Could Uric acid have a Pathogenic Role in Chronic Allograft Dysfunction?

Introduction: Chronic allograft dysfunction (CAD) is the primary cause of chronic graft failure after kidney transplantation. The pathogenesis of CAD involves both antigen-dependent and antigen-independent mechanisms. Serum uric acid could have a role in both mechanisms. Review: Hyperuricemia in subjects with renal transplantation is not usually viewed as clinically significant unless the subject develops gout. Drugs used in the treatment of hyperuricemia and gout are more likely to cause side effects in the kidney transplant reciepient. However, there are recent studies that raise the possibility that uric acid could have a role in CAD. Soluble uric acid has been shown to stimulate the proliferation of vascular smooth muscle, to inhibit endothelial cell proliferation and to reduce bioactive levels of endothelial NO. Studies in experimental models have found that hyperuricemia can cause hypertension associated with renal injury characterized by microvascular disease, tubulointerstitial disease, glomerular hypertrophy and glomerulosclerosis. Hyperuricemia was also found to worsen preexistent renal disease, and to be associated with the development of severe vascular lesions that are reminiscent of those observed in CAD. Furthermore, chronic cyclosporine nephropathy is very similar to what is observed in normal rats simply by raising uric acid levels. In addition, raising uric acid levels in rats receiving cyclosporine accelerates the nephropathy whereas lowering uric acid ameliorates the renal lesions. Conclusion: The pathogenic role of uric acid in CAD is still controversial. A controlled clinical trial would be the best approach to determine the effect of uric acid lowering treatment on the development of CAD and long term graft function. Keywords: chronic allograft dysfunction, cyclosporine, uric acid, hyperuricemia, vascular diseas

International longitudinal registry of patients with atrial fibrillation and treated with rivaroxaban: RIVaroxaban Evaluation in Real life setting (RIVER)

Background Real-world data on non-vitamin K oral anticoagulants (NOACs) are essential in determining whether evidence from randomised controlled clinical trials translate into meaningful clinical benefits for patients in everyday practice. RIVER (RIVaroxaban Evaluation in Real life setting) is an ongoing international, prospective registry of patients with newly diagnosed non-valvular atrial fibrillation (NVAF) and at least one investigator-determined risk factor for stroke who received rivaroxaban as an initial treatment for the prevention of thromboembolic stroke. The aim of this paper is to describe the design of the RIVER registry and baseline characteristics of patients with newly diagnosed NVAF who received rivaroxaban as an initial treatment. Methods and results Between January 2014 and June 2017, RIVER investigators recruited 5072 patients at 309 centres in 17 countries. The aim was to enroll consecutive patients at sites where rivaroxaban was already routinely prescribed for stroke prevention. Each patient is being followed up prospectively for a minimum of 2-years. The registry will capture data on the rate and nature of all thromboembolic events (stroke / systemic embolism), bleeding complications, all-cause mortality and other major cardiovascular events as they occur. Data quality is assured through a combination of remote electronic monitoring and onsite monitoring (including source data verification in 10% of cases). Patients were mostly enrolled by cardiologists (n = 3776, 74.6%), by internal medicine specialists 14.2% (n = 718) and by primary care/general practice physicians 8.2% (n = 417). The mean (SD) age of the population was 69.5 (11.0) years, 44.3% were women. Mean (SD) CHADS2 score was 1.9 (1.2) and CHA2DS2-VASc scores was 3.2 (1.6). Almost all patients (98.5%) were prescribed with once daily dose of rivaroxaban, most commonly 20 mg (76.5%) and 15 mg (20.0%) as their initial treatment; 17.9% of patients received concomitant antiplatelet therapy. Most patients enrolled in RIVER met the recommended threshold for AC therapy (86.6% for 2012 ESC Guidelines, and 79.8% of patients according to 2016 ESC Guidelines). Conclusions The RIVER prospective registry will expand our knowledge of how rivaroxaban is prescribed in everyday practice and whether evidence from clinical trials can be translated to the broader cross-section of patients in the real world

Physiological Studies and Ultrastructure of Vigna sinensis L. and Helianthus annuus L. under Varying Levels of Nitrogen Supply

