Dexamethasone treatment in the newborn rat: fatty acid profiling of lung, brain, and serum lipids.

Dexamethasone is used as treatment for a variety of neonatal syndromes, including respiratory distress. The present study utilized the power of comprehensive lipid profiling to characterize changes in lipid metabolism in the neonatal lung and brain associated with dexamethasone treatment and also determined the interaction of dexamethasone with hypoxia. A 4-day tapering-dose regimen of dexamethasone was administered at 0800 on postnatal days 3 (0.5 mg/kg), 4 (0.25 mg/kg), 5 (0.125 mg/kg), and 6 (0.05 mg/kg). A subgroup of rats was exposed to hypoxia from birth to 7 days of age. Dexamethasone treatment elicited numerous specific changes in the lipid profile of the normoxic lung, such as increased concentrations of saturated fatty acids in the phosphatidylcholine and cholesterol ester classes. These increases were more profound in the lungs of hypoxic pups. Additional increases in cardiolipin concentrations were also measured in lungs of hypoxic pups treated with dexamethasone. We measured widespread increases in serum lipids after dexamethasone treatment, but the effects were not equivalent between normoxic and hypoxic pups. Dexamethasone treatment in hypoxic pups increased 20:4n6 and 22:6n3 concentrations in the free fatty acid class of the brain. Our results suggest that dexamethasone treatment in neonates elicits specific changes in lung lipid metabolism associated with surfactant production, independent of changes in serum lipids. These findings illustrate the benefits of dexamethasone on lung function but also raise the potential for negative effects due to hyperlipidemia and subtle changes in brain lipid metabolism.     

Prepregnancy Obesity and Risk of Stillbirth in Viable Twin Gestations

We sought to estimate the impact of prepregnancy obesity on demise of one or both fetuses in twin gestations. We performed a retrospective cohort study using the Missouri maternally linked cohort files (years 1989–2005). Prepregnancy obesity was defined as a BMI ≥30. Outcomes of interest were stillbirth (intrauterine fetal death at ≥20 weeks' gestation) and demise of one (partial loss) or both (complete loss) fetuses, regardless of the cause. We used Cox Proportional Hazards with correction for intracluster correlation to obtain risk estimates. The overall stillbirth rate for twin gestations was 15.5/1,000 (18.4/1,000 vs. 14.5/1,000 in obese and normal weight mothers, respectively; P = 0.02). The rate for complete fetal loss was higher in obese mothers (8.3/1,000 vs. 5.6/1,000; P = 0.01) but was comparable for partial fetal loss (19.1/1,000 for obese vs. 16.3/1,000 for normal weight mothers; P = 0.1). Adjusted estimates confirmed these findings (adjusted hazards ratio (AHR) and 95% confidence interval (CI) = 1.31 (1.02–1.68) for stillbirth; AHR = 1.59; CI = 1.01–2.51) for complete loss; and AHR = 1.21; CI = 0.91–1.62) for partial loss. Subanalysis conducted on stillbirth showed that the risk associated with obesity was only elevated for same‐sex (AHR = 1.54; CI = 1.15–2.04) but not opposite‐sex twins (0.99; CI = 0.56–1.75). Our findings may find utility in counseling of obese women with twin gestations.     

Phylogenetic analysis of the outer-membrane-protein genes of Chlamydiae, and its implication for vaccine development

Examination of 18 complete and 6 partial sequences of the major outer- membrane protein from 24 chlamydiae isolates was used to reconstruct their evolutionary relationships. From this analysis, assuming that the clades with 100% bootstrap support are correct, come the following conclusions: (1) The tree of these sequences is not congruent with the phylogeny of the hosts, and thus host switching would seem to have occurred, thereby limiting the extent to which there has been coevolution of parasite and host. (2) The tree is also noncongruent with clustering by type of cell infected, thereby limiting the extent to which there has been coevolution of parasite and the cell type that it infects. (3) The tree is also noncongruent with clustering by the organ infected (eyes or genitalia), thereby limiting the extent to which there has been coevolution of parasite and the organ that it infects. (4) The tree is also noncongruent with genital strains arising from lymphogranuloma venereum strains. (5) The tree is also noncongruent with the geographic site at which the isolates were obtained, thereby limiting the extent of divergence explained by geographic separation. (6) There are estimated to be 185 amino acid positions that are invariable (as opposed to unvaried) in the major outer-membrane protein. There are 10 unvaried positions in the variable domains, of which 9 appear to be invariable, giving some reason to hope that development of a vaccine might be possible. (7) The rate of change of this protein is too small to see increased divergence over the time span of isolation of these genes, giving hope to any vaccine having longevity. Bootstrapping supports those portions of the tree on which the first five conclusions above depend. The picture that these results provide is more one of pathogen versatility than one of coevolutionary constraints. In addition, we examined 10 60-KDa, outer-membrane protein- 2 genes, all but one of which were from these same strains. The tree was not, among the trachomatis strains, congruent with the major-outer- membrane protein tree, suggesting that gene exchange could be occurring among strains. Moreover, there is an apparent slowdown in divergence in this gene, among the trachomatis strains.      

