Agency should be funded to lead strengthened Caribbean RIs in coordinated action on NCDs. At the international level, the United Nations should embed NCDs in a "whole-of-global-governance" approach, monitor implementation annually, foster transregional partnerships on NCD-related themes, engage civil society, and support regular regional and global summits to enhance implementation and improvement, aimed at future HLMs on NCDs, the 2025 WHO targets, and the SDG NCD targets.

Cytolethal distending toxins require components of the ER-associated degradation pathway for host cell entry.

Intracellular acting protein exotoxins produced by bacteria and plants are important molecular determinants that drive numerous human diseases. A subset of these toxins, the cytolethal distending toxins (CDTs), are encoded by several Gram-negative pathogens and have been proposed to enhance virulence by allowing evasion of the immune system. CDTs are trafficked in a retrograde manner from the cell surface through the Golgi apparatus and into the endoplasmic reticulum (ER) before ultimately reaching the host cell nucleus. However, the mechanism by which CDTs exit the ER is not known. Here we show that three central components of the host ER associated degradation (ERAD) machinery, Derlin-2 (Derl2), the E3 ubiquitin-protein ligase Hrd1, and the AAA ATPase p97, are required for intoxication by some CDTs. Complementation of Derl2-deficient cells with Derl2:Derl1 chimeras identified two previously uncharacterized functional domains in Derl2, the N-terminal 88 amino acids and the second ER-luminal loop, as required for intoxication by the CDT encoded by Haemophilus ducreyi (Hd-CDT). In contrast, two motifs required for Derlin-dependent retrotranslocation of ERAD substrates, a conserved WR motif and an SHP box that mediates interaction with the AAA ATPase p97, were found to be dispensable for Hd-CDT intoxication. Interestingly, this previously undescribed mechanism is shared with the plant toxin ricin. These data reveal a requirement for multiple components of the ERAD pathway for CDT intoxication and provide insight into a Derl2-dependent pathway exploited by retrograde trafficking toxins.

The political process in global health and nutrition governance: the G8's 2010 Muskoka Initiative on Maternal, Child, and Newborn Health.

Why do informal, plurilateral summit institutions such as the Group of Eight (G8) major market democracies succeed in advancing costly public health priorities such as maternal, newborn, and child health (MNCH), even when the formal, multilateral United Nations (UN) system fails to meet such goals, when G8 governments afflicted by recession, deficit, and debt seek to cut expenditures, and when the private sector is largely uninvolved, despite the growing popularity of public-private partnerships to meet global health and related nutrition, food, and agriculture needs? Guided by the concert-equality model of G8 governance, this case study of the G8's 2010 Muskoka Initiative on MNCH traces the process through which that initiative was planned within Canada, internationally prepared through negotiations with Canada's G8 partners, produced at Muskoka by the leaders in June, multiplied in its results by the UN summit in September, and reinforced by the new accountability mechanism put in place. It finds that the Muskoka summit succeeded in mobilizing major money and momentum for MNCH. This was due to the initiative and influence of children-focused nongovernmental organizations (NGOs), working with committed individuals and agencies within the host Canadian government, as well as supportive public opinion and the help of those in the UN responsible for realizing its Millennium Development Goals. Also relevant were the democratic like-mindedness of G8 leaders and their African partners, the deference of G8 members to the host's priority, and the need of the G8 to demonstrate its relevance through a division of labor between it and the new Group of Twenty summit. This study shows that G8 summits can succeed in advancing key global health issues without a global shock on the same subject to galvanize agreement and action. It suggests that, when committed, focused NGOs and government officials will lead and the private sector will follow, but that there will be a lag in the implementation needed to obtain the intended results. The need to improve the accompanying accountability mechanisms to improve implementation, thus, remains.