Consideration of Natural Sources in a Bacteria TMDLLines of Evidence, Including Beach Microbial Source Tracking

Total Maximum Daily Load (TMDL) stipulations remained unmet at a southern California beach despite a suite of management actions carried out since 2001, prompting exploration of a Natural Sources Exclusion (NSE) provision within the TMDL. Quantitative Microbial Source Tracking (MST) was employed from 2012 to 2015 to inventory sources of natural and anthropogenic fecal indicator bacteria (FIB). Data suggested FIB exceedances could be traced to gulls based on gull marker prevalence and correlations with FIB concentrations in seawater, sand, and eelgrass. In contrast, human marker concentrations and a tracer dye test did not indicate prevalent human sources. Exponential decay of gull marker in sand amended with live <i>Catellicoccus marimammalium</i> suggested that measured marker reflected fecal inputs versus growth outside the host. Improved water quality was coincident with a 2013 bird exclusion structure, consistent with NSE. However, load allocation needed for TMDL reconsideration was hampered by variable ratios of FIB, MST markers, and pathogens measured in seawater and in gull, cat, and raccoon feces. Quantitative Microbial Risk Assessment is a suggested path forward because such models can incorporate distributions from a combination of FIB sources and communicate criteria in terms of human health risk

Celecoxib use and circulating oxylipins in a colon polyp prevention trial

<div><p>Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E₂ are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (<i>P</i><0.05) and differences were greater among non-aspirin users. LOX derived 5- and 8-HETE were elevated with celecoxib and positively associated with systolic blood pressure (<i>P</i> = 0.011 and <i>P</i> = 0.019 respectively). 20-HETE, a prohypertensive androgen-sensitive CYP450 metabolite was higher with celecoxib absent aspirin and was positively associated with SBP in men (<i>P</i> = 0.040) but not women. Independent of celecoxib or aspirin, LOX derived metabolites from ARA were strongly associated with SBP including 5- and 8-HETE. These findings support oxylipins, particularly the ARA LOX-derived, in blood pressure control and indicate that pharmacologic inhibition of COX-2 has effects on LOX and CYP450 ARA metabolism that contribute to hypertension in some patients.</p></div

Celecoxib (<i>n</i> = 54) versus placebo (<i>n</i> = 49) among aspirin non-users only.

<p>(A) Summed oxylipins from ω-3 CYP450, ω-6 CYP450, and ω-6 LOX pathway arms. Asterisk (*) indicates <i>P</i> = 0.032. (B) Summed oxylipins from ω-3 LOX, ω-3 COX, and ω-6 COX pathways arms. Note that A and B are on different scales. Different colors represent the sum of all quantified oxylipins in a given pathway arm. (C) Overlapping box plots showing significantly different individual oxylipins between placebo (gray) and celecoxib (pink) groups. (D) Median (IQR) levels of oxylipins that are significantly different between groups, with Wilcoxon rank-sum test <i>P</i>-values. Note that the median value for 8-HETE is below the limit of quantitation (< 0.0008 nM).</p

No NSAID (<i>n</i> = 49) versus any NSAID (aspirin and/or celecoxib; <i>n</i> = 136) among all participants.

<p>(A) Summed oxylipins from ω-3 CYP450, ω-6 CYP450, and ω-6 LOX pathway arms. Asterisk (*) indicates <i>P</i> = 0.036. (B) Summed oxylipins from ω-3 LOX, ω-3 COX, and ω-6 COX pathways arms. Note that A and B are on different scales. Different colors represent the sum of all quantified oxylipins in a given pathway arm. (C) Overlapping box plots showing significantly different individual oxylipins between NSAID non-users (gray) and users (pink). (D) Median (IQR) levels of oxylipins that are significantly different between groups, with Wilcoxon rank-sum test <i>P</i>-values. Note that the median value for 8-HETE is below the limit of quantitation (< 0.0008 nM).</p

Pathway-based differences for all participants: Celecoxib (<i>n</i> = 90) versus placebo (<i>n</i> = 95).

<p>(A) Summed oxylipins from ω-3 CYP450, ω-6 CYP450, and ω-6 LOX pathway arms. Asterisk (*) indicates <i>P</i> = 0.054. (B) Summed oxylipins from ω-3 LOX, ω-3 COX, and ω-6 COX pathways arms. Note that A and B are on different scales. Different colors represent the sum of all quantified oxylipins in a given pathway arm.</p

No aspirin (<i>n</i> = 103) versus aspirin (<i>n</i> = 82) among all participants.

<p>(A) Summed oxylipins from ω-3 CYP450, ω-6 CYP450, and ω-6 LOX pathway arms. (B) Summed oxylipins from ω-3 LOX, ω-3 COX, and ω-6 COX pathways arms. Note that A and B are on different scales. Different colors represent the sum of all quantified oxylipins in a given pathway arm. (C) Overlapping box plots showing significantly different individual oxylipins between aspirin non-users (gray) and users (pink). (D) Median (IQR) levels of oxylipins that are significantly different between groups, with Wilcoxon rank-sum test <i>P</i>-values.</p

Celecoxib (<i>n</i> = 36) versus placebo (<i>n</i> = 46) among aspirin users only.

<p>(A) Summed oxylipins from ω-3 CYP450, ω-6 CYP450, and ω-6 LOX pathway arms. (B) Summed oxylipins from ω-3 LOX, ω-3 COX, and ω-6 COX pathways arms. Note that A and B are on different scales. Different colors represent the sum of all quantified oxylipins in a given pathway arm. (C) Overlapping box plots showing significantly different individual oxylipins between placebo (gray) and celecoxib (pink) groups. (D) Median (IQR) levels of oxylipins that are significantly different between groups, with Wilcoxon rank-sum test <i>P</i>-values. Note that the median value for 8-HETE among the Placebo is below the limit of quantitation (< 0.0008 nM).</p

Associations¹ between oxylipins and systolic blood pressure overall and stratified by sex².

<p>Associations<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196398#t003fn001" target="_blank">¹</a> between oxylipins and systolic blood pressure overall and stratified by sex<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0196398#t003fn002" target="_blank">²</a>.</p

Baseline characteristics of selected sample from the Sel/Cel Trial: Mean ± SD or <i>n</i> (%).

<p>Baseline characteristics of selected sample from the Sel/Cel Trial: Mean ± SD or <i>n</i> (%).</p

Oxylipin levels, by intervention arm: Median (interquartile range).

<p>Oxylipin levels, by intervention arm: Median (interquartile range).</p