Shifting Paradigms for Suppressing Fibrosis in Kidney Transplants: Supplementing Perfusion Solutions With Anti-fibrotic Drugs

Great efforts have been made toward addressing the demand for donor kidneys. One of the most promising approaches is to use kidneys from donation after circulatory death donors. These kidneys, however, suffer from more severe ischemia and reperfusion injury than those obtained via donation after brain death and are thus more prone to develop interstitial fibrosis and tubular atrophy. Even though machine perfusion is increasingly used to reduce ischemia and reperfusion injury, there are no effective treatments available to ameliorate interstitial fibrosis and tubular atrophy, forcing patients to resume dialysis, undergo re-transplantation, or suffer from premature death. Safe and effective anti-fibrotic therapies are therefore greatly desired. We propose a new therapeutic approach in which machine perfusion solutions are supplemented with anti-fibrotic compounds. This allows the use of higher concentrations than those used in humans whilst eliminating side effects in other organs. To the authors' knowledge, no one has reviewed whether such an approach could reduce interstitial fibrosis and tubular atrophy; we therefore set out to explore its merit. In this review, we first provide background information on ischemia and reperfusion injury as well as interstitial fibrosis and tubular atrophy, after which we describe currently available approaches for preserving donor kidneys. We then present an evaluation of selected compounds. To identify promising compounds, we analyzed publications describing the effects of anti-fibrotic molecules in precision-cut kidneys slices, which are viable explants that can be cultured ex vivo for up to a few days whilst retaining functional and structural features. LY2109761, galunisertib, imatinib, nintedanib, and butaprost were shown to exert anti-fibrotic effects in slices within a relatively short timeframe (<48 h) and are therefore considered to be excellent candidates for follow-up ex vivo machine perfusion studies.

Capabilities of Modern Semiconductor Gamma Cameras in Radionuclide Diagnosis of Coronary Artery Disease

This paper presents a review of the literature concerning the clinical application of modern semiconductor (CZT) gamma cameras in the radioinuclide diagnosis of coronary artery disease. It contains information on the diagnostic efficacy of myocardial perfusion studies performed with those cameras compared with the widely used scintillation (Anger) cameras, an overview of their effectiveness in comparison with coronary angiography (also fractional flow reserve) and currently available clinical results of a myocardial flow reserve measured with a dynamic SPECT study. Introduction of this imaging modality to the measurement of a myocardial flow reserve aims to facilitate access to this type of study compared to the less available and more expensive PET method used so far.

Perfusion Patterns in Patients with Chronic Limb-Threatening Ischemia versus Control Patients Using Near-Infrared Fluorescence Imaging with Indocyanine Green

In assessing the severity of lower extremity arterial disease (LEAD), physicians rely on clinical judgements supported by conventional measurements of macrovascular blood flow. However, current diagnostic techniques provide no information about regional tissue perfusion and are of limited value in patients with chronic limb-threatening ischemia (CLTI). Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has been used extensively in perfusion studies and is a possible modality for tissue perfusion measurement in patients with CLTI. In this prospective cohort study, ICG NIR fluorescence imaging was performed in patients with CLTI and control patients using the Quest Spectrum Platform® (Middenmeer, The Netherlands). The time–intensity curves were analyzed using the Quest Research Framework. Fourteen parameters were extracted. Successful ICG NIR fluorescence imaging was performed in 19 patients with CLTI and in 16 control patients. The time to maximum intensity (seconds) was lower for CLTI patients (90.5 vs. 143.3, p = 0.002). For the inflow parameters, the maximum slope, the normalized maximum slope and the ingress rate were all significantly higher in the CLTI group. The inflow parameters observed in patients with CLTI were superior to the control group. Possible explanations for the increased inflow include damage to the regulatory mechanisms of the microcirculation, arterial stiffness, and transcapillary leakage.

