Fetal growth restriction: adaptations and consequences

A range of pathophysiological factors can result in a perturbation or restriction of fetal growth, and the cardiovascular, neuroendocrine and metabolic adaptations of the fetus to these stimuli will depend on their nature, timing and intensity. The critical importance of these physiological adaptations for both immediate survival and long-term health outcomes has provided an impetus for experimental studies of the nature and consequences of specific fetal adaptations to a poor intrauterine environment. This review summarizes data from recent studies that have focused on the responses of the fetal cardiovascular, sympathoadrenal, hypothalamo-pituitary-adrenal and renin-angiotensin systems to experimental restriction of placental function in the sheep and discusses the consequences of these adaptations for fetal, neonatal and adult health.     

Ovine brain natriuretic peptide in cardiac tissues and plasma: effects of cardiac hypertrophy and heart failure on tissue concentration and molecular forms

It is well established that lymphoid dendritic cells (DC) play an important role in the immune system. Beside their role as potent inducers of primary T cell responses, DC seem to play a crucial part as major histocompatibility complex (MHC) class II+ "interdigitating cells" in the thymus during thymocyte development. Thymic DC have been implicated in tolerance induction and also by some authors in inducing major histocompatibility complex restriction of thymocytes. Most of our knowledge about thymic DC was obtained using highly invasive and manipulatory experimental protocols such as thymus reaggregation cultures, suspension cultures, thymus grafting, and bone marrow reconstitution experiments. The DC used in those studies had to go through extensive isolation procedures or were cultured with recombinant growth factors. Since the functions of DC after these in vitro manipulations have been reported to be not identical to those of DC in vivo, we intended to establish a system that would allow us to investigate DC function avoiding artificial interferences due to handling. Here we present a transgenic mouse model in which we targeted gene expression specifically to DC. Using the CD 11c promoter we expressed MHC class II I-E molecules specifically on DC of all tissues, but not on other cell types. We report that I-E expression on thymic DC is sufficient to negatively select I-E reactive CD4+ T cells, and to a less complete extent, CD8+ T cells. In contrast, it only DC expressed I-E in a class II-deficient background, positive selection of CD4+ T cells could not be observed. Thus negative, but not positive, selection events can be induced by DC in vivo.     

Monoarthritis of the knee as an isolated manifestation of paracoccidioidomycosis

Osteoarthritis in paracoccidioidomycosis has been rarely reported. The present case describes a 36-"year"-old woman, with chronic monoarthritis in the knee lasting 4 years. The diagnosis was achieved only after synovial biopsy, by anatomopathological examination showing granulomatous reaction with a large number of the characteristic "pilot wheel"Paracoccidioides brasiliensis yeast cells. Specific therapy, initially with ketoconazole and followed by cotrimoxazole led to complete functional recovery of the compromised joint. No other affected site was detected by various propaedeutic methods, including computed axial tomography of the thorax and abdomen. The authors emphasize the rarity of the case and discuss its possible pathophysiology.     

Are DTTO and iso‐DTTO Worthwhile Targets for Synthesis?

Theoretical calculations were carried out for the isomeric di‐1,2,3,4‐tetrazine tetraoxides (DTTO and iso‐DTTO). The most important explosion performance parameters, the detonation pressure and detonation velocity, are dominated by the densities and not by the heats of formation of these compounds. Since DTTO and iso‐DTTO are unknown, reliable predictions of their crystal densities are crucial for an evaluation of the potential of these materials as explosives. In this study, the crystal densities were predicted using both Ammon’s Atom/Functional Group and Atom Code Volume Additivity Parameters and Quantum Mechanical molecular Volume methods, resulting in similar densities and explosion parameters. Although the likely uncertainties in our predicted density values are difficult to assess due to a lack of experimental data for closely related known compounds, our results demonstrate that Shechter’s originally proposed densities and performance parameters were grossly overestimated. Furthermore, it is shown that, based on our predicted density value ranges, DTTO and iso‐DTTO could match or substantially outperform the best state of the art explosives, such as CL‐20. Therefore, the synthesis of DTTO and iso‐DTTO should be further pursued.     

