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Masivna opstetrička krvarenja učestali su uzrok smrti rodilja u zemljama u razvoju, ali i u razvijenim zemljama. Najnoviji epidemiološki podatci upozoravaju na njihov trend rasta u razvijenim zemljama, što ukazuje na istinsku potrebu za njihovim dubljim razumijevanjem. Stoga je cilj ovoga narativnog preglednog rada na temelju pretraživanja dostupne literature (baze podataka Web of Science [All Databases] i Scopus) čitateljima dati uvid u najnovije dijagnostičke i terapijske pristupe ovome važnom medicinskom problemu. Utvrdili smo kako uterotonici i dalje čine osnovu liječenja te kako su standardni koagulacijski testovi sve manje zastupljeni u dijagnostici, dok je naglasak stavljen na analize „point of care“ poput tromboelastografije i tromboelastometrije. Zaključno, nužno je poznavanje i usvajanje intervencijskih algoritama masivnih opstetričkih krvarenja te uvježban multidisciplinaran pristup u svakom rodilištu.

It is hard to imagine living in a color-free world, where color is weaved at every moment of life, and used to determine everything from our appearance to our mood. Humans perceive color before shape, words, or movement; the trait of color is to give contrast, contradiction, homogeneity, and harmony in the combination of the overall visual unit of design. This is reflected in trademark design, where choosing its colors correctly helps communicate better and more effectively with the target audience. When choosing the trademark colors, you also choose the feelings and associations that it seeks to evoke with the audience, and the color becomes a shortcut for conveying visual details for that trademark. The subjective experience of the target audience is one of the important factors that influence their perception for color connotations in trademark. It also plays an important role in the process of visual perception, as it helps interpret new things and give them meaning. The subjective experience also affects the interpretation of the symbols used in the trademark; as it gives the target audience the meanings of things he perceives and helps him understand the trademark. This subjective experience is built by many factors such as family, cultural and social environment.The research attempts to clarify the importance of the designer's study of the subjective experience of target audience in order to choose the color of the trademark that is appropriate to them and that does not conflict with their culture or experience.

There is growing demand for separation of 90Y carrier free from 90Sr coexisting to produce high purity 90Y essential for radiopharmaceutical uses. Thus, in this context the sorption profiles of Y3+ and Sr2+ from aqueous solutions containing diethylenetriaminepenta acetic acid (DTPA), ethylenediaminetetra-acetic acid (EDTA), acetic acid, citric acid, or NaCl onto Chelex-100 (anion ion exchange) solid sorbent were critically studied for developing an efficient and low-cost methodology for selective separation of Y3+ from Sr2+ ions (1.0 × 10−5 M). Batch experiments displayed relative chemical extraction percentage (98 ± 5.4%) of Y3+ from aqueous acetic acid solution onto Chelex-100 (anion ion exchanger), whereas Sr2+ species showed no sorption. Hence, a selective separation of Y3+ from its parent 90Sr2+ has been established based upon percolation of the aqueous solution of Y3+ and Sr2+ ions containing acetic acid at pH 1-2 through Chelex-100 sorbent packed column at a 2 mL min−1 flow rate. Y3+ species were retained quantitatively while Sr2+ ions were not sorbed and passed through the sorbent packed column without extraction. The sorbed Y3+ species were then recovered from the sorbent packed column with HNO3 (1.0 M) at a 1.0 mL min−1 flow rate. A dual extraction mechanism comprising absorption associated to “weak-base anion exchanger” and “solvent extraction” of Y3+ as (YCl6)3− and an extra part for “surface adsorption” of Y3+ by the sorbent is proposed. The established method was validated by measuring the radiochemical (99.2 ± 2 1%), radionuclide purity and retardation factor (Rf = 10.0 ± 0.1 cm) of 90Y3+ recovered in the eluate. Ultimately, the sorbent packed column also presented high stability for reusing 2-3 cycles without drop in its efficiency (±5%) towards Y3+ uptake and relative chemical recovery. A proposed flow sheet describing the analytical procedures for the separation of 90Y3+ from 90Sr2+ using chelating Chelex 100 (anion exchange) packed column is also included.