Substrate binding in protein-tyrosine phosphatase-like inositol polyphosphatases

Protein-tyrosine phosphatase-like inositol polyphosphatases are microbial enzymes that catalyze the stepwise removal of one or more phosphates from highly phosphorylated myo-inositols via a relatively ordered pathway. To understand the substrate specificity and kinetic mechanism of these enzymes we have determined high resolution, single crystal, x-ray crystallographic structures of inactive Selenomonas ruminantium PhyA in complex with myo-inositol hexa- and pentakisphosphate. These structures provide the first glimpse of a myo-inositol polyphosphatase-ligand complex consistent with its known specificity and reveal novel features of the kinetic mechanism. To complement the structural studies, fluorescent binding assays have been developed and demonstrate that the K(d) for this enzyme is several orders of magnitude lower than the K(m). Together with rapid kinetics data, these results suggest that the protein tyrosine phosphatase-like inositol polyphosphatases have a two-step, substrate-binding mechanism that facilitates catalysis.     

Evidence for the late MMN as a neurophysiological endophenotype for dyslexia

Dyslexia affects 5-10% of school-aged children and is therefore one of the most common learning disorders. Research on auditory event related potentials (AERP), particularly the mismatch negativity (MMN) component, has revealed anomalies in individuals with dyslexia to speech stimuli. Furthermore, candidate genes for this disorder were found through molecular genetic studies. A current challenge for dyslexia research is to understand the interaction between molecular genetics and brain function, and to promote the identification of relevant endophenotypes for dyslexia. The present study examines MMN, a neurophysiological correlate of speech perception, and its potential as an endophenotype for dyslexia in three groups of children. The first group of children was clinically diagnosed with dyslexia, whereas the second group of children was comprised of their siblings who had average reading and spelling skills and were therefore "unaffected" despite having a genetic risk for dyslexia. The third group consisted of control children who were not related to the other groups and were also unaffected. In total, 225 children were included in the study. All children showed clear MMN activity to/da/-/ba/contrasts that could be separated into three distinct MMN components. Whilst the first two MMN components did not differentiate the groups, the late MMN component (300-700 ms) revealed significant group differences. The mean area of the late MMN was attenuated in both the dyslexic children and their unaffected siblings in comparison to the control children. This finding is indicative of analogous alterations of neurophysiological processes in children with dyslexia and those with a genetic risk for dyslexia, without a manifestation of the disorder. The present results therefore further suggest that the late MMN might be a potential endophenotype for dyslexia.     

Western Palaearctic phylogeography of an inquiline oak gall wasp,Synergus umbraculus

Insect‐induced galls on plants comprise species‐rich but self‐contained communities of herbivores and natural enemies. In the present study, we focus on galls induced by cynipid gall wasps on oaks, and on the least‐known trophic level that these galls contain: inquilines. These insects, also cynipids, feed on gall tissue and are an abundant but taxonomically poorly understood part of an otherwise well‐studied system. We used DNA sequence data to examine spatial patterns in the genetic diversity of Synergus umbraculus Olivier 1791 (Hymenoptera: Cynipidae: Synergini), a widespread species attacking many host galls across the Western Palaearctic. Analysis of 239 cytochrome b sequences revealed eight haplogroups showing significant phylogeographic pattern across the Western Palaearctic, corresponding to putative glacial refugia in Iberia, Central Europe, Turkey, and Iran. There were significant genetic discontinuities across the Pyrenees and the Anatolian diagonal but no impact of the Alps, suggesting that significant discontinuities have biotic rather than physical causes. Detailed analysis of sites in the Carpathian Basin reveal a high diversity and low spatial structure, and identify Central Europe as the source of colonists for Quaternary colonization of Germany, France, and Britain. We found no evidence for host‐associated differentiation of S. umbraculus lineages associated with the most common cynipid host galls, suggesting frequent shifts within the host gall assemblage by inquiline lineages. © 2011 The Linnean Society of London, Biological Journal of the Linnean Society, 2011, 102 , 750–764.     

Are we ready for therapeutic drug monitoring of biologic therapeutics?

In the previous issue of Arthritis Research & Therapy, Ducourau and colleagues report that they retrospectively detected anti-infliximab antibodies in 21% of patients with rheumatic diseases. Patients with anti-infliximab antibodies had lower serum drug concentrations. These findings contribute to the existing evidence of immunogenicity of biologicals and its clinical relevance. We argue for therapeutic drug monitoring to optimize treatment response.