DEVELOPMENT OF RIVASTIGMINE LOADED SELF ASSEMBLED NANOSTRUCTURES OF NONIONIC SURFACTANTS FOR BRAIN DELIVERY

Objective: Aim of the study is to develop rivastigmine-loaded niosomal in situ gel via the intranasal route to the brain by crossing the Blood-Brain Barrier. For the treatment of Alzheimer’s disease, it provides a speedy onset of action, a faster therapeutic effect, avoidance of the first-pass metabolism, and enhanced bioavailability. Methods: Rivastigmine niosomal in situ nasal gel was developed, refined and tested with the goal of delivering the medicine to the brain via the intranasal route Rivastigmine niosomes were formulated by thin-film hydration technique, optimized using (32) factorial design and characterized for its physicochemical parameters. Rivastigmine-loaded niosomes were further incorporated into Carbopal-934P and HPMC-K4M liquid gelling system to form in situ nasal gel. The resulting solution was evaluated for several parameters including, viscosity at pH 5 and pH 6, gelling capacity and gelling time. Results: Optimized best formulation containing span 60 (A) and cholesterol (B) with (1:0.5) ratio identified from the model developed from Design-Expert®12 software, exhibited Entrapment efficiency (76.5±0.23%), particle size (933.4±0.14 nm), in vitro drug release maximum (68.94±0.26%) at 8th hour and further studied for its characteristics by SEM and TEM showed stable vesicles. Polynomial equations of Y1, Y2, and Y3 were conducted and ANOVA results showed a significant impact (p<0.05) on three levels. In vivo perfusion studies using rat model showed, the niosomes developed has good perfusion compared to pure drug with 27.2% of drug absorption in the brain at the end of 3 h. In vitro permeation of Rivastigmine through the dialysis membrane showed that 60.74% w/w drug permeated after 8 h. The formation of stable vesicles was proved by Zeta potential measurements and SEM analysis. Conclusion: Optimized formulation had greater perfusion and was expected to have a good bioavailability compared to conventional other drug delivery systems.

Reliability and Reproducibility of Hadamard Encoded Pseudo-Continuous Arterial Spin Labeling in Healthy Elderly

The perfusion parameters cerebral blood flow (CBF) and arterial transit time (ATT) measured with arterial spin labeling (ASL) magnetic resonance imaging (MRI) provide valuable essentials to assess the integrity of cerebral tissue. Brain perfusion changes, due to aging, an intervention, or neurodegenerative diseases for example, could be investigated in longitudinal ASL studies with reliable ASL sequences. Generally, pseudo-continuous ASL (pCASL) is preferred because of its larger signal-to-noise ratio (SNR) compared to pulsed ASL (PASL) techniques. Available pCASL versions differ regarding their feature details. To date only little is known about the reliability and reproducibility of CBF and ATT measures obtained with the innovative Hadamard encoded pCASL variant, especially if applied on participants in old age. Therefore, we investigated an in-house developed Hadamard encoded pCASL sequence on a group of healthy elderly at two different 3 Tesla Siemens MRI systems (Skyra and mMR Biograph) and evaluated CBF and ATT reliability and reproducibility for several regions-of-interests (ROI). Calculated within-subject coefficients of variation (wsCV) demonstrated an excellent reliability of perfusion measures, whereas ATT appeared to be even more reliable than CBF [e.g., wsCV(CBF) = 2.9% vs. wsCV(ATT) = 2.3% for a gray matter (GM) ROI on Skyra system]. Additionally, a substantial agreement of perfusion values acquired on both MRI systems with an inter-session interval of 78 ± 17.6 days was shown by high corresponding intra-class correlation (ICC) coefficients [e.g., ICC(CBF) = 0.704 and ICC(ATT) = 0.754 for a GM ROI]. The usability of this novel Hadamard encoded pCASL sequence might improve future follow-up perfusion studies of the aging and/or diseased brain.