The multiple rogue wave solutions technique is engaged to seek the multifold soliton solutions for the generalized (2 + 1)‐dimensional Kadomtsev–Petviashvili (gKP) equation, which contains one wave, two waves, and triple waves solutions. The second‐order derivative will be perused to get the minimum or maximum amount of lump solution. For one case, the lump solution will be shown the bright‐dark lump structure, and for another case, the dark lump structure two small peaks and one deep hole can be present. Also, the interaction of lump with periodic waves and the interaction between the lump and two stripe solitons can be catched by introducing the Hirota forms. Simultaneously, the interaction between k‐lump and k‐stripe soliton wave solutions can be gained by the Hirota operator. The physical phenomena of these gained multiple soliton solutions are analyzed and indicated in diagrams by choosing proper amounts. [ABSTRACT FROM AUTHOR]

The coccyx, the last segment of the spine, joins the sacrum at the base. It has three to five vertebrae, which are typically fused. In front of the sacrococcygeal junction is the ganglion impar, the only unpaired autonomic ganglion. The two sympathetic chains come to a close there. The impar ganglion is traversed by sympathetic nerves carrying pain fibers from the perineum, distal sections of the rectum, the vagina and the urethra. The painful disorder known as coccygodynia, which affects the tail end of the spine, is frequently brought on by birth trauma or is caused by an unidentified factor. Even though the pain may go away on its own or with therapy, it may also linger and worsen over time. Due to increased stress from the female pelvis on the coccyx, it affects women five times more frequently than it does men. Conservative, invasive or surgical treatment options are available for coccygodynia (partial or total coccygectomy). Rest, nonsteroidal anti-inflammatory medicines (NSAIDs) or COX-2 inhibitors, acupuncture, coccyx cushions, physical therapy, manual therapy and invasive therapy, which involves ganglion impar block with injections of local anesthetic and corticosteroid under fluoroscopy, followed by radiofrequency ablation, spinal cord stimulation (SCS) or peripheral nerve stimulation, are examples of conservative treatments. Coccygectomy is recommended in refractory situations.

The gathered information elucidated that subfamily Meligethinae is represented in Egypt by 10 species in nine genera. This study was planned to identify and to determine the recent taxonomic status of this group of meligethins species in Egypt. An illustrated key was given for all Meligethinae genera and species. [ABSTRACT FROM AUTHOR]

The linear stability of two stationary dipolar modon solutions of the nondivergent barotropic vorticity equation on a rotating sphere is investigated. A numerical normal mode analysis of the linearized equation is performed by solving the eigenvalue problem in a spectral model. The modons are models of observed vortical structures in the atmosphere such as planetary waves and atmospheric blocks. The wavelike modon in an eastward zonal flow represents the class of partially localized vortical waves with phase velocities inside the Rossby wave regime. The localized modon in a westward zonal flow represents the class of desingularized point vortex pairs with phase velocities outside the Rossby wave regime. The research into the stability properties of these modons may lead to a deeper insight into the decay and persistency of planetary waves and atmospheric blocks and thereby into the low-frequency variability of the atmosphere. The convergence of the modes with resolution is studied with the matrix method for each resolution T10-T100 and with the iterative power method for every five resolutions T80-T170 and for T341. The modes are tracked through the resolutions using correlations between eigenvectors at subsequent resolutions. The four most unstable modes of the wavelike modon are convergent over T22. For the localized modon, the most unstable mode is convergent over T66, whereas other modes appear to converge to zero growth rate over T100. Both modons are unstable with an e-folding time of several days. The structure of the modes is studied in detail for resolution T85. The most unstable modes have their largest local amplitudes in regions with the strongest gradients of potential vorticity. The modes propagate around the amphidromic points, local centers of revolution, which characterize the topological structure of the modes. The most unstable mode of the wavelike modon has a tripolar structure and propagates unhindered across the boundary circle between the inner and outer region of the modon. The most unstable mode of the localized modon has a quadrupolar structure and propagates north and south of the boundary circle, which is a critical line and an impenetrable barrier. The modons are representatives of two different classes of vortical structures and their quite distinct mode structures can be understood using the refractive index interpretation. The Eliassen-Palm theorem applied to modes as perturbations on modons leads to a condition on the mean spectral wavenumber for an unstable mode: the barotropic wedge of instability in the diagram of perturbation relative vorticity versus perturbation streamfunction. A causal argument regarding the time required for an instability to radiate propagating waves leads to the phase speed condition for a global propagating mode: the spatial extent of the mode is related to the ratio of its e-folding time and oscillation period. These theoretical results are supported by high-resolution numerical results: wavelike modons have localized (trapped) modes, whereas localized modons have all but one wavelike (radiating) mode. The localized modon has a single isolated unstable mode with an additional continuum of propagating neutral modes. For both modons, the most unstable mode propagates eastward between the cells in the inner region and westward along the boundary circle in the outer region.

