Heme Induced Progressive Loss of Endothelial Protein C Receptor Promotes Development of Chronic Kidney Disease in Sickle Cell Disorders

Chronic kidney disease (CKD), widespread among the individuals with sickle cell disease (SCD), is a major contributor to early death in this patient population. The progressive deterioration of renal health in SCD is associated with chronic persistent intravascular hemolysis leading to anemia. We have previously reported that extracellular heme, released during acute intravascular hemolysis triggers clinically relevant acute kidney injury (AKI) in SCD mice (SS) (Blood (2020) 135 (13): 1044-1048). Although AKI is reversible, it is considered as a risk factor for CKD. The mechanistic approach elucidating the hemolysis driven pathogenesis of AKI-to-CKD transition in SCD is unknown. We found that CKD develops in the SS mice by progressive (1-10 months of age) increase in albuminuria (urinary albumin and creatinine ratio, uACR) and decrease in glomerular filtration rate (GFR) (n=5; p<0.001). Histopathology of the kidney showed age-dependent deterioration in renal peritubular vascular congestion in SS mice compared to that of the AA mice. Alongside, Evan's blue extravasation experiments showed that the SS mice are susceptible to vascular leakage that is correlated positively with age (Pearson r=0.98, p<0.001) and negatively with anemia (Pearson r= -0.46, p<0.05). We hypothesized that multiple acute hemolytic events may instigate persistent endothelial damage that ensues CKD development in SCD. To test this hypothesis, we intravenously infused vehicle or heme (14 μmoles/kg body weight; 5 times on alternate days) to 1-month old SS mice and monitored for 3 weeks following first heme injection. These mice developed severe albuminuria (n=5; p<0.01) with substantial loss of GFR (n=5; p<0.001), indicating heme induced CKD development. Next, we used ultrasound super-resolution (USR) imaging technology to determine renal microvascular changes in older SS mice (6-months) without heme challenge and in young SS mice (1-month) challenged with heme. Analysis of the USR data showed reduced renal blood volume (rBV) and substantial loss of vessel density in renal cortex as well as in corticomedullary areas of the older SS mice compared to the age-matched AA mice. Accordingly, multiple heme challenge reduced rBV and vessel density extensively in young SS mice comparable to the older SS mice without heme challenge. Since endothelial protein C receptor (EPCR) maintains vascular barrier integrity by activating protease activated receptor-1 (PAR1) signaling in the endothelium, we tested whether alterations in EPCR expression contribute to progressive endothelial damage in SS mice during CKD development. Using immunofluorescence microscopy, we determined that renal endothelium lacks expression of EPCR in older SS mice while younger SS mice retains EPCR cellular expression. In corroboration, infusion of heme in younger SS mice results in loss of renal endothelial EPCR. Shedding of EPCR from endothelium often results in a soluble form of EPCR (sEPCR). We found that SS mice had higher plasma levels of soluble EPCR (sEPCR) compared to their AA counterparts. While age dependent increase in plasma and urinary sEPCR were evident in SS mice (n=6; p<0.01), infusion of heme in younger SS mice results in significant increase in plasma sEPCR (n=6; p<0.01). In consistent with the mouse data, we discovered that the plasma sEPCR was significantly elevated in SCD patients compared to normal individuals (n=8-16; p<0.05). Moreover, the plasma sEPCR was significantly associated with the baseline albuminuria in a cohort of SCD patients (n=16; Pearson r=0.64; p<0.01). This study supports the conclusion that multiple hemolytic events may trigger CKD development in SCD by gradual loss of renal microvascular EPCR expression. Clinically, the sEPCR can be developed as risk factor for sickle CKD. Finally, our data suggest that restoration of EPCR function may protect SCD patients from CKD. Disclosures No relevant conflicts of interest to declare.

