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Chronic kidney disease (CKD) results in calcitriol deficiency and altered vitamin D metabolism. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D 3 and 1,25(OH) 2 D 3 in a cross-sectional analysis of participants with a range of kidney function assessed by precise measured GFR (mGFR) (N = 143) and in rats with the induction and progression of experimental kidney disease. Vitamin D metabolites were assessed with LC–MS/MS. Circulating measures of 24-hydroxylation of 25(OH)D 3 (24,25(OH) 2 D 3 :25(OH)D 3 ) precisely decreased according to mGFR in humans and progressively in rats with developing CKD. In contrast, the 1,24,25(OH)3D3: 1,25(OH) 2 D 3 vitamin D metabolite ratio increased in humans as the mGFR decreased and in rats with the induction and progression of CKD. Human participants taking cholecalciferol had higher circulating 1,24,25(OH) 3 D 3 , despite no increase of 1,25(OH) 2 D 3 . This first report of circulating 1,24,25(OH) 3 D 3 in the setting of CKD provides novel insight into the uniquely altered vitamin D metabolism in this setting. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies. The potential that 24-hydroxylated products have biological activity of is an important area of future research.

Abstract Context Dietary consumption of phosphate is increasing, and elevated serum phosphate is associated with increased cardiovascular disease (CVD) risk. Sex differences in phosphate homeostasis and response to changes in dietary phosphate intake, which are not captured by clinically measured analytes, may contribute to differences in CVD presentation and bone disease. Objective To assess sex differences in acute phosphate homeostasis in response to a single oral phosphate challenge. Design Cross-sectional. Setting General community. Participants 78 participants (40-76 years) with measured glomerular filtration rate >60 mL/min/1.73 m2 and no clinically diagnosed CVD and 14 young healthy adults. Main Outcome Measures To elucidate subtle alterations in phosphate homeostasis, we employ an acute challenge whereby the hormonal response, circulating mineral levels, and urinary excretion are assessed following an oral challenge of phosphate. Results Although both males and females had similar changes in circulating phosphate, calcium, and parathyroid hormone in response to the challenge, females excreted ∼1.9x more phosphate and ∼2.7x more calcium than males, despite not consuming calcium. These sex differences were recapitulated in healthy young adults. This excretion response did not correlate to age, serum phosphate, or estradiol levels. The females with greater excretion of phosphate had higher levels of bone resorption markers compared to formation markers. Conclusions Taken together, these data identify sex differences in acute phosphate homeostasis, specifically that females may mobilize and excrete endogenous sources of calcium and phosphate in response to oral phosphate compared to males. While high levels of dietary phosphate negatively impact bone, our results suggest that females may incur more risk from these diets.

The purpose of this review is to summarize the research to date on the impact of chronic kidney disease (CKD) on the vitamin K metabolome. Vitamin K-dependent proteins contribute to cardiovascular disease (CVD) prevention via the prevention of ectopic mineralization. Sub-clinical vitamin K deficiency is common in CKD patients, and evidence suggests that it may contribute to the CVD burden in this population. Research from animal models suggests that CKD alters tissue measures of the two predominant forms of vitamin K: KI and MK-4. The expression and/or activity of enzymes that regulate the recycling of vitamin K and the carboxylation of vitamin K-dependent proteins also appear to be altered in CKD. Evidence suggests that statins, a common pharmaceutical prescribed to CKD patients to prevent cardiovascular events, may impact the metabolism of vitamin K and therefore contribute to its relative inefficiency at preventing CVD in this population as kidney disease progresses. Human research on the tissue vitamin K metabolome in CKD patients is lacking.

It is often suggested that Western peacebuilding in the occupied Palestinian territory has failed because it has not delivered a viable Palestinian state. But if peacebuilding is reinterpreted as a form of counterinsurgency whose goal is to secure a population, then it has not failed – in fact, on the contrary, it has been quite successful. This article therefore critically evaluates the idea and practice of peacebuilding as counterinsurgency by exploring the symbiosis in the philosophy and methods of COIN and peacebuilding, and charts its implementation in the oPt through the realms of governance, development, and security. It argues that peacebuilding in this context operates as another layer of pacification techniques whose goal is to secure the Palestinian population and ensure acquiescence in the face of violent dispossession.

In the April 2010 Review of International Studies, Roland Paris argued that liberal peacebuilding is the only viable solution for rebuilding war-torn societies, and supported this by assailing critics of the liberal peace. In this article we challenge four key claims made by Paris: imposed and consensual peacebuilding are different experiences; there are no echoes of imperialism in modern peacebuilding; there is no alternative to the capitalist free market; and critics of the liberal peace are ‘closet liberals’. We argue that Paris ignores the extent to which all peacebuilding strategies have had a core of common prescriptions: neoliberal policies of open markets, privatisation and fiscal restraint, and governance policies focused on enhancing instruments of state coercion and ‘capacity building’ – policies that have proved remarkably resilient even while the democracy and human rights components of the liberal peace have been substantially downgraded. There is little space to (formally) dissent from these policy prescriptions – whether international peacebuilders were originally invited in or not. Furthermore, the deterministic assumption by Paris that ‘there is no alternative’ is unjustifiable. Rather than trying to imagine competing meta-alternatives to liberalism, it is more constructive to acknowledge and investigate the variety of political economies in post-conflict societies rather than measuring them against a liberal norm.

