MR elastography of the ex vivo bovine globe

Purpose:

To evaluate the feasibility of using MR elastography (MRE) to assess the mechanical properties of the eye.

Materials and Methods:

The elastic properties of the corneoscleral shell of an intact, enucleated bovine globe specimen were estimated using MRE and finite element modeling (FEM), assuming linear, isotropic behavior. The two‐dimensional (2D), axisymetric model geometry was derived from a segmented 2D MR image, and estimations of the Young's modulus in both the cornea and sclera were made at various intraocular pressures using an iterative flexural wave speed matching algorithm.

Results:

Estimated values of the Young's moduli of the cornea and sclera varied from 40 to 185 kPa and 1 to 7 MPa, respectively, over an intraocular pressure range of 0.85 to 9.05 mmHg (1.2 to 12.3 cmH₂O). They also varied exponentially as functions of both wave speed and intraocular dP/dV, an empirical measure of “ocular rigidity.”

Conclusion:

These results show that it is possible to estimate the intrinsic elastic properties of the corneoscleral shell in an ex vivo bovine globe, suggesting that MRE may provide a useful means to assess the mechanical properties of the eye and its anatomy. Further development of the technique and modeling process will enhance its potential, and further investigations are needed to determine its clinical potential. J. Magn. Reson. Imaging 2010;32:44–51. © 2010 Wiley‐Liss, Inc.     

Subacute exposure to N-ethyl perfluorooctanesulfonamidoethanol results in the formation of perfluorooctanesulfonate and alters superoxide dismutase activity in female rats

Perfluorooctanesulfonamides, such as N-ethyl perfluorooctanesulfonamidoethanol (N-EtFOSE), are large scale industrial chemicals but their disposition and toxicity are poorly understood despite significant human exposure. The hypothesis that subacute exposure to N-EtFOSE, a weak peroxisome proliferator, causes a redox imbalance in vivo was tested using the known peroxisome proliferator, ciprofibrate, as a positive control. Female Sprague–Dawley rats were treated orally with N-EtFOSE, ciprofibrate or corn oil (vehicle) for 21 days, and levels of N-EtFOSE and its metabolites as well as markers of peroxisome proliferation and oxidative stress were assessed in serum, liver and/or uterus. The N-EtFOSE metabolite profile in liver and serum was in good agreement with reported in vitro biotransformation pathways in rats and the metabolite levels decreasing in the order perfluorooctanesulfonate ? perfluorooctanesulfonamide ~ N-ethyl perfluorooctanesulfonamidoacetate ? perfluorooctanesulfonamidoethanol ~ N-EtFOSE. Although N-EtFOSE treatment significantly decreased the growth rate, increased relative liver weight and activity of superoxide dismutases (SOD) in liver and uterus (total SOD, CuZnSOD and MnSOD), a metabolic study revealed no differences in the metabolome in serum from N-EtFOSE-treated and control animals. Ciprofibrate treatment increased liver weight and peroxisomal acyl Co-A oxidase activity in the liver and altered antioxidant enzyme activities in the uterus and liver. According to NMR metabolomic studies, ciprofibrate treated animals had altered serum lipid profiles compared to N-EtFOSE-treated and control animals, whereas putative markers of peroxisome proliferation in serum were not affected. Overall, this study demonstrates the biotransformation of N-EtFOSE to PFOS in rats that is accompanied by N-EtFOSE-induced alterations in antioxidant enzyme activity.     

Upregulation of the β-form of 14-3-3 protein in telencephalon of goldfish (Carassius auratus): its possible role in spatial learning

In the present study, we observed variations in the expression pattern of proteins isolated from the telencephalon of goldfish (Carassius auratus). The expression of a 28 kDa protein was elevated in the individuals trained in a spatial task when compared with the untrained individuals. The ～28 kDa protein was analyzed using liquid chromatography and mass spectrometry; further, the data were analyzed using the MASCOT search engine. The analysis showed that the ～28 kDa protein is a β form of 14-3-3 protein with 35.1% identity. In addition, the semiquantitative PCR confirmed the variation in the expression of 14-3-3 between the trained and the untrained groups. Subsequently, we examined the effect of upregulation of 14-3-3 (β) in the neurotransmitters; that is, serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA). Notably, the level of 5-HT and DA was found to be significantly elevated in the telencephalon of individuals trained in the spatial task than in the untrained individuals. Our results suggest that the spatial learning increases the expression of 14-3-3 (β), which in turn leads to an increase in the level of 5-HT and DA. The upregulated 5-HT and DA may facilitate synapse formation during spatial learning in a novel environment.     

Detection of the JAK2 V617F mutation by LightCycler PCR and probe dissociation analysis

A point mutation in the JAK2 gene, a member of the tyrosine kinase family, was recently identified and shown to be associated with several myeloproliferative disorders. Several studies identified the same JAK2 point mutation (1,849G>T), resulting in the substitution of a valine to phenylalanine at codon 617 (V617F). We developed a simple and sensitive method to detect this mutation via polymerase chain reaction and probe dissociation analysis using the LightCycler platform, and we compared this method to existing restriction fragment-length polymorphism, direct sequencing, and amplification refractory mutation system methods. We found that the LightCycler method offered advantages of speed, reliability, and more straightforward interpretation over the restriction fragment-length polymorphism and sequencing approaches.     

Heterotricyclic himbacine analogs as potent, orally active thrombin receptor (protease activated receptor-1) antagonists

Pursuing our earlier efforts in the himbacine-based thrombin receptor antagonist area, we have synthesized a series of compounds that incorporate heteroatoms in the C-ring of the tricyclic motif. This effort has resulted in the identification of several potent heterocyclic analogs with excellent affinity for the thrombin receptor. Several of these compounds demonstrated robust inhibition of platelet aggregation in an ex vivo model in cynomolgus monkeys following oral administration. A detailed profile of 28b, a benchmark compound in this series, with a Ki of 4.3 nM, is presented.     

Regulatory mechanisms in lymphatic vessel contraction under normal and inflammatory conditions

The lymphatic system is composed of a dense network of lymphatic vessels, which are critical components of physiological interstitial fluid transport. These vessels possess intrinsic contractile properties providing the driving force for the fluid to be drained away from the tissues and propelled, as lymph, back into the bloodstream. Lymphatic pumping is also important to carry immune cells, bacteria, macromolecules, viruses and their products to and through lymph nodes, the other component of the lymphatic system, to initiate the adaptive immune response. In addition, among the many circulating mediators known to modulate lymphatic contractile activity and thus lymph flow, mediators of inflammation have potent excitatory or inhibitory actions. The involvement of lymphatic vessels in edema resolution, immune cell trafficking and their sensitivity to inflammatory mediators make them pivotal players of the inflammation process. The ability of lymphatic vessels to generate and regulate lymph flow is provided by the lymphatic muscle present in the vessels’ wall. Although molecular studies investigating the mechanisms of lymphatic vessel contraction are still very limited, recent findings suggest that lymphatic pumping requires complicated muscle activities that have similarities to those seen in both the heart (striated muscle) and blood vessels (smooth muscle). This review article focuses on presenting and discussing the mechanisms that regulate lymphatic vessel contraction under normal and pathophysiological states, specifically pertaining to inflammatory conditions.     

Himbacine-Derived Thrombin Receptor Antagonists: C7-Aminomethyl and C9a-Hydroxy Analogues of Vorapaxar

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