Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina

Clinical epidemiological studies have revealed relatively weak, yet statistically significant, associations between dyslipidemia/dyslipoproteinemia and diabetic retinopathy (DR). Recent large interventional studies, however, demonstrated an unexpectedly robust efficacy of fenofibrate on the development of DR, possibly independent of plasma lipids. To unify the apparent discrepancies, we hypothesize that plasma lipoproteins play an indirect but important role in DR, contingent on the integrity of the blood-retina-barrier (BRB). In retinas with an intact BRB, plasma lipoproteins may be largely irrelevant; however, important effects become operative after the BRB is impaired in diabetes, leading to lipoprotein extravasation and subsequent modification, hence toxicity to the neighbouring retinal cells. In this hypothesis, BRB leakage is the key, plasma lipoprotein concentrations mainly modulate its consequences, and fenofibrate has intra-retinal actions. This review summarizes our current knowledge of the direct effects and mechanisms of modified lipoproteins on retinal cells and their potential contribution to the pathogenesis of DR.

Political Posturing or Real Powers: Control of Genetically Modified Crops by the Member States and their Regions

The cultivation of genetically modified (GM) crops in the EU is highly harmonised, involving a central authorisation procedure that aims to ensure a high level of environmental and human health protection. However conflicts over authority persist and the Commission has responded to a combination of internal and external pressures with a more flexible approach to coexistence, a proposed opt-out clause and recently a promise by the head of the Commission to review the existing EU GM legislative regime, providing an opportunity to consider and suggest paths of development. In light of the significance of multilevel governance and subsidiarity for GM cultivation, this paper considers the policy-making powers of the Member States and subnational regions in this regime, focussing upon post-authorisation options in particular. A number of core mechanisms exist, including voluntary measures, safeguard clauses, coexistence measures, a proposed express opt-out and Article 4(2) TEU on ‘national identity. These mechanisms are examined in light of the goals and challenges of multilevel governance, in order to consider whether the relevant powers are located at the appropriate level. Overall, it is apparent that the developments occurring at the EU level are strengthening multilevel governance, but with significant opportunities to improve it further through focussing on the supporting roles and the regional levels in particular.

Biofilm Eradication Kinetics of the Ultrashort Lipopeptide C12-OOWW-NH2 Utilizing a Modified MBEC Assay™

In this study, we report the antimicrobial planktonic and biofilm kill kinetics of ultrashort cationic lipopeptides previously demonstrated by our group to have a minimum biofilm eradication concentration (MBEC) in the microgram per mL (μg/mL) range against clinically relevant biofilm-forming micro-organisms. We compare the rate of kill for the most potent of these lipopeptides, dodecanoic (lauric) acid-conjugated C₁₂-Orn-Orn-Trp-Trp-NH₂ against the tetrapeptide amide H-Orn-Orn-Trp-Trp-NH₂ motif and the amphibian peptide Maximin-4 via a modification of the MBEC Assay™ for Physiology & Genetics (P&G). Improved antimicrobial activity is achieved upon N-terminal lipidation of the tetrapeptide amide. Increased antimicrobial potency was demonstrated against both planktonic and biofilm forms of Gram-positive micro-organisms. We hypothesize rapid kill to be achieved by targeting of microbial membranes. Complete kill against established 24-h Gram-positive biofilms occurred within 4 h of exposure to C₁₂-OOWW-NH₂ at MBEC values [methicillin-resistant Staphylococcus epidermidis (ATCC 35984): 15.63 μg/mL] close to the values for the planktonic minimum inhibitory concentration (MIC) [methicillin-resistant Staphylococcus epidermidis (ATCC 35984): 1.95 μg/mL]. Such rapid kill, especially against sessile biofilm forms, is indicative of a reduction in the likelihood of resistant strains developing with the potential for quicker resolution of pathogenic infection. Ultrashort antimicrobial lipopeptides have high potential as antimicrobial therapy.

Role of capsular modified heptose in the virulence of Campylobacter jejuni

The Campylobacter jejuni capsular polysaccharide is important for virulence and often contains a modified heptose. In strain ATCC 700819 (a.k.a. NCTC 11168), the modified heptose branches off from the capsular backbone and is directly exposed to the environment. We reported previously that the enzymes encoded by wcaG, mlghB and mlghC are involved in heptose modification. Here, we show that inactivation of any of these genes leads to production of capsule lacking modified heptose and alters the transcription of other capsule modification genes differentially. Inactivation of mlghB or mlghC, but not of wcaG, decreased susceptibility to bile salts and abrogated invasion of intestinal cells. All mutants showed increased sensitivity to serum killing, especially wcaG::cat, and had defects in colonization and persistence in chicken intestine, but did not show significant differences in adhesion, phagocytosis and intracellular survival in murine macrophages. Together, our findings suggest that the capsular heptose modification pathway contributes to bacterial resistance against gastrointestinal host defenses and supports bacterial persistence via its role in serum resistance and invasion of intestinal cells. Our data further suggest a dynamic regulation of expression of this pathway in the gastrointestinal tract.

Regulating Genetically Modified Organisms in Ireland – Laissez faire approach?

This chapter examines the legal framework applicable to genetically modified organisms (GMOs) in Ireland, bearing in mind the limited presence of GMOs. As a member of the European Union (EU), a specific, process-based regime applies regarding the authorisation and regulation of GMOs. This is intended to ensure a high level of environmental and human health protection and also enable producer and consumer choice. This regime is highly harmonized, but allows some flexibility regarding its implementation and, soon, the potential to opt-out from cultivation in part or entirely. Although, Ireland has only legislated on the area to the extent and in the manner required by the EU, it may avail of the opt-out in future – understandable in light of the lack of any cultivation currently and the green image of Ireland.
Complementary horizontal legislation and common law principles, relevant to labelling and varying forms of liability, deal with most issues that might arise quite comprehensively. However, they are quite complicated, overlapping and untailored and it is worth considering whether specific legislation should be developed to deal with liability related to GMOs.
Overall, Ireland holds varying stances to different forms of GMOs, with the greatest acceptance and use of GM-feed for pragmatic reasons. It has not developed a specific Irish approach, copy-pasting EU legislation and relying upon existing law to deal with any issues. This is understandable in light of the high level of harmonization and limited presence of GMOs in Ireland, but nonetheless will need to be developed as the availability of GMOs increases.

Attaining Subsidiarity-Based Multilevel Governance of Genetically Modified Cultivation?

The cultivation of genetically modified (GM) crops in the EU is highly harmonised, but with persisting conflicts over authority. The Commission responded to internal and external pressures with a more flexible approach to coexistence, a proposed opt-out clause and a promise to review the existing EU GM regime, providing an opportunity to consider and suggest paths of development. This article considers the post-authorisation policy-making powers of Member States and subnational regions, in light of subsidiarity-based multilevel governance. It considers the different approaches to risk-centred issues and more general policy choices. Overall, the developments occurring at the EU level are strengthening subsidiarity-based multilevel governance within the GM cultivation regime, but with significant opportunities to improve it further through focussing on the complementary powers, coordination and the regional levels in particular.