Causes, dynamics and financial losses associated with red offal condemnation at a beef abattoir in Namibia

There are limited studies on red offal condemnations and their financial implications at high throughput abattoirs in Namibia. Causes of condemnation, temporal distributions and financial losses associated with red offal condemnations at a beef abattoir in Namibia from 2016 to 2018 were determined. A total of 39157 red offal valued at N$6 422 586.00 (US$364 805) were condemned following the slaughter of 251697 cattle. Condemnations were dependent on the year [X 2 (14) = 587.13, p<0.001], month [X 2 (77) = 1898.72, p<0.001] and season [X 2 (7) = 111.12, p<0.001] of study. Overall, 2016 had the most and 2018 the least condemnation of red offal (38.73% and 23.22%, respectively; p<0.05). Most red offal condemnations (13.34%, p<0.001) occurred in June, with livers and lungs as the most condemned organs (54.32% and 29.88%, respectively; p<0.001). The highest condemnations were caused by miscellaneous causes (such as abscesses and hematomas) followed, in descending order, by inflammatory, parasitic and bacterial causes and contaminations (38.3%, 29.4%, 16.6% and 15.8%, respectively, p<0.05). Liver condemnations varied with the year and season under study [X 2 (20) = 1834.02, p<0.001 and X 2 (9) = 1010.43, p<0.001; respectively], as were lung condemnations according to pathological condition [X 2 (12) = 492.43, p<0.001 and X 2 (6) = 45.84, p<0.001; respectively]. The occurrence of hydatidosis in the summer and pneumonia in winter were greater than expected (15.1% and 4.3%; respectively, p<0.05). A substantial loss of revenue to the abattoir due to the condemnation of livers and lungs was determined. Meat inspection served as a control point for hydatidosis.

Inventory Management Evaluation and Inventory Forecast Using EOQ

The fashion industry that is gamis in Indonesia is growing rapidly because the majority of the population is Moslem. Elzatta is a company that does business on Moslem clothing, one of its products is the gamis. The company is experiencing problems with stockpiling in warehouses, because of models that were not sold, as well as outdated models. With the accumulation of products in warehouses in 2017 and 2018, many products will be damaged. For this reason, the company runs a buy one get one business strategy and sells products at low prices. As a result, the company suffered a substantial loss. For this reason, it is necessary to evaluate the inventory management that has been carried out using the EOQ model. For 2019, it is necessary to plan the number of products to be sold and apply the EOQ model. The results of evaluations in 2017 and 2018, by using EOQ the company could save 64.78% for 2017 and 63.40% for 2018. Whereas for 2019, after forecasting the number of sales using the seasonal model, sales projections are similar to the number of sales in the previous years, so that the number of products needed for a single order is 1364 pcs.

Effects of the Invasion of Caulerpa cylindracea in a Cymodocea nodosa Meadow in the Northern Adriatic Sea

Graphical AbstractEffects of the presence of the invasive macroalgae C. cylindracea in the seagrass meadow evidenced by substantial loss in below-ground biomass of C. nodosa and lowering of the redox transition depth in the sediment underlying the mixed settlement.

Assessment of Salts Effect in Sugar-aqueous System

In the present study, the preferential salvation of salts in sugar-aqueous systems has been considered. It is carried out by using conductometric observation of analytical grade sugar and plantation white sugar aqueous system with salts viz. CaCl2, MgCl2, KCl, NaCl. It shows that the conductivity is in a linear relationship with the electrolytes and non-sugar present in both analytical grade sugar and plantation white sugar over a range of 5 to 25 W/V percent. The optimum range of concentration found to be for both the sugars is about 20%. Encouraging results could be obtained in the determination of sugars i.e. non-electrolytes and electrolytes in aqueous sugar solution products. The present study shows valid technological interest to understand the Maillard reaction due to the adoption of MgCl2 salt in place of sulphite. These sugars–salts complexes are responsible for the formation of molasses which leads to substantial loss of sugar of around ten percent of the total sugar present in cane.

A Feasibility Study for Developing a Computerized Adaptive Form of Raven’s Colored Progressive Matrices Test for Omani Children Based on the Item Response Theory

The current study investigated the feasibility of developing a computerized adaptive form of Raven’s Colored Progressive Matrices test, one of the most important culture-free intelligent tests, using the Item Response Theory. The test consists of 36 items divided into three groups. The data used in the current study were adapted from the study by Kadhim et al. (2008), which included 1042 subjects, aged 5 to 10 from both genders and distributed into 11 Omani governorates. Item Response Theory assumptions were met and then the mirtCAT package was used to evaluate a computerized adaptive form of the test. Raven’s test items were compatible with the three-parameter model which was used to scale the test items. The Maximum Fisher Information method was used to select items in the adaptive form. The full and the adaptive forms were compared to each other across the different simulated conditions in the current study. The results indicated that using 17 items of the adaptive form could accurately estimate the subjects’ abilities without a substantial loss of information. The previous finding is a preliminary indication of the possibility of developing an adaptive form of the colored progressive matrices test that can be used in various assessments that practitioners may need to assess, classify or diagnose children.

