An investigation of human and rat liver microsomal mycophenolic acid glucuronidation: evidence for a principal role of UGT1A enzymes and species differences in UGT1A specificity.

Mycophenolic acid (MPA; 1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzylfuranyl)-4-methyl-4-hexenoate), the active metabolite of the immunosuppressant prodrug, mycophenolate mofetil, undergoes glucuronidation to its 7-O-glucuronide as a primary route of metabolism. Because differences in glucuronidation may influence the efficacy and/or toxicity of MPA, we investigated the MPA UDP-glucuronosyltransferase (UGT) activities of human liver microsomes (HLMs) and rat liver microsomes with the goal of identifying UGTs responsible for MPA catalysis. HLMs (n = 23) exhibited higher average MPA glucuronidation rates (14.7 versus 6.0 nmol/mg/min, respectively, p < 0.001) and higher apparent affinity for MPA (K(m) = 0.082 mM versus 0.20 mM, p < 0.001) compared with rat liver microsomes. MPA UGT activities were reduced >80% in liver microsomes from Gunn rats. To identify the active enzymes, human and rat UGT1A enzymes were screened for MPA-glucuronidating activity. UGT1A9 was the only human liver-expressed UGT1A enzyme with significant activity and exhibited both high affinity (K(m) = 0.077 mM) and high activity (V(max) = 28 nmol x min(-1) x mg(-1)). Spearman correlation analyses revealed a stronger relationship between HLM MPA UGT activities and 1A9-like content (r(2) = 0.79) relative to 1A1 (r(2) = 0.20), 1A4-like (r(2) = 0.22), and 1A6 (r(2) = 0.41) protein. A different profile was observed for rat with three active liver-expressed UGT1A enzymes: 1A1 (medium affinity/capacity), 1A6 (low affinity/medium capacity), and 1A7 (high affinity/capacity). Our data suggest that UGT1A enzymes are the major contributors to hepatic MPA metabolism in both species, but 1A9 is dominant in human, whereas 1A1 and 1A7 are likely the principal mediators in control rat liver. This information should be useful for interpretation of MPA pharmacokinetic and toxicity data in clinical and animal studies.     

Construction of 0D/2D Schottky Heterojunctions of ZnO and Ti3C2 Nanosheets with the Enriched Transfer of Interfacial Charges for Photocatalytic Hydrogen Evolution

The development of cost-effective co-catalysts of high photocatalytic activity and recyclability is still a challenge in the energy transformation domain. In this study, 0D/2D Schottky heterojunctions, consisting of 0D ZnO and 2D Ti₃C₂, were successfully synthesized by the electrostatic self-assembling of ZnO nanoparticles on Ti₃C₂ nanosheets. In constructing these heterojunctions, Ti₃C₂ nanosheets acted as a co-catalyst for enhancing the transfer of excitons and their separation to support the photocatalytic response of ZnO. The as-prepared ZnO/Ti₃C₂ composites demonstrate an abbreviated charge transit channel, a huge interfacial contact area and the interfacial electrons’ transport potential. The extended optical response and large reactive area of the ZnO/Ti₃C₂ composite promoted the formation of excitons and reactive sites on the photocatalyst’s surface. The ZnO/Ti₃C₂ Schottky heterojunction showed significantly high photocatalytic activity for hydrogen production from a water–ethanol solution under the light illumination in the visible region. The hydrogen evolution overoptimized the ZnO/Ti₃C₂ composition with 30 wt.% of Ti₃C₂, which was eight times higher than the pristine ZnO. These findings can be helpful in developing 0D/2D heterojunction systems for photocatalytic applications by utilizing Ti₃C₂ as a low-cost co-catalyst.     

