DISCUSSION: CONTEMPORARY DAIRY POLICY CHANGES IN CANADA: A WESTERN CANADA PERSPECTIVE

Agricultural and Food Policy,

The Herbal Cabinet

Description of a historical Eli Lilly herb identification collection belonging to University of New England professor David Mokler, including herb scientific names, common names, ranges, and uses. Each herb bottle is pictured, its label information is reproduced, and each herb’s historical and current uses are briefly described.https://dune.une.edu/biomed_facproj/1000/thumbnail.jp

Manganese in residential drinking water from a community-initiated case study in Massachusetts

Background: Manganese (Mn) is a metal commonly found in drinking water, but the level that is safe for consumption is unknown. In the United States (U.S.), Mn is not regulated in drinking water and data on water Mn concentrations are temporally and spatially sparse. Objective: Examine temporal and spatial variability of Mn concentrations in repeated tap water samples in a case study of Holliston, Massachusetts (MA), U.S., where drinking water is pumped from shallow aquifers that are vulnerable to Mn contamination. Methods: We collected 79 residential tap water samples from 21 households between September 2018 and December 2019. Mn concentrations were measured using inductively coupled plasma mass spectrometry. We calculated descriptive statistics and percent of samples exceeding aesthetic (secondary maximum containment level; SMCL) and lifetime health advisory (LHA) guidelines of 50 µg/L and 300 µg/L, respectively. We compared these concentrations to concurrent and historic water Mn concentrations from publicly available data across MA. Results: The median Mn concentration in Holliston residential tap water was 2.3 µg/L and levels were highly variable (range: 0.03–5,301.8 µg/L). Mn concentrations exceeded the SMCL and LHA in 14% and 12% of samples, respectively. Based on publicly available data across MA from 1994–2022, median Mn concentration was 17.0 µg/L (N = 37,210; range: 1–159,000 µg/L). On average 40% of samples each year exceeded the SMCL and 9% exceeded the LHA. Samples from publicly available data were not evenly distributed between MA towns or across sampling years. Impact statement: This study is one of the first to examine Mn concentrations in drinking water both spatially and temporally in the U.S. Findings suggest that concentrations of Mn in drinking water frequently exceed current guidelines and occur at concentrations shown to be associated with adverse health outcomes, especially for vulnerable and susceptible subpopulations like children. Future studies that comprehensively examine exposure to Mn in drinking water and its associations with children’s health are needed to protect public health. © 2023, The Author(s)

Endothelin Receptor A Antagonism Attenuates Renal Medullary Blood Flow Impairment in Endotoxemic Pigs

BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1), n = 8) or served as endotoxin-treated controls (n = 8). Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002). Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05) measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02) and increased medullary pyruvate levels (p = 0.03). Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury

Metal mixtures and the role of iron status in early adolescent cognition

Children are commonly exposed to metals in the environment, particularly those living in proximity to steel-producing ferroalloy industry. Exposure to metals, including lead (Pb), manganese (Mn), chromium (Cr) and copper (Cu), impacts neurodevelopment, but less attention has been given to examining associations of metal mixtures with cognitive function in children. Further, recent epidemiological studies have identified iron (Fe) status as a modifier of metals-induced neurotoxicity, such that adverse associations of metals (e.g., Mn or Pb) tend to be stronger among children with Fe deficiency. However, no study to date has quantified the modifying or mediating role of Fe status on a complex metal mixture in relation to any neurodevelopmental outcome. We used data from the Public Health Impact of Metals Exposure Study (PHIME), a cohort of 720 Italian adolescents (10–14 years) to quantify the association of an industry-relevant metal mixture (Pb, Mn, Cr, Cu) with neurodevelopment, and examine the role of Fe status as a modifier or mediator of these associations. Metals were measured in blood (Pb) or hair (Mn, Cr, Cu) using inductively-coupled plasma mass spectrometry, and Fe status was assessed using three clinically relevant biomarkers (ferritin, hemoglobin, transferrin) measured in whole blood or serum using luminescent or immunoassays. Of note, there was no indication of Fe deficiency in the study population. In Chapter 2, we identified associations of the metal mixture with verbal learning and memory, measured using the California Verbal Learning Test for Children (CVLT-C), using Bayesian Kernel Machine Regression (BKMR). In adjusted models, we found that the mixture was jointly associated with higher scores for the recall trials: compared to the 50th percentile, the 90th percentile of the mixture was associated with a 0.12 standard deviation increase (95% credible interval [CI]= -0.27, 0.50) in the number of words recalled on trial 5 recall, indicating better cognitive performance. This association was driven primarily by Cu, which was further modified by Fe status: the beneficial association of Cu with recall was stronger at increasing percentiles of ferritin. In Chapter 3, we found that the metal mixture was jointly associated with self-reported attention-related behaviors measured on the Conners Rating Scales. For example, the 90th percentile of the mixture, compared to the 50th percentile, was associated with a 4.1% increase (β= 0.04; 95% CI= 0.00, 0.08) in self-reported inattention T-scores in BKMR models, reflecting worse cognitive performance. These associations were driven primarily by Mn, though there was no indication of modification by Fe status. Lastly, in Chapter 4, we quantified the mediating role of Fe status on the association between the metal mixture and CVLT-C scores using the newly developed BKMR Causal Mediation Analysis (BKMR-CMA). Though the metal mixture was associated with aspects of Fe status (e.g., ferritin), there was no evidence that Fe status mediated the association between the metal mixture and CVLT-C scores. Overall, the findings from this dissertation suggest that an industry-relevant metal mixture can impact aspects of neurodevelopment, including learning, memory and attention-related behaviors, and that Fe status may be a modifier of these associations. These findings have significant implications for potential public health interventions aimed at improving cognitive development in adolescents. However, the generalizability of our findings in a Fe-replete population of healthy adolescents may be limited, and further research in Fe-deficient populations is warranted.  2025-04-26T00:00:00

