Background Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. Objective Through a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type-2 diabetes (T2D), coronary heart disease (CHD), ischemic stroke and heart failure. Methods We investigated 28 SNPs known to regulate serum urate levels in association with a range of vascular and non-vascular risk factors to assess pleiotropy. To limit genetic confounding, 14 SNPs found exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2D (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312) and heart failure (4,526/18,400). As a positive control, we also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. Results Serum urate levels, raised by 1 standard deviation (SD) due to the genetic score, were not associated with T2D (odds ratio [OR] 0.95, 95% CI, 0.86–1.05), CHD (OR. 1.02, 95% CI, 0.92–1.12), ischemic stroke (OR. 0.99, 95% CI, 0.88–1.12), or heart failure (OR. Q1.07, 95% CI, 0.88–1.30). These results were in contrast with previous prospective studies that observed increased risks of T2D (OR. 1.25, 95% CI, 1.13–1.37), CHD (OR. 1.06, 95% CI, 1.03–1.09), ischemic stroke (OR. 1.17, 95% CI, 1.00–1.37), and heart failure (OR. 1.19, 95% CI, 1.17–1.21) for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (OR. 5.84, 95% CI, 4.56–7.49), which was directionally consistent with associations observed in previous epidemiological studies Conclusions Evidence from this study does not support a causal role of circulating serum urate levels in T2D, CHD, ischemic stroke, or heart failure. Lowering serum urate levels may not translate into risk reductions for cardiometabolic conditions.

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Mean number of collection days was similar in LEN pos vs. LEN neg group (2.11 vs. 2, P = .47). Median collected CD34 was 8.6 vs. 11.3 in LEN pos and LEN neg group with no significant difference (P = .12). Mean time to neutrophil engraftment was not different between LEN pos vs. LEN neg (10. 58 vs. 10.55, days P = .45). Mean time to platelet engraftment was also similar (19.3 vs. 21.7 days, P = .19). There was one platelet engraftment failure in LEN neg group. There was a significant correlation between collected TNC and BFU-E as well as TNC and CFU-GM, however there was no significant difference between LEN pos and LEN neg group. The overall rate of day 1 collection failure was 14.2% with no statistically significant difference between LEN pos and LEN neg groups (Median: 13.5% vs. 14.6%; P = .39). There was no detected difference in progression-free survival. Conclusion: In this cohort of heavily pretreated pts, use of LEN prior to PBSC collection did not affect stem cell collection, graft quality or engraftment. High usage of Plerixafor may have overcome the deleterious effect of LEN. The impact of LEN on stem cell collection and transplantation should be evaluated in prospective clinical trials (Figures 1-3).

in the subfornical organ inhibits the dipsogenic response to angiotensin II. Am J Physiol Regul Integr Comp Physiol 303: R921-R928, 2012. First published August 29, 2012 doi:10.1152 doi:10. /ajpregu.00057.2012 for the calcium-regulating glycoprotein hormone stanniocalcin-1 (STC-1) have been found within subfornical organ (SFO), a central structure involved in the regulation of electrolyte and body fluid homeostasis. However, whether SFO neurons produce STC-1 and how STC-1 may function in fluid homeostasis are not known. Two series of experiments were done in Sprague-Dawley rats to investigate whether STC-1 is expressed within SFO and whether it exerts an effect on water intake. In the first series, experiments were done to determine whether STC-1 was expressed within cells in SFO using immunohistochemistry, and whether protein and gene expression for STC-1 existed in SFO using Western blot and quantitative RT-PCR, respectively. Cells containing STC-1 immunoreactivity were found throughout the rostrocaudal extent of SFO. STC-1 protein expression within SFO was confirmed with Western blot, and SFO was also found to express STC-1 mRNA. In the second series, microinjections (200 nl) of STC-1, ANG II, a combination of the two or the vehicle were made into SFO in conscious, unrestrained rats. Water intake was measured at 0700 for a 1-h period after each injection in animals. Microinjections of STC-1 (17.6 or 176 nM) alone had no effect on water intake compared with controls. However, STC-1 not only attenuated the drinking responses to ANG II for about 30 min, but also decreased the total water intake over the 1-h period. These data suggest that STC-1 within the SFO may act in a paracrine/autocrine manner to modulate the neuronal responses to blood-borne ANG II. These findings also provide the first direct evidence of a physiological role for STC-1 in central regulation of body fluid homeostasis. body fluid homeostasis; thirst; circumventricular organs; calciumregulating glycoprotein STANNIOCALCIN (STC) IS A GLYCOPROTEIN hormone first identified and characterized within bony fish corpuscles of Stannius, endocrine glands derived from renal tubular cells (18,24,29,63,64). These glands are thought to produce and release STC into the circulation in response to rising serum calcium levels (11,18,29,64). The STC then acts on the gills and gut epithelial cells to reduce calcium uptake, while STC within the kidney causes increases in reabsorption of phosphate (11,18,24), a mechanism that likely aids in chelating excess extracellular calcium (18,24). The net effect of these STC actions is the restoration of serum calcium levels (14,18,24,62).A mammalian homolog of STC has been identified that shares a 73% amino acid sequence homology with fish STC (41). Mammalian STC-1 is a disulfide-linked glycoprotein dimer of identical subunits (41), which is expressed in a variety of tissues, including heart, kidney, adipose tissue, skeletal muscle, lung, ovaries (18, 24), and brain (67-69). STC-1 functions in the cells of these tissues ...

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