Augmented expression and activity of extracellular matrix-degrading enzymes in regions of low endothelial shear stress colocalize with coronary atheromata with thin fibrous caps in pigs

Background- The molecular mechanisms that determine the localized formation of thin-capped atheromata in the coronary arteries remain unknown. This study tested the hypothesis that low endothelial shear stress augments the expression of matrix-degrading proteases and thereby promotes the formation of thin-capped atheromata. Methods and Results- Intravascular ultrasound-based, geometrically correct 3-dimensional reconstruction of the coronary arteries of 12 swine was performed in vivo 23 weeks after initiation of diabetes mellitus and a hyperlipidemic diet. Local endothelial shear stress was calculated in plaque-free subsegments of interest (n=142) with computational fluid dynamics. At week 30, the coronary arteries (n=31) were harvested and the same subsegments were identified. The messenger RNA and protein expression and elastolytic activity of selected elastases and their endogenous inhibitors were assessed. Subsegments with low preceding endothelial shear stress at week 23 showed reduced endothelial coverage, enhanced lipid accumulation, and intense infiltration of activated inflammatory cells at week 30. These lesions showed increased expression of messenger RNAs encoding matrix metalloproteinase-2, -9, and -12, and cathepsins K and S relative to their endogenous inhibitors and increased elastolytic activity. Expression of these enzymes correlated positively with the severity of internal elastic lamina fragmentation. Thin-capped atheromata developed in regions with lower preceding endothelial shear stress and had reduced endothelial coverage, intense lipid and inflammatory cell accumulation, enhanced messenger RNA expression and elastolytic activity of MMPs and cathepsins, and severe internal elastic lamina fragmentation. Conclusions- Low endothelial shear stress induces endothelial discontinuity and accumulation of activated inflammatory cells, thereby augmenting the expression and activity of elastases in the intima and shifting the balance with their inhibitors toward matrix breakdown. Our results provide new insight into the mechanisms of regional formation of plaques with thin fibrous caps.     

WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus

Recent spread of avian influenza A (H5N1) virus to poultry and wild birds has increased the threat of human infections with H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specific recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefits, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal influenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel influenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely.     

Sinus floor augmentation with recombinant human growth and differentiation factor-5 (rhGDF-5): a pilot study in the Goettingen miniature pig comparing autogenous bone and rhGDF-5

Aim: The aim of this study was to test the hypothesis that recombinant human growth and differentiation factor-5 (rhGDF-5) in combination with a β-tricalcium phosphate (β-TCP) scaffold material results in superior bone formation in sinus floor augmentations in miniature pigs compared with a particulated autogenous bone graft combined with the scaffold material.
Material and methods: Six adult female Goettingen minipigs underwent a maxillary sinus floor augmentation procedure. In a split-mouth design, the sinus floors were augmented with β-TCP mixed with autogenous cortical bone chips, in a ratio of approximately 1 : 1, on one side. The contralateral test site was augmented using β-TCP coated with two concentrations of rhGDF-5 (400 μg rhGDF-5/g β-TCP or 800 μg rhGDF-5/g β-TCP; three animals in each case). Simultaneously, one dental implant was inserted into each sinus floor augmentation. After 12 weeks, a histological and histomorphometric assessment of non-decalcified histological specimens was made.
Results: There were significantly higher mean values of volume density of newly formed bone using β-TCP coated with two concentrations of rhGDF-5 (400 μg: 32.9%; 800 μg: 23.9%) than with the corresponding control (autogenous bone/β-TCP) (14.6%, 12.9%) ( P =0.012, P =0.049). The bone-to-implant contact rates (BIC) were significantly enhanced in test sites (400 μg: 84.2%; 800 μg: 69.8%) compared with the corresponding control sites (24.8%, 40.8%) ( P =.027, P =.045).
Conclusion: rhGDF-5 delivered on β-TCP significantly enhanced bone formation compared with β-TCP combined with autogenous bone in sinus lift procedures in miniature pigs.