Own experience of mri T2 and ct perfusion of the brain, how to avoid «failures»

Introduction. To reduce the number of cerebral perfusion studies, the interpretation of which is not possible or can be performed with errors, we retrospectively analyzed cerebral perfusion studies for three years, analyzed the identified errors at the stage of data collection and the stage of study interpretation.Aims and objectives: to analyze and divide into groups the reasons that led to limitations or impossibility to assess perfusion during interpretation of the obtained data, to develop an algorithm of actions to reduce the number of uninterpreted studies.Materials and Methods. The study retrospectively evaluated 275 CT and MRI brain perfusion studies performed between 2017 and 2019 on 1.5 T MR and 32-slice CT scans.Results. The result of this study was a better understanding of the causes of the most common errors in perfusion studies. Analysis of the causes allowed us to identify factors that affect the performance of the study and the interpretation of the data obtained. Discussion. In order to perform a quality perfusion study, given the many factors affecting the interpretation of the data obtained, a number of conditions on the planning and execution of the study, as well as on the evaluation of the data obtained, must be followed. Conclusions. Understanding the reasons that lead to limitations or inability to evaluate MRI and CT perfusion studies, adhering to guidelines for planning and evaluating studies allows for correct data and avoids obtaining uninformative studies or studies whose interpretation is limited.

Dosimetry of radiopharmaceuticals used in adult patients with suspected pulmonary embolism

The absorbed dose of radiopharmaceuticals is estimated in adults with suspected pulmonary embolism explored by ventilation/perfusion studies. For pulmonary ventilation studies 81mKr, 133Xe, 99mTc (Technegas)-aerosol and 99mTc (DTPA)-aerosol are used. For perfusion agents, 99mTc(MAA), 99mTc (MSA) (macroaggregates and albumin microspheres) are used. For the dose calculation, the MIRD methodology and the anthropomorphic representation of the biokinetic organs of Cristy-Eckerman are used. In ventilation/perfusion studies, the lowest dose absorbed by the lungs with suspected embolism is due to 81mKr/ 99mTc (MSA), and the highest dose is due to 99mTc (Technegas)/99mTc (MAA) calculated for activities of 150 MBq for perfusion agents and 40 MBq for ventilation agents.

Prediction of Intraoperative Fluorescence of Brain Gliomas: Correlation between Tumor Blood Flow and the Fluorescence

Introduction: The prediction of the fluorescent effect of 5-aminolevulinic acid (5-ALA) in patients with diffuse gliomas can improve the selection of patients. The degree of enhancement of gliomas has been reported to predict 5-ALA fluorescence, while, at the same time, rarer cases of fluorescence have been described in non-enhancing gliomas. Perfusion studies, in particular arterial spin labeling perfusion, have demonstrated high efficiency in determining the degree of malignancy of brain gliomas and may be better for predicting fluorescence than contrast enhancement. The aim of the study was to investigate the relationship between tumor blood flow, measured by ASL, and intraoperative fluorescent glow of gliomas of different grades. Materials and methods: Tumoral blood flow was assessed in 75 patients by pCASL (pseudo-continuous arterial spin labeling) within 1 week prior to surgery. In all cases of tumor removal, 5-ALA had been administered preoperatively. Maximum values of tumoral blood flow (TBF max) were measured, and normalized tumor blood flow (nTBF) was calculated. Results: A total of 76% of patients had significant contrast enhancement, while 24% were non-enhancing. The histopathology revealed 17 WHO grade II gliomas, 12 WHO grade III gliomas and 46 glioblastomas. Overall, there was a relationship between the degree of intraoperative tumor fluorescence and ASL-TBF (Rs = 0.28, p = 0.02 or the TBF; Rs = 0.34, p = 0.003 for nTBF). Non-enhancing gliomas were fluorescent in 9/18 patients, with nTBF in fluorescent gliomas being 54.58 ± 32.34 mL/100 mg/s and in non-fluorescent gliomas being 52.99 ± 53.61 mL/100 g/s (p > 0.05). Enhancing gliomas were fluorescent in 53/57 patients, with nTBF being 170.17 ± 107.65 mL/100 g/s in fluorescent and 165.52 ± 141.71 in non-fluorescent gliomas (p > 0.05). Conclusion: Tumoral blood flow levels measured by non-contrast ASL perfusion method predict the fluorescence by 5-ALA; however, the additional value beyond contrast enhancement is not clear. ASL is, however, useful in cases with contraindication to contrast.