Salmon olfaction is impaired by an environmentally realistic pesticide mixture

Many of the salmon-producing waterways of the world contain pesticides known to harm olfactory sensory neurons (OSNs) that are critically important throughout the salmon lifecycle. The ability of OSNs to retain functionality after exposure to complex pesticide mixtures remains unknown. Here we show that a 96-h exposure to an environmentally realistic concentration of a mixture made from the ten most frequently occurring pesticides in British Columbia's Nicomekl River reduced the OSN responses of rainbow troutto a behaviorally relevant odorant. Odor-evoked responses were not altered by exposure to one-fifth of the realistic concentration, and this may have been due an upregulation in detoxification enzymes, since glutathione-S-transferase activity reached a maximum (> 32% above control) at this concentration. Mixture exposure did not help to prevent OSN impairment from a second, brief (5 min) exposure to a higher (20 x) concentration of the mixture, suggesting longer-term, low-concentration exposures may not prevent damage from brief, high-concentration pulse exposures. This study demonstrates that environmentally observed pesticide mixtures can injure salmon olfactory tissue, and by extension, contribute to the threatened and endangered status of many salmon stocks.     

Coupling global methylation and gene expression profiles reveal key pathophysiological events in liver injury induced by a methyl-deficient diet

Scope : A methyl‐deficient diet induces liver injury similar to human nonalcoholic steatohepatitis, one of the main risk factors for the development of hepatocellular carcinoma. Previous studies have demonstrated that this diet perturbs DNA methylation by causing a profound loss of global cytosine methylation, predominantly at heavily methylated repetitive sequences. However, whether methyl deficiency affects the methylation status of gene promoters has not been explored. Methods and results : Mouse gene expression and CpG island microarrays were used to characterize the gene expression and CpG island methylation profiles in the livers of C57BL/6J mice fed a methyl‐deficient diet. We detected 164 genes that were differentially expressed and exhibited an inverse relationship between the gene expression and the extent of CpG island methylation. Furthermore, these genes were associated with altered lipid and glucose metabolism, DNA damage and repair, apoptosis, the development of fibrosis, and liver tissue remodeling. Although there were both increased and decreased levels of CpG island methylation, the number of hypomethylated genes was substantially greater than the number of hypermethylated genes. Conclusion : The results this study demonstrate that pairing methylation profiles with gene expression profiles is a powerful approach to identify dysregulated high‐priority fundamental pathophysiological pathways associated with disease development.     

Investigation of Antigen-Antibody Interactions of Sulfonamides with a Monoclonal Antibody in a Fluorescence Polarization Immunoassay Using 3D-QSAR Models

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAb(SMR)) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The affinities of the MAb(SMR), expressed as Log(10)IC(50), for 17 sulfonamide analogs were determined by competitive fluorescence polarization immunoassay (FPIA). The results demonstrated that the proposed pharmacophore model containing two hydrogen-bond acceptors, two hydrogen-bond donors and two hydrophobic centers characterized the structural features of the sulfonamides necessary for MAb(SMR) binding. Removal of two outliers from the initial set of 17 sulfonamide analogs improved the predictability of the models. The 3D-QSAR models of 15 sulfonamides based on CoMFA and CoMSIA resulted in q(2) (cv) values of 0.600 and 0.523, and r(2) values of 0.995 and 0.994, respectively, which indicates that both methods have significant predictive capability. Connolly surface analysis, which mainly focused on steric force fields, was performed to complement the results from CoMFA and CoMSIA. This novel study combining FPIA with pharmacophore modeling demonstrates that multidisciplinary research is useful for investigating antigen-antibody interactions and also may provide information required for the design of new haptens.