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Williams, Jonathan

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Williams

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Jonathan

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Williams, Jonathan
Author's Publications: search.filters.isAuthorOfPublication.9c9699ab-9220-4f3b-b82b-0481e7a746ad

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    Atmospheric Chemistry and the Biosphere: General Discussion
    (Royal Society of Chemistry (RSC), 2017) Archibald, Alexander; Freedman, Arnold; Bejan, Lustian; Brown, Steven; Brüggemann, Martin; Carpenter, Lucy; Collins, John; Evans, Mathew; Finlayson-Pitts, Barbara; George, Christian; Hastings, Meredith; Heard, Dwayne; Hewitt, Christopher; Isaacman-VanWertz, Gabriel; Kalberer, Markus; Keutsch, Frank; Kiendler-Scharr, Astrid; Knopf, Daniel; Lelieveld, Jos; Marais, Eloise; Petzold, Andreas; Ravishankara, A.; Reid, Jonathan; Rovelli, Grazia; Scott, Catherine; Sherwen, Tomás; Shindell, Drew; Tinel, Liselotte; Unger, Nadine; Wallington, Timothy J.; Wahner, Andreas; Williams, Jonathan; Young, Timothy; Zelenyuk, Alla; Wallington, Timothy
    Lucy Carpenter opened discussion of the paper by Christian George: Your previous work has emphasised the abiotic production of VOCs from surface ocean processes, mainly from photosensitized chemistry of surfactants. Does this work indicate that decay of microbial cells is the really dominant source of these VOC-producing surfactants and photosensitizers, and if so - does this really mean this is an abiotic process? Christian George responded: As shown in our paper, VOC emissions increased drastically when the microbial cells were dying. Moreover, the highest VOC production was observed for the cellular fraction of the biofilms, i.e. intracellular material and cellular debris.
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    Angiotensin-Converting Enzyme Inhibition and Parathyroid Hormone Secretion
    (Hindawi, 2017) Zaheer, Sarah; Brown, Jenifer; Connors, Molly; Williams, Jonathan; Adler, Gail; Vaidya, Anand
    Background: Prior studies suggest that renin-angiotensin-aldosterone system (RAAS) inhibitors decrease parathyroid hormone (PTH) secretion. Objective: To evaluate the effect of angiotensin-converting enzyme inhibitors (ACEi) on serum PTH in participants with and without primary hyperparathyroidism (P-HPT). Methods: An open-label, single-arm, pilot study whereby participants with and without P-HPT had PTH were evaluated before and after 1 week of maximally tolerated lisinopril therapy. Results: A total of 12 participants with, and 15 participants without, P-HPT successfully completed the protocol. Following 1 week of lisinopril, participants with P-HPT had a decrease in systolic blood pressure (SBP) (−6.4 mmHg, P < 0.01), an increase in plasma renin activity (PRA) (+1.50 ng/mL/h, P = 0.06), and a decrease in PTH (79.5 (21.6) to 70.9 (19.6) pg/mL, ∆ = −8.6 pg/mL, P = 0.049); however, serum and urine calcium did not change. In contrast, although 1 week of lisinopril significantly decreased SBP and increased PRA among participants without P-HPT, there were no changes in PTH or calcium. Conclusion: In this short pilot investigation, 1 week of maximally titrated ACEi did not impact PTH in participants without P-HPT, but resulted in a modest and marginally significant reduction of PTH but not calcium, among participants with P-HPT. This trial is registered with ClinicalTrials.gov NCT01691781.