The gathered information indicated that subfamily Brachycerinae is represented in Egypt by a single genus, Brachycerus that contains 8 species. Their diagnostic characters were introduced in this work according to previous investigators. This study was planned to identify and to determine the recent taxonomic status of Brachycerides species for the first time in Egypt. An illustrated key was given for all Brachycerides species. [ABSTRACT FROM AUTHOR]

In Egypt genus Leichenum is represented by two species, Leichenum mulleri Grid., 1939 and Leichenum pulchellum Kust., 1849. Few studies have reported on both species all over the world. Both species are difficult for species identification so, the present study was examined specimens by SEM and found microstructural characters that facilitate identification of them. A number of new characters were added to the previous e.g. shape of setae and other vestitures, shape and structure of the intercoxal processes and submentum, also some old characters were emended. [ABSTRACT FROM AUTHOR]

Pearson's chi-squared test can detect outliers in the data distribution of a given set of histograms. However, in fields such as demographics (for e.g. birth years), outliers may be more easily found in terms of the histogram smoothness where techniques such as Whipple's or Myers' indices handle successfully only specific anomalies. This paper proposes smoothness outliers detection among histograms by using the relation between their discrete total variations (DTV) and their respective sample sizes. This relation is mathematically derived to be applicable in all cases and simplified by an accurate linear model. The deviation of the histogram's DTV from the value predicted by the model is used as the outlier score and the proposed method is named Total Variation Outlier Recognizer (TVOR). TVOR requires no prior assumptions about the histograms' samples' distribution, it has no hyperparameters that require tuning, it is not limited to only specific patterns, and it is applicable to histograms with the same bins. Each bin can have an arbitrary interval that can also be unbounded. TVOR finds DTV outliers easier than Pearson's chi-squared test. In case of distribution outliers, the opposite holds. TVOR is tested on real census data and it successfully finds suspicious histograms. The source code is given at https://github.com/DiscreteTotalVariation/TVOR.

Subfamily Meloinae, were represented by 5 tribes: Cerocomini Leach, 1815, Epicautini Denier, 1935, Lyttini Solier, 1851, Mylabrini Laporte, 1840 and Meloini Gyllenhal, 1810. Tribe Mylabrini was covered by Elmetwaly et. al. (2015), and trbie Meloini was covered by El-Gharbawy (2006). Accordingly, the present study was planned to revise and update the available information about tribe Cercomini, Epicautini and Lyttini. Key to the tribes and species was treated. During the present work, twenty two species in ten genera recorded in three tribes are covered in the present work. [ABSTRACT FROM AUTHOR]