Stoichiometric Excess of H2O2 as Strategy of Oxidant Dosing for Intensifying Both Degradation and Mineralization of the Hydrochlorothiazide via UVCH2O2, Dark-Fenton, and Photo-Fenton

<div>Hydrochlorothiazide (HCT) is a pharmaceutical micropollutant highly toxic to the environment, being strictly mandatory to oxidize it completely toward CO2. In this context, how could the HCT oxidation via advanced oxidative processes benefit from the accelerated oxidation rates promoted by the mineralization stoichiometric excess of H2O2 ? Overall, this work elucidates the role of stoichiometric H2O2 concentration on promoting fast degradation/mineralization rates across Advanced Oxidative Processes (AOP). Employing 0.68 excess of H2O2, it was found absolute (100%) HCT degradation within 60 minutes and 95% within 30 min for UVC-H2O2 oxidation; however, the mineralization of HCT suffered limited optimization even at high H2O2 excess, being at the best performance 26.76% HCT mineralized via UVC photo-Fenton within 60 min at initial 2.00 H2O2 excess. Very presumably, the evaporation of H2O2 was the underlying reason for a low mineralization performance. Together with a detailed mathematical methodology, the time-synchronized evolution of both the residual H2O2 concentration and the TOC depletion were employed to infer the quantity of radical ∙OH that effectively was consumed by the micropollutant mineralization. The global mean efficiency of radicals •OH consumption by the HCT mineralization laid around 15% for UVC Fenton considering H2O2 excess of 2.00. Under these conditions, the residual H2O2 concentration depletes significantly within 30 minutes of UVC photo-Fenton oxidation, which indicates that either the solution heating or stirring is very likely to promote a substantial loss of H2O2 by evaporation in the beaker-assembled reactor<br></div>

Stoichiometric Excess of H2O2 as Strategy of Oxidant Dosing for Intensifying Both Degradation and Mineralization of the Hydrochlorothiazide via UVCH2O2, Dark-Fenton, and Photo-Fenton

<div>Hydrochlorothiazide (HCT) is a pharmaceutical micropollutant highly toxic to the environment, being strictly mandatory to oxidize it completely toward CO2. In this context, how could the HCT oxidation via advanced oxidative processes benefit from the accelerated oxidation rates promoted by the mineralization stoichiometric excess of H2O2 ? Overall, this work elucidates the role of stoichiometric H2O2 concentration on promoting fast degradation/mineralization rates across Advanced Oxidative Processes (AOP). Employing 0.68 excess of H2O2, it was found absolute (100%) HCT degradation within 60 minutes and 95% within 30 min for UVC-H2O2 oxidation; however, the mineralization of HCT suffered limited optimization even at high H2O2 excess, being at the best performance 26.76% HCT mineralized via UVC photo-Fenton within 60 min at initial 2.00 H2O2 excess. Very presumably, the evaporation of H2O2 was the underlying reason for a low mineralization performance. Together with a detailed mathematical methodology, the time-synchronized evolution of both the residual H2O2 concentration and the TOC depletion were employed to infer the quantity of radical ∙OH that effectively was consumed by the micropollutant mineralization. The global mean efficiency of radicals •OH consumption by the HCT mineralization laid around 15% for UVC Fenton considering H2O2 excess of 2.00. Under these conditions, the residual H2O2 concentration depletes significantly within 30 minutes of UVC photo-Fenton oxidation, which indicates that either the solution heating or stirring is very likely to promote a substantial loss of H2O2 by evaporation in the beaker-assembled reactor<br></div>

Sulfonated Tetraphenylethylene-Based Hypercrosslinked Polymer as a Heterogeneous Catalyst for the Synthesis of Symmetrical Triarylmethanes via a Dual C–C Bond-Cleaving Path

A sulfonic acid functionalized tetraphenylethylene-based hypercrosslinked polymer (THP-SO3H) with a well-developed porous network and accessible sulfonic acid sites was synthesized and characterized by different analytical techniques. The catalytic prowess of the synthesized material THP-SO3H was investigated in a challenging dual C–C bond-breaking reaction for the synthesis of symmetrical triarylmethanes (TRAMs) in high yield. The scope of the developed metal-free method was also explored with a wide variety of substrates. The organocatalyst can be easily recovered by filtration and reused up to five consecutive cycles without substantial loss in its catalytic efficacy.