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    A randomized intervention study to evaluate the effect of calcitriol therapy on the renin-angiotensin system in diabetes
    (SAGE Publications, 2018) Zaheer, Sarah; Taquechel, Kiara; Brown, Jenifer; Adler, Gail; Williams, Jonathan; Vaidya, Anand
    Background: Prior studies suggest that vitamin D therapy may decrease cardiovascular disease risk in type 2 diabetes (T2DM) by lowering renin-angiotensin system (RAS) activity. However, randomized human intervention studies to evaluate the effect of vitamin D receptor (VDR) agonists on RAS activity are lacking. Objective: The objective of this article is to investigate the effect of direct VDR activation with calcitriol on circulating RAS activity and vascular hemodynamics in T2DM. Methods: A randomized, double-blinded, and placebo-controlled study wherein 18 participants with well-controlled T2DM without chronic kidney disease (CKD) were administered calcitriol or placebo for three weeks was conducted. Outcome measures included plasma renin activity (PRA), serum and urinary aldosterone, mean arterial pressure (MAP) before and after an infusion of angiotensin II, and renal plasma flow (RPF) via para-aminohippurate clearance. Results: Despite an increase in 1,25(OH)2D with calcitriol administration (45.4 to 61.8 pg/ml, p = 0.03) and no change with placebo, there were no significant differences in PRA, serum or urinary aldosterone, baseline and angiotensin II-stimulated MAP, or basal and angiotensin II-stimulated RPF between interventions. Conclusion: In this randomized and placebo-controlled study in participants with T2DM without CKD, calcitriol therapy to raise 1,25(OH)2D levels, when compared with placebo, did not significantly change circulating RAS activity or vascular hemodynamics.
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    POLYMORPHISMS IN THE SERUM- AND GLUCOCORTICOID-INDUCIBLE KINASE 1 GENE ARE ASSOCIATED WITH BLOOD PRESSURE AND RENIN RESPONSE TO DIETARY SALT INTAKE
    (2012) Rao, Ajay D; Sun, Bei; Saxena, Aditi; Hopkins, Paul N; Jeunemaitre, Xavier; Brown, Nancy J; Adler, Gail; Williams, Jonathan
    Serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a central role in epithelial sodium channel (ENaC)-dependent Na+ transport in the distal nephron. We hypothesized that SGK1 gene variants may contribute to the effect of dietary salt intake on BP in humans with hypertension, and consequentially influence renin-angiotensin-aldosterone (RAA) system activity. Our study population included 421 hypertensive Caucasian participants of the HyperPath group who had completed a dietary salt protocol with measurement of BP and RAA system activity. Three SGK1 tagging single nucleotide polymorphisms (SNPs) from the HapMap CEU population captured the genetic variation in the SGK1 region. Assuming an additive genetic model, two SNPs (rs2758151 and rs9402571) were associated with BP and plasma renin activity (PRA) effects of dietary salt intake. Major alleles were associated with higher systolic BP on high salt and decreased PRA on low salt. In contrast, low salt neutralized genotype differences. Similar, non-significant trends were observed in a normotensive population (N=152). Genotype was also associated with two salt-sensitive subtypes of hypertension. SGK1 genetic variants are associated with salt sensitivity of BP and PRA in human hypertension. Genotype status at these SGK1 variants may identify individuals prone to salt-sensitive hypertension.