Function of Endothelin-A – and Endothelin-B-receptors in the ET-1 response in glomerular arterioles of the mouse

Das Endothelinsystem hat für die physiologische Funktion der Niere und für die Entstehung von Nierenerkrankungen eine große Bedeutung. Endothelineffekte an der Niere werden über zwei Rezeptortypen, den ETA-Rezeptor und den ETB- Rezeptor, vermittelt. ETA-Rezeptoren und ETB-Rezeptoren sind auf der glatten Muskelzelle exprimiert, wo sie vasokonstriktorisch wirken können. ETB- Rezeptoren sind zudem auf der Endothelzelle exprimiert und vermitteln eine Vasodilatation. Ziel der Studie war es, die differentielle Beteiligung der Endothelinrezeptoren auf die Endothelin-1 induzierte vaskuläre Kontraktiliät der afferenten und efferenten Arteriolen darzustellen. Wir verwendeten das Modell der rescued-ETB-Rezeptor-defizienten Maus. Diese Mäuse haben keinen funktionsfähigen renal vaskulären ETB-Rezeptor. Die Gefäßreaktivität isolierter glomerulärer Arteriolen wurde mit Hilfe eines Mikroperfusionsmeßplatzes untersucht: Arteriolen mit Glomerulus wurden unter Verwendung von Halte- und Perfusionspipetten perfundiert und die Gefäßdurchmesseränderungen wurden videomikroskopisch aufgezeichnet. Wirkstoffe wurden in die Badlösung appliziert. Die Analyse der Durchmesseränderungen erfolgte computergestützt. In afferenten Arteriolen -führte die kumulative Endothelin-1-Applikation zu einer dosisabhängigen und ähnlich starken Vasokonstriktion in Wildtypen und in rescued-ETB-Rezeptor-defizienten Mäusen. -Selektive ETA-Rezeptor-Blockade hob den vasokonstriktorischen Endothelin-1-Effekt in Wildtypen und in rescued-ETB-R-defizienten Mäusen auf. -Kumulative ETB-Rezeptor-Stimulation führte zu keiner Änderung der luminalen Durchmesser in Wildtypen und in rescued-ETB-Rezeptor-defizienten Mäusen. -Unspezifische Blockade der NO-Synthase änderte die arterioläre Antwort in Wildtypen und in rescued-ETB-Rezeptor-defizienten Mäusen auf Endothelin-1-Applikation nicht signifikant. -ETA-Rezeptor- und NO-Synthase- Blockade beeinflussten den basalen Durchmesser in Wildtypen und in rescued- ETB-Rezeptor-defizienten Mäusen nicht signifikant. In efferenten Arteriolen -führte die kumulative Endothelin-1-Applikation zu einer konzentrationsabhängigen Konstriktion in Wildtypen und in rescued-ETB- Rezeptor-defizienten Mäusen, welche in Wildtypen signifikant stärker war als in rescued-ETB-Rezeptor-defizienten Mäusen. -Während selektiver ETA-Rezeptor- Blockade war die Endothelin-1 vermittelte Vasokonstriktion in den Wildtypen abgeschwächt und in rescued-ETB-Rezeptor-defizienten Mäusen vollständig aufgehoben. -Kumulative ETB-Rezeptor-Aktivierung führte zu einer Vasokonstriktion in Wildtypen, während es keinen Effekt in den rescued-ETB- Rezeptor-defizienten Mäusen hatte. -Während Blockade der NO-Synthase war die vasokonstriktorische Antwort auf kumulative Endothelin-1-Applikation in Wildtypen und in rescued-ETB-Rezepto- defizienten Mäusen signifikant stärker als ohne NO-Synthase-Blockade. -Selektive ETA-Rezeptor-Blockade veränderte den basal arteriolären Durchmesser nicht. -Blockade der NO-Synthase reduzierte den basalen Durchmesser in Wildtypen. Afferente Arteriolen kontrahierten auf kumulative Endothelin-1-Applikation stärker als efferente Arteriolen in Wildtypen. Die funktionellen Ergebnisse unterstützen die Annahme eines speziesspezifisch variabel ausgeprägten Endothelinsystems. Diese Speziesspezifität bezieht sich auf die differentielle Beteiligung von ETA- und ETB-Rezeptoren an der Vasokonstriktion beziehungsweise Vasodilatation glomerulärer Arteriolen. Unsere Befunde weisen erstmalig auf eine dilatative Wirkung von ETA-Rezeptoren in diesen Gefäßen hin. Die Arbeit leistet einen Beitrag zum Verständnis der