The 24 kD form of secreted phosphoprotein (SPP-24), a cytokine-binding bone matrix protein with various truncated C-terminal products, is primarily synthesized by the liver. SPP-24 shares homology with fetuin-A, a potent vascular and soft tissue calcification inhibitor and SPP-24 is one component of calciprotein particles (CPPs), a circulating fetuin–mineral complex. The limited molecular evidence to date suggests that SPP-24 may also function as an inhibitor of bone formation and ectopic vascular calcification, potentially through bone morphogenic protein 2 (BMP-2) and Wnt-signaling mediated actions. The C-terminal products of SPP-24 bind to BMP-2 and attenuate BMP-2-induced bone formation. The aim of this study was to assess circulating SPP-24 in relation to kidney function and in concert with markers of mineral metabolism in humans. SPP-24 was measured in the serum of total of 192 subjects using ELISA-based measurements. Subjects were participants of one of two cohorts: (1) mGFR Cohort (n = 80) was participants of a study of measured GFR (mGFR) using inulin urinary clearance, recruited mostly from a chronic kidney disease clinic with low-range kidney function (eGFR 38.7 ± 25.0 mL/min/1.73 m2) and (2) CaMOS Cohort (n = 112) was a subset of randomly selected, community-dwelling participants of year 10 of the Canadian Multicentre Osteoporosis Study with eGFR in the normal range of 75.0 ± 15.9 mL/min/1.73 m2. In the combined cohort, the mean SPP-24 was 167.7 ± 101.1 ng/mL (range 33.4–633.6 ng/mL). The mean age was 66.5 ± 11.3, 57.1% female and mean eGFR (CKD-EPI) was 59.9 ± 27.0 mL/min/1.73 m2 (range 8–122 mL/min/1.73 m2). There was a strong inverse correlation between SPP-24 and eGFR (R = − 0.58, p < 0.001) that remained after adjustment for age. Following adjustment for age, eGFR, and sex, SPP-24 was significantly associated with phosphate (R = − 0.199), PTH (R = 0.298), and the Wnt-signaling inhibitor Dickkopf-related protein 1 (R = − 0.156). The results of this study indicate that SPP-24 is significantly altered by kidney function and is the first human data linking levels of SPP-24 to other biomarkers involved in mineral metabolism. Whether there is a role for circulating SPP-24 in bone formation and ectopic mineralization requires further study.

Diets containing inorganic phosphate additives are unbalanced with respect to calcium and these diets have been linked to the development of altered bone metabolism. Using 2 randomized cross-over studies in healthy humans, we (1) characterized the hormonal and urinary response to 2 meals with the same reported phosphorus amount (562–572 mg), where one was manufactured with inorganic phosphate additives and a comparatively lower Ca:P molar ratio (0.26 vs 0.48), and (2) assessed how acute homeostatic mechanisms adapt following 5-d exposure to recommended dietary phosphorus amount (~700 mg P/d) compared to a diet enriched with inorganic phosphate additives (~1100 mg P/d). Participants were then challenged with 500 mg of oral phosphorus in the form of inorganic phosphate after an overnight fast following each diet condition. Measurements included serum calcium, phosphate, PTH, and fibroblast growth factor 23 , vitamin D metabolites, and urine calcium and phosphate excretion. Following the meal containing inorganic phosphate additives with a low Ca:P ratio, serum phosphate was higher and more phosphate was excreted in the urine compared to the low additive meal. Although the Ca:P and calcium content was lower in the high additive meal, the same amount of calcium was excreted into the urine. Subsequently, increasing only dietary phosphate through additives resulted in lower 24-h excretion of calcium. The oral phosphate challenge promoted urinary calcium excretion, despite no consumption of calcium, which was attenuated when pre-acclimated to a high phosphate diet. These data suggest that ingestion of inorganic phosphate promotes calcium excretion, but homeostatic mechanisms may exist to reduce calcium excretion that are responsive to dietary intake of phosphate. Future studies are required to evaluate potential implication of diets enriched with inorganic phosphate additives on bone health. Lay Summary Excessive dietary phosphorus has been linked to the development of bone and vascular disorders. Further, highly bioavailable inorganic phosphate additives, which are unregulated, have been estimated to comprise approximately 50% of an individual’s consumed dietary phosphorus. Using 2 randomized cross-over studies in young healthy participants, we assessed (1) the hormonal and urinary response to 2 meals with the same reported phosphate amount, but one manufactured with inorganic phosphate additives, and (2) how acute homeostatic mechanisms adapt following 5-d of a diet supplemented with inorganic phosphate additives. The results suggest that ingestion of meals containing phosphate additives promotes excess calcium excretion, but homeostatic mechanisms in young healthy adults are sufficient to reduce calcium excretion in response to a 5-d dietary intake of these phosphate additives. These findings indicate an important role of inorganic phosphate additives on acute and chronic calcium homeostasis that will need to be carefully explored for potential implications on bone and/or vascular outcomes. Together these findings also indicate the critical importance of bioavailability of phosphate and the balance with calcium in dietary management. Graphical Abstract Graphical Abstract

Richard Falk’s quest to combine academic scholarship with political activism is witnessed throughout his lifework, but perhaps especially so during his tenure as United Nations special rapporteur on human rights in the Palestinian territories occupied since 1967, a position he held from 2008 to 2014. Falk is a vocal critic of Israel’s occupation and a staunch supporter of Palestinian self-determination, positions that have drawn strong condemnation from Israel and its supporters, but praise from Palestinians and their supporters. There is little doubt that Falk’s work has had a huge influence on public debate and activism pertaining to this issue, both within Israel-Palestine as well as globally. This article outlines Falk’s scholarship and activism regarding Palestine, analyzes the post of UN special rapporteur in general, reviews both criticism of and support for Falk’s work, and assesses Falk’s concept of the “citizen pilgrim.” It concludes by reflecting on what this reveals about the experience of praxis for politically engaged academics.