Arterial media calcification refers to the pathological deposition of calcium phosphate crystals in the arterial wall. This pathology is a common and life-threatening complication in chronic kidney disease, diabetes and osteoporosis patients. Recently, we reported that the use of a TNAP inhibitor, SBI-425, attenuated arterial media calcification in a warfarin rat model. Employing a high-dimensionality unbiased proteomic approach, we also investigated the molecular signaling events associated with blocking arterial calcification through SBI-425 dosing. The remedial actions of SBI-425 were strongly associated with (i) a significant downregulation of inflammatory (acute phase response signaling) and steroid/glucose nuclear receptor signaling (LXR/RXR signaling) pathways and (ii) an upregulation of mitochondrial metabolic pathways (TCA cycle II and Fatty Acid β-oxidation I). Interestingly, we previously demonstrated that uremic toxin-induced arterial calcification contributes to the activation of the acute phase response signaling pathway. Therefore, both studies suggest a strong link between acute phase response signaling and arterial calcification across different conditions. The identification of therapeutic targets in these molecular signaling pathways may pave the way to novel therapies against the development of arterial media calcification.

Arterial media calcification is an active cell process. This encompasses osteochondrogenic transdifferentiation of vascular smooth muscle cells followed by the deposition of calcium-phosphate crystals. Increasing evidence suggests a significant role for endothelial cells (ECs) in the development of arterial media calcification. This manuscript explores a role for endothelial dysfunction in the disease progression of arterial media calcification. Male rats were randomly assigned to four different groups. The first group received standard chow. The second group was given L-NAME (≈50 mg kg -1 · d -1 ), to induce endothelial dysfunction, in addition to standard chow. The third group and fourth group received a warfarin-supplemented diet to induce mild calcification and the latter group was co-administered L-NAME. Prior to sacrifice, non-invasive measurement of aortic distensibility was performed. Animals were sacrificed after 6 weeks. Arterial media calcification was quantified by measuring aortic calcium and visualized on paraffin-embedded slices by the Von Kossa method. Arterial stiffness and aortic reactivity was assessed on isolated carotid segments using specialized organ chamber setups. Warfarin administration induced mineralization. Simultaneous administration of warfarin and L-NAME aggravated the arterial media calcification process. Through organ chamber experiments an increased vessel tonus was found, which could be linked to reduced basal NO availability, in arteries of warfarin-treated animals. Furthermore, increased calcification because of L-NAME administration was related to a further compromised endothelial function (next to deteriorated basal NO release also deteriorated stimulated NO release). Our findings suggest early EC changes to impact the disease progression of arterial media calcification., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Current treatment strategies for chronic kidney disease (CKD) mainly focus on controlling risk factors. Metformin, a first-line drug for type 2 diabetes, exerts beneficial pleiotropic actions beyond its prescribed use and incipient data have revealed protective effects against the development of kidney impairment. This study evaluated the therapeutic efficacy of metformin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor recently approved by the United States Food and Drug Administration to treat diabetic nephropathy, in slowing the progression of established non-diabetic CKD. Rats with adenine-induced CKD were assigned to different treatment groups to receive either 200 mg/kg metformin, four or five weeks after the start of the adenine diet (established mild-moderate CKD), or 25 mg/kg canagliflozin four weeks after the start of the diet, by daily oral gavage administered during four weeks. Each treatment group was compared to a vehicle group. Chronic adenine dosing resulted in severe CKD in vehicle-treated rats as indicated by a marked rise in serum creatinine levels, a marked decrease in creatinine clearance, and a disturbed mineral metabolism. Metformin, but not canagliflozin, halted functional kidney decline. Additionally, kidneys of metformin-treated animals showed less interstitial area and inflammation as compared to the vehicle group. Proteomic analyses revealed that metformin's kidney-protective effect was associated with the activation of the Hippo signaling pathway, a highly conserved multiprotein kinase cascade that controls tissue development, organ size, cell proliferation, and apoptosis. Thus, metformin demonstrated therapeutic efficacy by halting the progression of established CKD in a rat model., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Sclerostin is a negative regulator of the Wnt/β-catenin signaling and is, therefore, an important inhibitor of bone formation and turnover. Because ectopic vascular calcification develops in a similar way to bone formation, one might reasonably attribute a role to sclerostin in this pathological process. Ectopic calcification, especially vascular calcification, importantly contributes to mortality in elderly and patients with diabetes, osteoporosis, chronic kidney