Funktion von Endothelinrezeptoren im Bereich der glomerulären Gefäße, der Effekte von Endothelin auf die Nierenperfusion und auf die glomeruläre Filtrationsrate in der Maus.Endothelins play an important role in the physiology and pathophysiology of the kidney. In the kidney endothelins mediate their effects by two receptors: The ETA-receptor and the ETB-receptor. ETA- and ETB-receptors are expressed on smooth muscle cells, where they act to induce vasoconstriction. ETB-receptors are also expressed on endothelial cells, where they can mediate vasodilation. The aim of this study was to investigate the differential involvement of the endothelin-receptors on the Endothelin-1 mediated vascular contractility of the afferent and efferent arterioles. We used the model of the rescued-ETB- receptor-deficient mice. These mice lack a functional renal vascular ETB- receptor. The vascular reactivity of the isolated glomerular arterioles was investigated using the technique of microperfusion. Arterioles with intact glomeruli were pefused with the help of holding- and perfusionpipettes. The changes in the luminal diameter of the vessels were documented with videomicroscopy. Different drugs were added to the bath solution. The changes of luminal diameter were analyzed with specific computer programs. In afferent arterioles -cumulative Endothelin-1-application led to a dose-dependet and strong vasoconstriction in both wildtypes and rescued-ETB-receptor-deficient mice. -Selective blocking of the ETA-receptor abolished the vasoconstrictory effect of Endothelin-1 in wildtypes and rescued-ETB-receptor-deficient mice. -Cumulative ETB-receptor-stimulation did not change the luminal diameter in wildtypes and rescued-ETB-receptor-deficient mice. -NO-Synthase-blockade did not significantly change the arteriolar response to Endothelin-1-application of wildtypes and rescued-ETB-receptor-deficient mice. -ETA-receptor- and NO- Synthase blockade did not significantly influence the basal luminal diameter in wildtypes and rescued-ETB-receptor-deficient mice. In efferent arterioles -cumulative Endothelin-1-application led to a dose dependent vasoconstriction in wildtypes and rescued-ETB-receptor-deficient mice. The effect in wildtype mice was significantly stronger than in rescued-ETB-receptor-deficient mice. -A selective block of the ETA-receptor decreased the Endothelin-1 mediated vasoconstrictory response in wildtypes and abolished the Endothelin-1 mediated vasoconstrictory response in rescued-ETB-receptor-deficient mice. -Cumulative ETB-receptor-stimulation led to a vasoconstriction in wildtypes but had no effect in rescued-ETB-receptor-deficient mice. -The vasoconstrictory response to cumulative Endothelin-1-application in wildtypes and rescued-ETB-receptor- deficient mice was significantly stronger during NO-Synthase-blockade than it was without NO-Synthase-blockade. -Selective ETA-receptor-blockade did not change the basal arteriolar diameter. -NO-Synthase-blockade reduced the basal arteriolar diameter in wildtypes. The vasoconstriction to cumulative Endothelin-1-application was stronger in afferent than in efferent arterioles. The functional results support the assumption of species specific, variabel expression of the endothelin system. This species specificity refers to the differential contribution of the ETA- and ETB-receptor on vasoconstriction and vasodilation of glomerular arterioles. Our results point for the first time to a dilatory effect of the ETA-receptor in these vessels. This study contributes for the understanding of the function of endothelin receptors in glomerular vessels, the effects of endothelin on the perfusion of the kidney and on the glomerular filtration rate in the mouse