This experiment was conducted to investigate the effects of different nitrogen fertilizers (potassium nitrate and/or urea) on shoot parameters, relative growth rate, net assimilation rate, and nitrogen fractions, as well as to conduct transmission electron microscopy, of Vigna sinensis L. (cowpea) and Helianthus annuus L. (sunflower) leaves. A general improvement was recorded in the shoot parameters of the two plants, except for a decrease in the net assimilation rate by treatment of the two plants with 100% potassium nitrate plus 100% urea. The total nitrogen, insoluble protein, and total soluble nitrogen generally decreased in cowpea shoots from the treatments but increased in case of cowpea roots and sunflower shoots and roots. The examination of the ultrastructure changes in cowpea leaves confirmed the presence of two starch granules (in response to 100% potassium nitrate, 100% potassium nitrate plus 100% urea, and the control) and three granules (in response to 50% potassium nitrate plus 50% urea) and the disappearance of the starch granules (in response to 100% urea). Despite the starch granules not being detected in the leaves of the untreated sunflower, the treated plant showed the appearance of the highest number after treatment with 50% potassium nitrate plus 50% urea (2) and the most cell size with the 100% potassium nitrate treatment. Generally, our findings demonstrated that fertilization with 50% potassium nitrate plus 50% urea has the best influence on the growth parameters and nitrogen content in the two plants, but the magnitude of response was more pronounced in case of cowpea plants

Transforming Growth Factor Beta (TGF-β) Is a Muscle Biomarker of Disease Progression in ALS and Correlates with Smad Expression.

We recently identified Smads1, 5 and 8 as muscle biomarkers in human ALS. In the ALS mouse, these markers are elevated and track disease progression. Smads are signal transducers and become activated upon receptor engagement of ligands from the TGF-β superfamily. Here, we sought to characterize ligands linked to activation of Smads in ALS muscle and their role as biomarkers of disease progression. RNA sequencing data of ALS muscle samples were mined for TGF-β superfamily ligands. Candidate targets were validated by qRT-PCR in a large cohort of human ALS muscle biopsy samples and in the G93A SOD1 mouse. Protein expression was evaluated by Western blot, ELISA and immunohistochemistry. C2C12 muscle cells were used to assess Smad activation and induction. TGF-β1, 2 and 3 mRNAs were increased in ALS muscle samples compared to controls and correlated with muscle strength and Smads1, 2, 5 and 8. In the G93A SOD1 mouse, the temporal pattern of TGF-β expression paralleled the Smads and increased with disease progression. TGF-β1 immunoreactivity was detected in mononuclear cells surrounding muscle fibers in ALS samples. In muscle cells, TGF-β ligands were capable of activating Smads. In conclusion, TGF-β1, 2 and 3 are novel biomarkers of ALS in skeletal muscle. Their correlation with weakness in human ALS and their progressive increase with advancing disease in the ALS mouse suggest that they, as with the Smads, can track disease progression. These ligands are capable of upregulating and activating Smads and thus may contribute to the Smad signaling pathway in ALS muscle

Role of Biotransformation of <i>Acacia nilotica</i> Metabolites by <i>Aspergillus subolivaceus</i> in Boosting <i>Lupinus termis</i> Yield: A Promising Approach to Sustainable Agriculture

Biotransformation plays a significant role in sustainable agriculture. This process involves utilizing microorganisms, such as bacteria and fungi, to transform organic compounds and metabolites into bioactive compounds which have beneficial effects on plant growth, yield, and soil characters. Accordingly, the present study aims to explore the role of biotransformation of Acacia nilotica metabolites by Aspergillus subolivaceus in boosting L. termis yield, as an important strategy in agricultural sustainability. A pilot experiment was performed on five fungal strains (Fusarium oxysporium A. aculeatus, Aspergillus. subolivaceus, Rhizopus oryzae and Trichoderma viride) which were grown on different parts of plants (A. nilotica leaves; green tea leaves, green pepper fruits and pomegranate fruits), and the results indicated that the most active metabolite for the growth of L. termis seeds was the fungal metabolite of A. subolivaceus growing on A. nilotica. More specifically, we assess how metabolites produced by Aspergillus subolivaceus using A. nilotica leaves affect the biochemical properties and chemical composition of L. termis seeds. A. subolivaceus was grown on leaves from A. nilotica to obtain metabolites and fractionated into four extracts. Two concentrations of each extract were examined by pretreating the seeds of L. termis. The study found that all four extracts contributed to an increase in yield and some biochemical properties of the yielded seeds. The best results were obtained by treating the L. termis seeds with an extract obtained from diethyl ether, which led to a significant increase in total nitrogen, amino nitrogen, glucose and protein contents of the seeds. According to 1H NMR guided GC/MS analysis, our results showed an increase in phytochemicals such as terpenes, fatty materials, and flavonoids including 3′,4′,7-trimethoxyquercetin and 4-methyl-p-menth-8-en-3-one, which have not been stated before from A. nilotica suggesting that biotransformation may have occurred due to the presence of A. subolivaceus