disease (CKD), and hypertension. The central players in this ectopic calcification process are the vascular smooth muscle cells that undergo dedifferentiation and thereby acquire characteristics of bonelike cells. Therefore, we hypothesize that depletion/deactivation of the Wnt/β-catenin signaling inhibitor sclerostin may promote the development of ectopic calcifications through stimulation of bone-anabolic effects at the level of the arteries. We investigated the role of sclerostin (encoded by the Sost gene) during vascular calcification by using either Sost -/- mice or anti-sclerostin antibody. Sost -/- and wild-type (WT) mice (C57BL/6J background) were administered an adenine-containing diet to promote the development of CKD-induced vascular calcification. Calcifications developed more extensively in the cardiac vessels of adenine-exposed Sost -/- mice, compared to adenine-exposed WT mice. This could be concluded from the cardiac calcium content as well as from cardiac tissue sections on which calcifications were visualized histochemically. In a second experiment, DBA/2J mice were administered a warfarin-containing diet to induce vascular calcifications in the absence of CKD. Here, warfarin exposure led to significantly increased aortic and renal tissue calcium content. Calcifications, which were present in the aortic medial layer and renal vessels, were significantly more pronounced when warfarin treatment was combined with anti-sclerostin antibody treatment. This study demonstrates a protective effect of sclerostin during vascular calcification. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Arterial medial calcification (AMC) is the deposition of calcium phosphate in the arteries. AMC is widely thought to share similarities with physiological bone formation; however, emerging evidence suggests several key differences between these processes. N-acetylcysteine (NAC) displays antioxidant properties and can generate hydrogen sulphide (H 2 S) and glutathione (GSH) from its deacetylation to l-cysteine. This study found that NAC exerts divergent effects in vitro, increasing osteoblast differentiation and bone formation by up to 5.5-fold but reducing vascular smooth muscle cell (VSMC) calcification and cell death by up to 80%. In vivo, NAC reduced AMC in a site-specific manner by 25% but had no effect on the bone. The actions of l-cysteine and H 2 S mimicked those of NAC; however, the effects of H 2 S were much less efficacious than NAC and l-cysteine. Pharmacological inhibition of H 2 S-generating enzymes did not alter the actions of NAC or l-cysteine; endogenous production of H 2 S was also unaffected. In contrast, NAC and l-cysteine increased GSH levels in calcifying VSMCs and osteoblasts by up to 3-fold. This suggests that the beneficial actions of NAC are likely to be mediated via the breakdown of l-cysteine and the subsequent GSH generation. Together, these data show that while the molecular mechanisms driving the actions of NAC appear similar, the downstream effects on cell function differ significantly between osteoblasts and calcifying VSMCs. The ability of NAC to exert these differential actions further supports the notion that there are differences between the development of pathological AMC and physiological bone formation. NAC could represent a therapeutic option for treating AMC without exerting negative effects on bone., (© 2021 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Purpose: The purpose of this study was to determine the learning curve for total operative time using a novel cutting guide positioning robotic assistant for total knee arthroplasty (raTKA). Additionally, we compared complications and final limb alignment between raTKA and manual TKA (mTKA), as well as accuracy to plan for raTKA cases., Methods: We performed a retrospective cohort study on a series of patients (n = 180) that underwent raTKA (n = 90) using the ROSA Total Knee System or mTKA (n = 90) by one of three high-volume (> 200 cases per year) orthopaedic surgeons between December 2019 and September 2020, with minimum three-month follow-up. To evaluate the learning curve surgical times and postoperative complications were reviewed., Results: The cumulative summation analysis for total operative time revealed a change point of 10, 6, and 11 cases for each of three surgeons, suggesting a rapid learning curve. There was a significant difference in total operative times between the learning raTKA and both the mastered raTKA and mTKA groups (p = 0.001) for all three surgeons combined. Postoperative complications were minimal in all groups. The proportion of outliers for the final hip-knee-ankle angle compared to planned was 5.2% (3/58) for the mastered raTKA compared to 24.1% (19/79) for mTKA (p = 0.003). The absolute mean difference between the validated and planned resections for all angles evaluated was < 1 degree for the mastered raTKA cases., Conclusion: As the digital age of medicine continues to develop, advanced technologies may disrupt the industry, but should not disrupt the care provided. This cutting guide positioning robotic system can be integrated relatively quickly with a rapid initial learning curve (6-11 cases) for operative times, similar 90-day complication rates, and improved component positioning compared to mTKA. Proficiency of the system requires additional analysis, but it can be expected to improve over time., Level of Evidence: Level III Retrospective Therapeutic Cohort Study., (© 2021. The Author(s).)