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    Evaluating hormonal mechanisms of vitamin D receptor agonist therapy in diabetic kidney disease: the VALIDATE-D study
    (BioMed Central, 2013) Brown, Jenifer; Secinaro, Kristina; Williams, Jonathan; Vaidya, Anand
    Background: Insufficient vitamin D status and increased renin-angiotensin system (RAS) activity have been associated with renal-vascular disease and nephropathy in diabetes. Accumulating evidence indicates that vitamin D receptor (VDR) activation lowers unfavorable RAS activity; however, more human intervention studies evaluating whether this mechanism could influence diabetic kidney disease are needed. We previously reported that both vitamin D levels and genetic variation at the VDR predict human RAS activity, and that vitamin D therapy can lower RAS activity in non-diabetics. The VALIDATE-D study is a randomized, placebo-controlled, intervention study designed to extend these findings by evaluating whether direct VDR activation in diabetes lowers circulating and local renal-vascular tissue RAS activity (Aims 1 and 2) in a manner similar to the action of ACE inhibitors (Aim 3). Methods/Design Forty subjects with type 2 diabetes, microalbuminuria, and without chronic kidney disease will be recruited to undergo detailed assessment of the RAS before and after randomization to calcitriol 0.75 mcg/day or placebo. Primary analyses will evaluate whether calcitriol therapy reduces circulating and renal-vascular tissue-RAS activity in comparison to placebo. All subjects will thereafter be treated with lisinopril and followed for 3.5 months to evaluate whether combination therapy (calcitriol + lisinopril vs. placebo + lisinopril) additively or synergistically improves renal-vascular function, and lowers proteinuria. Discussion The VALIDATE-D study is the first human intervention study to evaluate whether direct VDR activation can lower the human RAS in diabetes, compared to the effect of an ACE inhibitor, and whether this mechanism can translate to clinically relevant endpoints for diabetic kidney disease. The outcomes of VALIDATE-D will have major implications for the recommendation of vitamin D supplementation for the primary prevention of kidney complications in diabetes. Trial registration ClinicalTrials.gov, NCT01635062
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    Weight Loss, Saline Loading, and the Natriuretic Peptide System
    (Ovid Technologies (Wolters Kluwer Health), 2015) Arora, P.; Reingold, J.; Baggish, Aaron; Guanaga, Derek Philip; Wu, Connie; Ghorbani, Anahita; Song, Y.; Chen-Tournaux, A.; Khan, A. M.; Tainsh, L. T.; Buys, Emmanuel; Williams, Jonathan; Heublein, D. M.; Burnett, J. C.; Semigran, Marc J.; Bloch, K. D.; Scherrer-Crosbie, Marielle; Newton-Cheh, Christopher; Kaplan, Lee; Wang, T. J.
    Background-—In epidemiologic studies, obesity has been associated with reduced natriuretic peptide (NP) concentrations. Reduced NP production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances NP production before and after salt loading. Methods and Results-—We enrolled 15 obese individuals (mean BMI 45 5.4 kg/m2) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large-volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre-operative visit to 6 months after surgery, subjects had a mean BMI decrease of 27%. At the 6-month visit, N-terminal pro-atrial NP (Nt-proANP) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre-operative visit (P<0.001). The rise in Nt-pro-ANP induced by the saline infusion (50%) was similar both before and after surgery (saline, P<0.001; interaction, P=0.2). Similar results were obtained for BNP and Nt-proBNP; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in NP concentrations after surgery was accompanied by significant decreases in mean arterial pressure (P=0.004) and heart rate (P<0.001), and an increase in mitral annular diastolic velocity (P=0.02). Conclusion-—In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating NP concentrations. Higher NP concentrations could contribute to an enhanced ability to handle salt loads after weight loss.
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    Caveolin 1 Modulates Aldosterone‐Mediated Pathways of Glucose and Lipid Homeostasis
    (John Wiley and Sons Inc., 2016) Baudrand, Rene; Gupta, Nidhi; Garza, Amanda; Vaidya, Anand; Leopold, Jane; Hopkins, Paul N.; Jeunemaitre, Xavier; Ferri, Claudio; Romero, Jose; Williams, Jonathan; Loscalzo, Joseph; Adler, Gail; Williams, Gordon; Pojoga, Luminita
    Background: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav‐1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav‐1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav‐1–null mice and humans with a prevalent variant in the CAV1 gene. Methods and Results: In mouse studies, cav‐1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high‐ to low‐density lipoprotein (all P<0.001 versus wild type). Moreover, cav‐1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40–3.64]) and low high‐density lipoprotein (odds ratio 1.54 [95% CI 1.01–3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high‐density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav‐1 expression in adipose tissues by the rs926198 minor allele. Conclusions: Our findings in mice and humans suggested that decreased cav‐1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR‐independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype‐mediated cav‐1 deficiency.