Gadolinium for hysterosalpingography

OBJECTIVE: To evaluate the use of gadolinium as an alternative to iodinated contrast medium for hysterosalpingography in patients with an increased risk for iodinated contrast hypersensitivity. STUDY DESIGN: Between March 2003 and March 2006, 3,616 hysterosalpingography examinations were performed. Hysterosalpingography was routinely performed using water-soluble, nonionic, iodinated contrast medium. Hysterosalpingography was performed with gadolinium in patients at risk for contrast hypersensitivity. We retrospectively reviewed the diagnostic quality, safety and clinical outcome in patients who underwent gadolinium hysterosalpingography. RESULTS: Hysterosalpingograms of diagnostic quality were successfully performed without adverse reactions in 11 patients. The density of gadolinium contrast opacification was diminished as compared with a conventional hysterosalpingogram with iodinated contrast. Two of the 8 patients who were not on oral contraceptives and had patent fallopian tubes became pregnant within 6 months of the hysterosalpingogram procedure. CONCLUSION: Gadolinium hysterosalpingography is of diagnostic value and is a safe alternative to iodinated contrast medium for hysterosalpingography in patients at increased risk for iodinated contrast hypersensitivity.     

Gene Therapy Strategies to Exploit TRIM Derived Restriction Factors against HIV-1

Restriction factors are a collection of antiviral proteins that form an important aspect of the innate immune system. Their constitutive expression allows immediate response to viral infection, ahead of other innate or adaptive immune responses. We review the molecular mechanism of restriction for four categories of restriction factors; TRIM5, tetherin, APOBEC3G and SAMHD1 and go on to consider how the TRIM5 and TRIMCyp proteins in particular, show promise for exploitation using gene therapy strategies. Such approaches could form an important alternative to current anti-HIV-1 drug regimens, especially if combined with strategies to eradicate HIV reservoirs. Autologous CD4⁺ T cells or their haematopoietic stem cell precursors engineered to express TRIMCyp restriction factors, and provided in a single therapeutic intervention could then be used to restore functional immunity with a pool of cells protected against HIV. We consider the challenges ahead and consider how early clinical phase testing may best be achieved.     

“Open” approach to aortic arch aneurysm repair

Aortic arch aneurysm is a relatively rare entity in cardiac surgery. Repair of such aneurysms, either in isolation or combined with other cardiac procedures, remains a challenging task. The need to produce a relatively bloodless surgical field with circulatory arrest, while at the same time protecting the brain, is the hallmark of this challenge. However, a clear understanding of the topic allows a better and less morbid approach to such a complex surgery.Literature has shown the advantage of selective cerebral perfusion techniques in comparison with only circulatory arrest. Ability to perfuse the brain has allowed circulatory arrest temperatures at moderate hypothermia without the need for deep hypothermia. Even though cannulation site selection appears to be a minor issue, literature has shown that the subclavian/axillary route has the best outcomes and that femoral cannulation should only be reserved for no access patients. Although different techniques for arch anastomosis have been described, we routinely perform the distal first technique as we find it to be less cumbersome and easiest to reproduce.In this review our aim is to outline a systematic approach to aortic arch surgery. Starting with indications for intervention and proceeding with approaches on site of cannulation, approaches to brain protection with hypothermia and selective cerebral perfusion and finally surgical steps in performing the distal and arch vessels anastomosis.     

Corticosteroid treatment exacerbates nephrotic syndrome in a zebrafish model of magi2a knockout

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HLA incompatible combined liver–kidney transplantation: Dynamics of antibody modulation revealed by a novel approach to HLA antibody characterisation

This case report confirms the utility of simultaneous liver transplantation in allowing successful kidney transplantation in the face of preformed, high levels of DSA, which would under normal circumstances be associated with hyperacute rejection and kidney graft failure. Antibody characterisation in terms of epitope specificity is more accurate and informative than antibodies described as “antigen-specific” and we suggest a method for identifying and tracking these antibodies; i.e. follow the epitope reaction not the antigen reactions. We consider that this will give a better insight into the behaviour and pathogenicity of HLA-specific sera. In the case presented here this approach has revealed some novel features of the post transplant antibody response in a sensitised recipient. These illustrate three phenomena which challenge current dogmas; an early resynthesis of DSA does not necessarily cause AMR, high levels of DSA can spontaneously modulate, and measurement of antibodies in terms of antigen specificity can give misleading results.