Arterial media calcification (AMC) is predominantly regulated by vascular smooth muscle cells (VSMCs), which transdifferentiate into pro-calcifying cells. In contrast, there is little evidence for endothelial cells playing a role in the disease. The current study investigates cellular functioning and molecular pathways underlying AMC, respectively by, an ex vivo isometric organ bath set-up to explore the interaction between VSMCs and ECs and quantitative proteomics followed by functional pathway interpretation. AMC development, which was induced in mice by dietary warfarin administration, was proved by positive Von Kossa staining and a significantly increased calcium content in the aorta compared to that of control mice. The ex vivo organ bath set-up showed calcified aortic segments to be significantly more sensitive to phenylephrine induced contraction, compared to control segments. This, together with the fact that calcified segments as compared to control segments, showed a significantly smaller contraction in the absence of extracellular calcium, argues for a reduced basal NO production in the calcified segments. Moreover, proteomic data revealed a reduced eNOS activation to be part of the vascular calcification process. In summary, this study identifies a poor endothelial function, next to classic pro-calcifying stimuli, as a possible initiator of arterial calcification.

Patients with chronic kidney disease (CKD) suffer from arterial media calcification and a disturbed bone metabolism. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the calcification inhibitor pyrophosphate (PPi) into inorganic phosphate (Pi) and thereby stimulates arterial media calcification as well as physiological bone mineralization. This study investigates whether the TNAP inhibitor SBI-425, PPi or the combination of both inhibit arterial media calcification in an 0.75% adenine rat model of CKD. Treatments started with the induction of CKD, including (i) rats with normal renal function (control diet) treated with vehicle and CKD rats treated with either (ii) vehicle, (iii) 10 mg/kg/day SBI-425, (iv) 120 µmol/kg/day PPi and (v) 120 µmol/kg/day PPi and 10 mg/kg/day SBI-425. All CKD groups developed a stable chronic renal failure reflected by hyperphosphatemia, hypocalcemia and high serum creatinine levels. CKD induced arterial media calcification and bone metabolic defects. All treatments, except for SBI-425 alone, blocked CKD-related arterial media calcification. More important, SBI-425 alone and in combination with PPi increased osteoid area pointing to a less efficient bone mineralization. Clearly, potential side effects on bone mineralization will need to be assessed in any clinical trial aimed at modifying the Pi/PPi ratio in CKD patients who already suffer from a compromised bone status.

Arterial calcification, the deposition of calcium-phosphate crystals in the extracellular matrix, resembles physiological bone mineralization. It is well-known that extracellular nucleotides regulate bone homeostasis raising an emerging interest in the role of these molecules on arterial calcification. The purinergic independent pathway involves the enzymes ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs), ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), 5'-nucleotidase and alkaline phosphatase. These regulate the production and breakdown of the calcification inhibitor-pyrophosphate and the calcification stimulator-inorganic phosphate, from extracellular nucleotides. Maintaining ecto-nucleotidase activities in a well-defined range is indispensable as enzymatic hyper- and hypo-expression has been linked to arterial calcification. The purinergic signaling dependent pathway focusses on the activation of purinergic receptors (P1, P2X and P2Y) by extracellular nucleotides. These receptors influence arterial calcification by interfering with the key molecular mechanisms underlying this pathology, including the osteogenic switch and apoptosis of vascular cells and possibly, by favoring the phenotypic switch of vascular cells towards an adipogenic phenotype, a recent, novel hypothesis explaining the systemic prevention of arterial calcification. Selective compounds influencing the activity of ecto-nucleotidases and purinergic receptors, have recently been developed to treat arterial calcification. However, adverse side-effects on bone mineralization are possible as these compounds reasonably could interfere with physiological bone mineralization.

