Expression of TRIM22 mRNA in chronic hepatitis C patients treated with direct-acting antiviral drugs

Hepatitis C is a global public health problem, and Pakistan is the second largest country in the globe with highest prevalence rate of hepatitis C virus (HCV). Until 2014, pegylated interferon (PEG-IFN) plus ribavirin (RBV) has been the standard therapy for HCV, however, owing to its adverse side effects and very low sustained virologic response (SVR) rates therapeutics trend is shifted toward direct-acting antivirals. Tripartite motif containing 22 (TRIM22) is a dynamic antiviral protein that can inhibit multiple viruses in vivo. Expression of TRIM22 mRNA has been linked to outcome of PEG-IFN and ribavirin therapy, where its higher expression leads to rapid virus clearance. However, in terms of therapy with direct-acting antiviral (DAA) or double DAA, impact of TRIM22 expression is largely unknown. These new drugs show more than 90% of SVR rates and lesser side effects and have proven to be better than IFN therapy. Endogenous IFN system suppresses various pathogens through the induction of antiviral effectors termed as interferon-stimulating genes (ISGs). We have studied the expression levels of one of these antiviral effectors, TRIM22 in response to sofosbuvir (SOF) and daclatasvir (DAC) in combination with RBV, using quantitative PCR in the peripheral blood mononuclear cells (PBMCs) of HCV-infected patients. We have observed sustained virus clearance in more than 90% of patients treated with DAA and double DAA and have seen the expression of TRIM22 to be higher in patients who attained SVR as compared to the untreated patients. We have also observed downregulation of TRIM22 in patients who failed to attain rapid virus clearance, and upregulation in those who achieved rapid clearance of virus. Genetic factors that determine the lower TRIM22 expression in these patients are needed to be explored that may also play a role in lower response to anti-HCV therapy. Endogenous IFN system and effects of antiviral proteins in response to DAA therapy is needed to be studied in order to better understand the host response toward these drugs to make them more effective.     

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.     

Investigating the Impact of Cu2+ Doping on the Morphological,Structural, Optical,and Electrical Properties of CoFe2O4 Nanoparticles for Use in Electrical Devices

This study investigated the production of Cu²⁺-doped CoFe₂O₄ nanoparticles (CFO NPs) using a facile sol−gel technique. The impact of Cu²⁺ doping on the lattice parameters, morphology, optical properties, and electrical properties of CFO NPs was investigated for applications in electrical devices. The XRD analysis revealed the formation of spinel-phased crystalline structures of the specimens with no impurity phases. The average grain size, lattice constant, cell volume, and porosity were measured in the range of 4.55–7.07 nm, 8.1770–8.1097 Å, 546.7414–533.3525 ų, and 8.77–6.93%, respectively. The SEM analysis revealed a change in morphology of the specimens with a rise in Cu²⁺ content. The particles started gaining a defined shape and size with a rise in Cu²⁺ doping. The Cu_0.12Co_0.88Fe₂O₄ NPs revealed clear grain boundaries with the least agglomeration. The energy band gap declined from 3.98 eV to 3.21 eV with a shift in Cu²⁺ concentration from 0.4 to 0.12. The electrical studies showed that doping a trace amount of Cu²⁺ improved the electrical properties of the CFO NPs without producing any structural distortions. The conductivity of the Cu²⁺-doped CFO NPs increased from 6.66 × 10⁻¹⁰ to 5.26 × 10⁻⁶ ℧ cm⁻¹ with a rise in Cu²⁺ concentration. The improved structural and electrical characteristics of the prepared Cu²⁺-doped CFO NPs made them a suitable candidate for electrical devices, diodes, and sensor technology applications.     

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.     

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

1. Download high-res image (304KB)
2. Download full-size image

     

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.