FTY720 decreases ceramides levels in the brain and prevents memory impairments in a mouse model of familial Alzheimer's disease expressing APOE4.

The protection mediated by the bioactive sphingolipid sphingosine-1-phosphate (S1P) declines during Alzheimer's disease (AD) progression, especially in patients carrying the apolipoprotein E ε4 (APOE4) isoform. The drug FTY720 mimics S1P bioactivity, but its efficacy in treating AD is unclear. Two doses of FTY720 (0.1 mg / kg and 0.5 mg / kg daily) were given by oral gavage for 15 weeks to transgenic mouse models of familial AD carrying human apolipoprotein E (APOE) APOE3 (E3FAD) or APOE4 (E4FAD). After 12 weeks of treatment, animals were subjected to behavioral tests for memory, locomotion, and anxiety. Blood was withdrawn at different time points and brains were collected for sphingolipids analysis by mass spectrometry, gene expression by RT-PCR and Aß quantification by ELISA. We discovered that low levels of S1P in the plasma is associated with a higher probability of failing the memory test and that FTY720 prevents memory impairments in E4FAD. The beneficial effect of FTY720 was induced by a shift of the sphingolipid metabolism in the brain towards a lower production of toxic metabolites, like ceramide d18:1/16:0 and d18:1/22:0, and reduction of amyloid-ß burden and inflammation. In conclusion, we provide further evidence of the druggability of the sphingolipid system in AD.

Population structure and connectivity in the Mediterranean sponge Ircinia fasciculata are affected by mass mortalities and hybridization.

Recent episodes of mass mortalities in the Mediterranean Sea have been reported for the closely related marine sponges Ircinia fasciculata and Ircinia variabilis that live in sympatry. In this context, the assessment of the genetic diversity, bottlenecks and connectivity of these sponges has become urgent in order to evaluate the potential effects of mass mortalities on their latitudinal range. Our study aims to establish (1) the genetic structure, connectivity and signs of bottlenecks across the populations of I. fasciculata and (2) the hybridization levels between I. fasciculata and I. variabilis. To accomplish the first objective, 194 individuals of I. fasciculata from 12 locations across the Mediterranean were genotyped at 14 microsatellite loci. For the second objective, mitochondrial cytochrome c oxidase subunit I sequences of 16 individuals from both species were analyzed along with genotypes at 12 microsatellite loci of 40 individuals coexisting in 3 Mediterranean populations. We detected strong genetic structure along the Mediterranean for I. fasciculata, with high levels of inbreeding in all locations and bottleneck signs in most locations. Oceanographic barriers like the Almeria-Oran front, North-Balearic front and the Ligurian-Thyrrenian barrier seem to be impeding gene flow for I. fasciculata, adding population divergence to the pattern of isolation by distance derived from the low dispersal abilities of sponge larvae. Hybridization between both species occurred in some populations that might be increasing genetic diversity and somewhat palliating the genetic loss caused by population decimation in I. fasciculata.

Criterion-related validity of the figure-of-eight method of measuring ankle edema.

STUDY DESIGN: Single-session, prospective, repeated-measures design. OBJECTIVE: To determine intratester reliability and criterion-related validity of the figure-of-eight method of measuring ankle edema. BACKGROUND: The measurement of edema is often necessary when physical therapists assess patients with ankle injuries. The figure-of-eight method has been shown to be a reliable method in measuring the size of ankles in subjects without edema but not in subjects with ankle swelling. The validity of this method of measurement has not been established. METHODS AND MEASURES: The subjects (mean age, 22.7 +/- 4.4 years) were 7 men and 8 women with observable ankle edema secondary to acute or chronic ankle sprains or injury to the lower extremity. Three figure-of-eight measurements were taken by one tester. These measurements were correlated to measurements taken by another tester using a foot volumeter. RESULTS: The intraclass correlation coefficient (ICC [2,1]) for the figure-of-eight measurements was 0.99. The Pearson Product Moment correlation coefficients between the figure-of-eight measurements and the first volumetric measurement were 0.89 (first figure-of-eight), 0.88 (second figure-of-eight), 0.91 (third figure-of-eight), and 0.90 (mean of all 3 figure-of-eight measurements). CONCLUSION: The figure-of-eight method was demonstrated to be a reliable and valid indirect method of measuring ankle edema in individuals with edema secondary to sprains or other lower-extremity musculoskeletal disorders.