Crystal structure of human PEDF, a potent anti-angiogenic and neurite growth-promoting factor

Pigment epithelium-derived factor (PEDF), a noninhibitory member of the serpin superfamily, is the most potent inhibitor of angiogenesis in the mammalian ocular compartment. It also has neurotrophic activity, both in the retina and in the central nervous system, and is highly up-regulated in young versus senescent fibroblasts. To provide a structural basis for understanding its many biological roles, we have solved the crystal structure of glycosylated human PEDF to 2.85 A. The structure revealed the organization of possible receptor and heparin-binding sites, and showed that, unlike any other previously characterized serpin, PEDF has a striking asymmetric charge distribution that might be of functional importance. These results provide a starting point for future detailed structure/function analyses into possible mechanisms of PEDF action that could lead to development of therapeutics against uncontrolled angiogenesis.     

Outside-in

In dermatology probiotic microorganisms have primarily been used orally for the prophylaxis and treatment of atopic disorders. In contrast to the successes achieved for gastrointestinal disorders, positive effects for atopic dermatitis only have been found in a few studies. New insights could now fundamentally change the impact of probiotics on dermatology. Probiotics are – like microflora of the skin – non-pathogenic microbes, which do not induce inflammatory responses in the skin. Common pathways for probiotics, non-pathogenic microbes, and microflora are characterized, in order to facilitate their more effective therapeutic use. These microbes display a majority of their effects directly at the site of application and thereby induce natural defense mechanisms. However, promotion of immunological tolerance is just as important in producing positive effects. Tolerance of the resident flora on surface organs developed during evolution and the mechanisms of action are multifaceted. Therefore, the topical application of probiotics and non-pathogenic microbes for prophylaxis and therapy of overwhelming cutaneous pro-inflammatory immune reactions is very promising. Results of recent clinical trials already have demonstrated the efficacy of this new therapeutic concept.     

MR imaging of facial nerve enhancement in Bell palsy or after temporal bone surgery

The authors evaluated magnetic resonance (MR) images obtained with intravenously administered gadolinium in ten patients who had facial paralysis and no facial nerve tumor. In patients with either Bell palsy (four patients) or facial paralysis after temporal bone surgery (six patients), intratemporal facial nerve enhancement was seen. Facial nerve enhancement on MR images proved to be a nonspecific finding.     

A study of adaptive responses in cell signaling in migraine and cluster headache: correlations between headache type and changes in gene expression

The project was an investigation into whether changes in the expression of G-proteins underlie altered cell signaling in migraine and cluster headache. The basis for this assumption is that altered physiological responses are seen in migraineurs and that differences in cell signaling are detected biochemically in various cell types isolated from peripheral blood. Levels of three G-protein mRNAs—Gsα, Giα, and Gqα were quantified in lymphocytes from clinically well-defined migraine and cluster headache patients and correlated with headache type and influence of drug treatment. Giα mRNA was reduced by 50% in all migraine patients compared with control subjects; similarly in patients with or without aura, in patients with a migraine headache at the time of sampling, and patients in a quiescent state. No reduction in the levels of Gsα or Gqα mRNA were seen in migraine patients. A smaller reduction was seen in cluster headache patients, most marked in those without medication. Levels of Gsα. mRNA were significantly reduced in cluster headache patients compared with migraine patients. The marked down-regulation of Giα mRNA in migraine, whether quiescent or acute, indicates either an adaptive response to headache in this group of patients or that low levels of Giα mRNA make individuals more susceptible to migraine.     

Using non-negative matrix factorization for single-trial analysis of fMRI data

The analysis of single trials of an fMRI experiment is difficult because the BOLD response has a poor signal to noise ratio and is sometimes even inconsistent across trials. We propose to use non-negative matrix factorization (NMF) as a new technique for analyzing single trials. NMF yields a matrix decomposition that is useful in this context because it elicits the intrinsic structure of the single-trial data. The results of the NMF analysis are then processed further using clustering techniques. In addition to analyzing single trials in one brain region, the method is also suitable for investigating interdependencies between trials across brain regions. The method even allows to analyze the effect that a trial has on a subsequent trial in a different region at a significant temporal offset. This distinguishes the present method from other methods that require interdependencies between brain regions to occur nearly simultaneously. The method was applied to fMRI data and found to be a viable technique that may be superior to other matrix decomposition methods for this particular problem domain.     

The effect of hypotonicity, glutamine, and glycine on red cell preservation

BACKGROUND : Red cells (RBCs) stored in hypo-os-molar additive solutions with the same concentrations of adenine, dextrose, mannitol, and sodium chloride and varied amounts of ammonium, phosphate, glycerol, and glutamine were better preserved than RBCs in the standard additive solution (Adsol). Cell swelling occurred in all the experimental additives. This observation prompted the evaluation of glutamine and glycine alone, as well as a combination of glutamine and glycine, all of which have been described as producing swelling of rat liver cells. STUDY DESIGN AND METHODS : Aliquots of RBCs were stored at 4°C in Adsol or experimental additive solutions (EASs) all containing adenine, 2 mM; dextrose, 110 mM; mannitol, 55 mM; and sodium chloride, 50 mM. EAS 42 had, in addition, glutamine, 10 mM; glycine 5 mM; and phosphate, 20 mM. EAS 43 had glutamine, 10 mM; glycine, 10 mM; and phosphate 20 mM. EAS 44 had glutamine, 10 mM; EAS 45 had glutamine, 10 mM, and phosphate, 20 mM; and EAS 46 had only glycine, 10 mM. At intervals, measurements were made of mean corpuscular volume, mean corpuscular hemoglobin concentration, morphology, ATP, hemolysis, supernatant potassium, ammonia, pH, and microvesicles shed. RESULTS : The initial mean corpuscular volumes were larger in all EASs than in Adsol, but the greatest difference was between EASs 44 and 46 (108 fL) and Adsol (86 fL) (p<0.001). The morphology scores were significantly better in all the EASs (p<0.04). The ATPs were significantly greater in all the EASs (p<0.001), and highest in those with phosphate. Potassium leakage and hemolysis were less in the EASs (p<0.001). The ammonia levels were higher in all the EASs than in Adsol, with the exception of EAS 46. During storage, the extracorpuscular and intracorpuscular pH levels were essentially identical. The shedding of microvesicles was greatly reduced in all the EASs. CONCLUSION : Cell swelling induced in RBCs after collection appears to improve preservation. Ammonia and phosphate enhance RBC ATP maintenance. Glycine decreases the formation of ammonia by RBCs stored in a hypotonic medium.