Introduction: Sucroferric oxyhydroxide (PA21) is an efficacious, well-tolerated iron-based phosphate binder and a promising alternative to existing compounds. We compared the effects of PA21 with those of a conventional phosphate binder on renal function, mineral homeostasis and vascular calcification in a chronic kidney disease-mineral and bone disorder (CKD-MBD) rat model., Methods: To induce stable renal failure, rats were administered a 0.25% adenine diet for 8 weeks. Concomitantly, rats were treated with vehicle, 2.5 g/kg/day PA21, 5.0 g/kg/day PA21 or 3.0 g/kg/day calcium carbonate (CaCO3). Renal function and calcium/phosphorus/iron metabolism were evaluated during the study course. Renal fibrosis, inflammation, vascular calcifications and bone histomorphometry were quantified., Results: Rats treated with 2.5 or 5.0 g/kg/day PA21 showed significantly lower serum creatinine and phosphorus and higher ionized calcium levels after 8 weeks of treatment compared with vehicle-treated rats. The better preserved renal function with PA21 went along with less severe anaemia, which was not observed with CaCO3. Both PA21 doses, in contrast to CaCO3, prevented a dramatic increase in fibroblast growth factor (FGF)-23 and significantly reduced the vascular calcium content while both compounds ameliorated CKD-related hyperparathyroid bone., Conclusions: PA21 treatment prevented an increase in serum FGF-23 and had, aside from its phosphate-lowering capacity, a beneficial impact on renal function decline (as assessed by the renal creatinine clearance) and related disorders. The protective effect of this iron-based phosphate binder on the kidney in rats, together with its low pill burden in humans, led us to investigate its use in patients with impaired renal function not yet on dialysis., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Arterial media calcification is frequently seen in elderly and patients with chronic kidney disease (CKD), diabetes and osteoporosis. Pyrophosphate is a well-known calcification inhibitor that binds to nascent hydroxyapatite crystals and prevents further incorporation of inorganic phosphate into these crystals. However, the enzyme tissue-nonspecific alkaline phosphatase (TNAP), which is expressed in calcified arteries, degrades extracellular pyrophosphate into phosphate ions, by which pyrophosphate loses its ability to block vascular calcification. Here, we aimed to evaluate whether pharmacological TNAP inhibition is able to prevent the development of arterial calcification in a rat model of warfarin-induced vascular calcification. To investigate the effect of the pharmacological TNAP inhibitor SBI-425 on vascular calcification and bone metabolism, a 0.30% warfarin rat model was used. Warfarin exposure resulted in distinct calcification in the aorta and peripheral arteries. Daily administration of the TNAP inhibitor SBI-425 (10 mg/kg/day) for 7 weeks significantly reduced vascular calcification as indicated by a significant decrease in calcium content in the aorta (vehicle 3.84 ± 0.64 mg calcium/g wet tissue vs TNAP inhibitor 0.70 ± 0.23 mg calcium/g wet tissue) and peripheral arteries and a distinct reduction in area % calcification on Von Kossa stained aortic sections as compared to vehicle. Administration of SBI-425 resulted in decreased bone formation rate and mineral apposition rate, and increased osteoid maturation time and this without significant changes in osteoclast- and eroded perimeter. Administration of TNAP inhibitor SBI-425 significantly reduced the calcification in the aorta and peripheral arteries of a rat model of warfarin-induced vascular calcification. However, suppression of TNAP activity should be limited in order to maintain adequate physiological bone mineralization., Competing Interests: Declaration of competing interest A.B.P. and J.L.M. are co-inventors on a patent application covering SBI-425 (PCT WO 2013126608). B.O., A.V., P.D.H. and E.N. have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG 2 ) 2 -IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG 2 ) 2 -IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG 2 ) 2 -IP4 disrupts the nucleation and growth of pathological calcification.

Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)